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Šestan M, Raposo B, Rendas M, Brea D, Pirzgalska R, Rasteiro A, Aliseychik M, Godinho I, Ribeiro H, Carvalho T, Wueest S, Konrad D, Veiga-Fernandes H. Neuronal-ILC2 interactions regulate pancreatic glucagon and glucose homeostasis. Science 2025; 387:eadi3624. [PMID: 39818880 DOI: 10.1126/science.adi3624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 04/02/2024] [Accepted: 11/08/2024] [Indexed: 01/19/2025]
Abstract
The immune system shapes body metabolism, while interactions between peripheral neurons and immune cells control tissue homeostasis and immunity. However, whether peripheral neuroimmune interactions orchestrate endocrine system functions remains unexplored. After fasting, mice lacking type 2 innate lymphoid cells (ILC2s) displayed disrupted glucose homeostasis, impaired pancreatic glucagon secretion, and inefficient hepatic gluconeogenesis. Additionally, intestinal ILC2s were found in the pancreas, which was dependent on their expression of the adrenergic beta 2 receptor. Targeted activation of catecholaminergic intestinal neurons promoted the accumulation of ILC2s in the pancreas. Our work provides evidence that immune cells can be regulated by neuronal signals in response to fasting, activating an inter-organ communication route that promotes pancreatic endocrine function and regulation of blood glucose levels.
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Affiliation(s)
- Marko Šestan
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - Bruno Raposo
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - Miguel Rendas
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - David Brea
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - Roksana Pirzgalska
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - Ana Rasteiro
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - Maria Aliseychik
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - Inês Godinho
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - Hélder Ribeiro
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - Tania Carvalho
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - Stephan Wueest
- Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, University of Zurich, Zurich, Switzerland
- Children's Research Center, University Children's Hospital, University of Zurich, Zurich, Switzerland
| | - Daniel Konrad
- Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, University of Zurich, Zurich, Switzerland
- Children's Research Center, University Children's Hospital, University of Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Henrique Veiga-Fernandes
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
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Zizzari P, Castellanos-Jankiewicz A, Yagoub S, Simon V, Clark S, Maître M, Dupuy N, Leste-Lasserre T, Gonzales D, Schoonjans K, Fénelon VS, Cota D. TGR5 receptors in SF1-expressing neurons of the ventromedial hypothalamus regulate glucose homeostasis. Mol Metab 2025; 91:102071. [PMID: 39603503 PMCID: PMC11650306 DOI: 10.1016/j.molmet.2024.102071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 11/12/2024] [Accepted: 11/18/2024] [Indexed: 11/29/2024] Open
Abstract
OBJECTIVE Steroidogenic factor-1 (SF1) neurons of the ventromedial hypothalamus play key roles in the regulation of food intake, body weight and glucose metabolism. The bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) is expressed in the hypothalamus, where it determines some of the actions of bile acids on food intake and body weight through still poorly defined neuronal mechanisms. Here, we examined the role of TGR5 in SF1 neurons in the regulation of energy balance and glucose metabolism. METHODS We used a genetic approach combined with metabolic phenotyping and molecular analyses to establish the effect of TGR5 deletion in SF1 neurons on meal pattern, body weight, body composition, energy expenditure and use of energy substrates as well as on possible changes in glucose handling and insulin sensitivity. RESULTS Our findings reveal that TGR5 in SF1 neurons does not play a major role in the regulation of food intake or body weight under standard chow, but it is involved in the adaptive feeding response to the acute exposure to cold or to a hypercaloric, high-fat diet, without changes in energy expenditure. Notably, TGR5 in SF1 neurons hinder glucose metabolism, since deletion of the receptor improves whole-body glucose uptake through heightened insulin signaling in the hypothalamus and in the brown adipose tissue. CONCLUSIONS TGR5 in SF1 neurons favours satiety by differently modifying the meal pattern in response to specific metabolic cues. These studies also reveal a novel key function for TGR5 in SF1 neurons in the regulation of whole-body insulin sensitivity, providing new insight into the role played by neuronal TGR5 in the regulation of metabolism.
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Affiliation(s)
- Philippe Zizzari
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux, France
| | | | - Selma Yagoub
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux, France
| | - Vincent Simon
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux, France
| | - Samantha Clark
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux, France
| | - Marlene Maître
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux, France
| | - Nathalie Dupuy
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux, France
| | | | - Delphine Gonzales
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux, France
| | - Kristina Schoonjans
- Institute of Bioengineering, Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland
| | - Valérie S Fénelon
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux, France
| | - Daniela Cota
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux, France.
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3
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Bu LF, Xiong CY, Zhong JY, Xiong Y, Li DM, Hong FF, Yang SL. Non-alcoholic fatty liver disease and sleep disorders. World J Hepatol 2024; 16:304-315. [PMID: 38577533 PMCID: PMC10989311 DOI: 10.4254/wjh.v16.i3.304] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 01/11/2024] [Accepted: 02/18/2024] [Indexed: 03/27/2024] Open
Abstract
Studies have shown that non-alcoholic fatty liver disease (NAFLD) may be associated with sleep disorders. In order to explore the explicit relationship between the two, we systematically reviewed the effects of sleep disorders, especially obstructive sleep apnea (OSA), on the incidence of NAFLD, and analyzed the possible mechanisms after adjusting for confounding factors. NAFLD is independently associated with sleep disorders. Different sleep disorders may be the cause of the onset and aggravation of NAFLD. An excessive or insufficient sleep duration, poor sleep quality, insomnia, sleep-wake disorders, and OSA may increase the incidence of NAFLD. Despite that some research suggests a unidirectional causal link between the two, specifically, the onset of NAFLD is identified as a result of changes in sleep characteristics, and the reverse relationship does not hold true. Nevertheless, there is still a lack of specific research elucidating the reasons behind the higher risk of developing sleep disorders in individuals with NAFLD. Further research is needed to establish a clear relationship between NAFLD and sleep disorders. This will lay the groundwork for earlier identification of potential patients, which is crucial for earlier monitoring, diagnosis, effective prevention, and treatment of NAFLD.
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Affiliation(s)
- Lu-Fang Bu
- Department of Physiology, Fuzhou Medical College, Nanchang University, Fuzhou 344000, Jiangxi Province, China
- Key Laboratory of Chronic Diseases, Fuzhou Medical University, Fuzhou 344000, Jiangxi Province, China
- Technology Innovation Center of Chronic Disease Research in Fuzhou City, Fuzhou Science and Technology Bureau, Fuzhou 344000, Jiangxi Province, China
| | - Chong-Yu Xiong
- Department of Physiology, Fuzhou Medical College, Nanchang University, Fuzhou 344000, Jiangxi Province, China
- Key Laboratory of Chronic Diseases, Fuzhou Medical University, Fuzhou 344000, Jiangxi Province, China
- Technology Innovation Center of Chronic Disease Research in Fuzhou City, Fuzhou Science and Technology Bureau, Fuzhou 344000, Jiangxi Province, China
| | - Jie-Yi Zhong
- Department of Physiology, Fuzhou Medical College, Nanchang University, Fuzhou 344000, Jiangxi Province, China
- Key Laboratory of Chronic Diseases, Fuzhou Medical University, Fuzhou 344000, Jiangxi Province, China
- Technology Innovation Center of Chronic Disease Research in Fuzhou City, Fuzhou Science and Technology Bureau, Fuzhou 344000, Jiangxi Province, China
| | - Yan Xiong
- Department of Physiology, Fuzhou Medical College, Nanchang University, Fuzhou 344000, Jiangxi Province, China
- Key Laboratory of Chronic Diseases, Fuzhou Medical University, Fuzhou 344000, Jiangxi Province, China
- Technology Innovation Center of Chronic Disease Research in Fuzhou City, Fuzhou Science and Technology Bureau, Fuzhou 344000, Jiangxi Province, China
| | - Dong-Ming Li
- Department of Physiology, Fuzhou Medical College, Nanchang University, Fuzhou 344000, Jiangxi Province, China
- Key Laboratory of Chronic Diseases, Fuzhou Medical University, Fuzhou 344000, Jiangxi Province, China
- Technology Innovation Center of Chronic Disease Research in Fuzhou City, Fuzhou Science and Technology Bureau, Fuzhou 344000, Jiangxi Province, China
| | - Fen-Fang Hong
- Experimental Center of Pathogen Biology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Shu-Long Yang
- Department of Physiology, Fuzhou Medical College, Nanchang University, Fuzhou 344000, Jiangxi Province, China
- Key Laboratory of Chronic Diseases, Fuzhou Medical University, Fuzhou 344000, Jiangxi Province, China
- Technology Innovation Center of Chronic Disease Research in Fuzhou City, Fuzhou Science and Technology Bureau, Fuzhou 344000, Jiangxi Province, China.
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4
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Yoshida T, Fujitani M, Farmer S, Harada A, Shi Z, Lee JJ, Tinajero A, Singha AK, Fujikawa T. VMHdm/c SF-1 neuronal circuits regulate skeletal muscle PGC1-α via the sympathoadrenal drive. Mol Metab 2023; 77:101792. [PMID: 37633515 PMCID: PMC10491730 DOI: 10.1016/j.molmet.2023.101792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 08/14/2023] [Indexed: 08/28/2023] Open
Abstract
OBJECTIVE To adapt to metabolically challenging environments, the central nervous system (CNS) orchestrates metabolism of peripheral organs including skeletal muscle. The organ-communication between the CNS and skeletal muscle has been investigated, yet our understanding of the neuronal pathway from the CNS to skeletal muscle is still limited. Neurons in the dorsomedial and central parts of the ventromedial hypothalamic nucleus (VMHdm/c) expressing steroidogenic factor-1 (VMHdm/cSF-1 neurons) are key for metabolic adaptations to exercise, including increased basal metabolic rate and skeletal muscle mass in mice. However, the mechanisms by which VMHdm/cSF-1 neurons regulate skeletal muscle function remain unclear. Here, we show that VMHdm/cSF-1 neurons increase the sympathoadrenal activity and regulate skeletal muscle peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) in mice via multiple downstream nodes. METHODS Optogenetics was used to specifically manipulate VMHdm/cSF-1 neurons combined with genetically-engineered mice and surgical manipulation of the sympathoadrenal activity. RESULTS Optogenetic activation of VMHdm/cSF-1 neurons dramatically elevates mRNA levels of skeletal muscle Pgc-1α, which regulates a spectrum of skeletal muscle function including protein synthesis and metabolism. Mechanistically, the sympathoadrenal drive coupled with β2 adrenergic receptor (β2AdR) is essential for VMHdm/cSF-1 neurons-mediated increases in skeletal muscle PGC1-α. Specifically, both adrenalectomy and β2AdR knockout block augmented skeletal muscle PGC1-α by VMHdm/cSF-1 neuronal activation. Optogenetic functional mapping reveals that downstream nodes of VMHdm/cSF-1 neurons are functionally redundant to increase circulating epinephrine and skeletal muscle PGC1-α. CONCLUSIONS Collectively, we propose that VMHdm/cSF-1 neurons-skeletal muscle pathway, VMHdm/cSF-1 neurons→multiple downstream nodes→the adrenal gland→skeletal muscle β2AdR, underlies augmented skeletal muscle function for metabolic adaptations.
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Affiliation(s)
- Takuya Yoshida
- Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, USA; Department of Clinical Nutrition School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan
| | - Mina Fujitani
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, USA; Laboratory of Nutrition Science, Department of Bioscience, Graduate School of Agriculture, Ehime University, Matsuyama, Japan
| | - Scotlynn Farmer
- Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, USA
| | - Ami Harada
- Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, USA; Nara Medical University, Nara, Japan
| | - Zhen Shi
- Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, USA; Department of Plastic Surgery, Hospital Zhejiang University School of Medicine, Zhejiang, China
| | - Jenny J Lee
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, USA
| | - Arely Tinajero
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, USA
| | - Ashish K Singha
- Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, USA
| | - Teppei Fujikawa
- Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, USA; Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, USA.
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Sundaram SM, Lenin RR, Janardhanan R. FGF4 alleviates hyperglycemia in diabetes and obesity conditions. Trends Endocrinol Metab 2023; 34:583-585. [PMID: 37625920 DOI: 10.1016/j.tem.2023.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/05/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023]
Abstract
Increasing evidence suggests that the brain plays a key role in glucose homeostasis, making it a potential target for the treatment of type 2 diabetes (T2D). Sun et al. recently reported that intracerebroventricular (ICV) administration of a single dose of fibroblast growth factor 4 (FGF4) can induce sustained T2D remission in mouse models in the absence of any risk of hypoglycemia.
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Affiliation(s)
- Sivaraj M Sundaram
- Division of Medical Research, Faculty of Medical and Health Sciences, SRM Institute of Science and Technology, Kattankulathur 603 203, Chengalpattu District, Tamil Nadu, India.
| | - Raji Rajesh Lenin
- Division of Medical Research, Faculty of Medical and Health Sciences, SRM Institute of Science and Technology, Kattankulathur 603 203, Chengalpattu District, Tamil Nadu, India
| | - Rajiv Janardhanan
- Division of Medical Research, Faculty of Medical and Health Sciences, SRM Institute of Science and Technology, Kattankulathur 603 203, Chengalpattu District, Tamil Nadu, India
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Byberg S, Blond MB, Holm S, Amadid H, Nielsen LB, Clemmensen KKB, Færch K, Holst B. LEAP2 is associated with cardiometabolic markers but is unchanged by antidiabetic treatment in people with prediabetes. Am J Physiol Endocrinol Metab 2023; 325:E244-E251. [PMID: 37436962 DOI: 10.1152/ajpendo.00023.2023] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 07/05/2023] [Accepted: 07/06/2023] [Indexed: 07/14/2023]
Abstract
To examine whether fasting plasma liver-expressed antimicrobial peptide 2 (FP-LEAP2) is associated with markers of cardiometabolic disease susceptibility in a cohort with prediabetes and overweight/obesity and whether antidiabetic interventions affect FP-LEAP2 levels. The analysis included 115 individuals with prediabetes [hemoglobin A1c (HbA1c) 39-47 mmol/mol, 5.7%-6.4%] and overweight/obesity [body mass index (BMI) ≥ 25 kg/m2] from a randomized controlled trial. Changes in FP-LEAP2 levels were assessed in relation to treatment with dapagliflozin (10 mg once daily), metformin (1,700 mg daily), or interval-based exercise (5 days/wk, 30 min/session) compared with control (habitual lifestyle) after 6 and 13 wk of treatment. FP-LEAP2 levels were positively associated with [standardized beta coefficient (95% CI)]: BMI 0.22 (0.03:0.41), P = 0.027; body weight 0.27 (0.06:0.48), P = 0.013; fat mass 0.2 (0.00:0.4), P = 0.048; lean mass 0.47 (0.13:0.8), P = 0.008; HbA1c 0.35 (0.17:0.53), P < 0.001; fasting plasma glucose (FPG) 0.32 (0.12:0.51), P = 0.001; fasting serum insulin 0.28 (0.09:0.47), P = 0.005; total cholesterol 0.19 (0.01:0.38), P = 0.043; triglycerides 0.31 (0.13:0.5), P < 0.001; and transaminases and fatty liver index (standardized beta coefficients 0.23-0.32), all P < 0.020. FP-LEAP2 levels were inversely associated with insulin sensitivity [-0.22 (-0.41: -0.03), P = 0.022] and kidney function [estimated glomerular filtration rate (eGFR) -0.34 (-0.56: -0.12), P = 0.003]. FP-LEAP2 levels were not associated with fat distribution or body fat percentage, fasting glucagon, postload glucose, β-cell function, or low-density lipoprotein. The interventions were not associated with changes in FP-LEAP2. FP-LEAP2 is associated with body mass, impaired insulin sensitivity, liver-specific enzymes, and kidney function. The findings highlight the importance of studying LEAP2 in obesity, type 2 diabetes, and nonalcoholic fatty liver disease. FP-LEAP2 was not affected by metformin, dapaglifloxin, or exercise in this population.NEW & NOTEWORTHY LEAP2, primarily secreted by the liver, increases with greater body mass, insulin resistance, and liver-specific enzymes in individuals with prediabetes and overweight or obesity. Fasting glucose, body mass, and alanine aminotransferase independently predict LEAP2 levels. LEAP2 is inversely linked to impaired kidney function. Elevated LEAP2 levels might indicate an increased metabolic risk, warranting further investigation into its potential involvement in glucose and body weight control.
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Affiliation(s)
- Sarah Byberg
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Martin Bæk Blond
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Research, Copenhagen University Hospital - Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Stephanie Holm
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Hanan Amadid
- Department of Data Science, Novo Nordisk, Herlev, Denmark
| | | | | | - Kristine Færch
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Research, Copenhagen University Hospital - Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Birgitte Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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7
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Cincotta AH. Brain Dopamine-Clock Interactions Regulate Cardiometabolic Physiology: Mechanisms of the Observed Cardioprotective Effects of Circadian-Timed Bromocriptine-QR Therapy in Type 2 Diabetes Subjects. Int J Mol Sci 2023; 24:13255. [PMID: 37686060 PMCID: PMC10487918 DOI: 10.3390/ijms241713255] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/19/2023] [Accepted: 07/27/2023] [Indexed: 09/10/2023] Open
Abstract
Despite enormous global efforts within clinical research and medical practice to reduce cardiovascular disease(s) (CVD), it still remains the leading cause of death worldwide. While genetic factors clearly contribute to CVD etiology, the preponderance of epidemiological data indicate that a major common denominator among diverse ethnic populations from around the world contributing to CVD is the composite of Western lifestyle cofactors, particularly Western diets (high saturated fat/simple sugar [particularly high fructose and sucrose and to a lesser extent glucose] diets), psychosocial stress, depression, and altered sleep/wake architecture. Such Western lifestyle cofactors are potent drivers for the increased risk of metabolic syndrome and its attendant downstream CVD. The central nervous system (CNS) evolved to respond to and anticipate changes in the external (and internal) environment to adapt survival mechanisms to perceived stresses (challenges to normal biological function), including the aforementioned Western lifestyle cofactors. Within the CNS of vertebrates in the wild, the biological clock circuitry surveils the environment and has evolved mechanisms for the induction of the obese, insulin-resistant state as a survival mechanism against an anticipated ensuing season of low/no food availability. The peripheral tissues utilize fat as an energy source under muscle insulin resistance, while increased hepatic insulin resistance more readily supplies glucose to the brain. This neural clock function also orchestrates the reversal of the obese, insulin-resistant condition when the low food availability season ends. The circadian neural network that produces these seasonal shifts in metabolism is also responsive to Western lifestyle stressors that drive the CNS clock into survival mode. A major component of this natural or Western lifestyle stressor-induced CNS clock neurophysiological shift potentiating the obese, insulin-resistant state is a diminution of the circadian peak of dopaminergic input activity to the pacemaker clock center, suprachiasmatic nucleus. Pharmacologically preventing this loss of circadian peak dopaminergic activity both prevents and reverses existing metabolic syndrome in a wide variety of animal models of the disorder, including high fat-fed animals. Clinically, across a variety of different study designs, circadian-timed bromocriptine-QR (quick release) (a unique formulation of micronized bromocriptine-a dopamine D2 receptor agonist) therapy of type 2 diabetes subjects improved hyperglycemia, hyperlipidemia, hypertension, immune sterile inflammation, and/or adverse cardiovascular event rate. The present review details the seminal circadian science investigations delineating important roles for CNS circadian peak dopaminergic activity in the regulation of peripheral fuel metabolism and cardiovascular biology and also summarizes the clinical study findings of bromocriptine-QR therapy on cardiometabolic outcomes in type 2 diabetes subjects.
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8
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Meng A, Ameroso D, Rios M. mGluR5 in Astrocytes in the Ventromedial Hypothalamus Regulates Pituitary Adenylate Cyclase-Activating Polypeptide Neurons and Glucose Homeostasis. J Neurosci 2023; 43:5918-5935. [PMID: 37507231 PMCID: PMC10436691 DOI: 10.1523/jneurosci.0193-23.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 05/09/2023] [Accepted: 07/16/2023] [Indexed: 07/30/2023] Open
Abstract
The ventromedial hypothalamus (VMH) is a functionally heterogeneous nucleus critical for systemic energy, glucose, and lipid balance. We showed previously that the metabotropic glutamate receptor 5 (mGluR5) plays essential roles regulating excitatory and inhibitory transmission in SF1+ neurons of the VMH and facilitating glucose and lipid homeostasis in female mice. Although mGluR5 is also highly expressed in VMH astrocytes in the mature brain, its role there influencing central metabolic circuits is unknown. In contrast to the glucose intolerance observed only in female mice lacking mGluR5 in VMH SF1 neurons, selective depletion of mGluR5 in VMH astrocytes enhanced glucose tolerance without affecting food intake or body weight in both adult female and male mice. The improved glucose tolerance was associated with elevated glucose-stimulated insulin release. Astrocytic mGluR5 male and female mutants also exhibited reduced adipocyte size and increased sympathetic tone in gonadal white adipose tissue. Diminished excitatory drive and synaptic inputs onto VMH Pituitary adenylate cyclase-activating polypeptide (PACAP+) neurons and reduced activity of these cells during acute hyperglycemia underlie the observed changes in glycemic control. These studies reveal an essential role of astrocytic mGluR5 in the VMH regulating the excitatory drive onto PACAP+ neurons and activity of these cells facilitating glucose homeostasis in male and female mice.SIGNIFICANCE STATEMENT Neuronal circuits within the VMH play chief roles in the regulation of whole-body metabolic homeostasis. It remains unclear how astrocytes influence neurotransmission in this region to facilitate energy and glucose balance control. Here, we explored the role of the metabotropic glutamate receptor, mGluR5, using a mouse model with selective depletion of mGluR5 from VMH astrocytes. We show that astrocytic mGluR5 critically regulates the excitatory drive and activity of PACAP-expressing neurons in the VMH to control glucose homeostasis in both female and male mice. Furthermore, mGluR5 in VMH astrocytes influences adipocyte size and sympathetic tone in white adipose tissue. These studies provide novel insight toward the importance of hypothalamic astrocytes participating in central circuits regulating peripheral metabolism.
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Affiliation(s)
- Alice Meng
- Graduate Program in Cell, Molecular and Developmental Biology, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts 02111
| | - Dominique Ameroso
- Graduate Program in Neuroscience, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts 02111, United States
| | - Maribel Rios
- Graduate Program in Cell, Molecular and Developmental Biology, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts 02111
- Graduate Program in Neuroscience, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts 02111, United States
- Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111
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9
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Rashid M, Kondoh K, Palfalvi G, Nakajima KI, Minokoshi Y. Inhibition of high-fat diet-induced inflammatory responses in adipose tissue by SF1-expressing neurons of the ventromedial hypothalamus. Cell Rep 2023; 42:112627. [PMID: 37339627 DOI: 10.1016/j.celrep.2023.112627] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 03/27/2023] [Accepted: 05/24/2023] [Indexed: 06/22/2023] Open
Abstract
Inflammation and thermogenesis in white adipose tissue (WAT) at different sites influence the overall effects of obesity on metabolic health. In mice fed a high-fat diet (HFD), inflammatory responses are less pronounced in inguinal WAT (ingWAT) than in epididymal WAT (epiWAT). Here we show that ablation and activation of steroidogenic factor 1 (SF1)-expressing neurons in the ventromedial hypothalamus (VMH) oppositely affect the expression of inflammation-related genes and the formation of crown-like structures by infiltrating macrophages in ingWAT, but not in epiWAT, of HFD-fed mice, with these effects being mediated by sympathetic nerves innervating ingWAT. In contrast, SF1 neurons of the VMH preferentially regulated the expression of thermogenesis-related genes in interscapular brown adipose tissue (BAT) of HFD-fed mice. These results suggest that SF1 neurons of the VMH differentially regulate inflammatory responses and thermogenesis among various adipose tissue depots and restrain inflammation associated with diet-induced obesity specifically in ingWAT.
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Affiliation(s)
- Misbah Rashid
- Division of Endocrinology and Metabolism, Department of Homeostatic Regulation, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8585, Japan; Graduate Institute for Advanced Studies, SOKENDAI, Okazaki, Aichi 444-8585, Japan
| | - Kunio Kondoh
- Division of Endocrinology and Metabolism, Department of Homeostatic Regulation, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8585, Japan; Graduate Institute for Advanced Studies, SOKENDAI, Okazaki, Aichi 444-8585, Japan.
| | - Gergo Palfalvi
- Division of Evolutionary Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki, Aichi 444-8585, Japan
| | - Ken-Ichiro Nakajima
- Division of Endocrinology and Metabolism, Department of Homeostatic Regulation, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8585, Japan; Graduate Institute for Advanced Studies, SOKENDAI, Okazaki, Aichi 444-8585, Japan
| | - Yasuhiko Minokoshi
- Division of Endocrinology and Metabolism, Department of Homeostatic Regulation, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8585, Japan; Graduate Institute for Advanced Studies, SOKENDAI, Okazaki, Aichi 444-8585, Japan.
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10
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Huang Y, Wang JB, Parker JJ, Shivacharan R, Lal RA, Halpern CH. Spectro-spatial features in distributed human intracranial activity proactively encode peripheral metabolic activity. Nat Commun 2023; 14:2729. [PMID: 37169738 PMCID: PMC10174612 DOI: 10.1038/s41467-023-38253-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 04/17/2023] [Indexed: 05/13/2023] Open
Abstract
Mounting evidence demonstrates that the central nervous system (CNS) orchestrates glucose homeostasis by sensing glucose and modulating peripheral metabolism. Glucose responsive neuronal populations have been identified in the hypothalamus and several corticolimbic regions. However, how these CNS gluco-regulatory regions modulate peripheral glucose levels is not well understood. To better understand this process, we simultaneously measured interstitial glucose concentrations and local field potentials in 3 human subjects from cortical and subcortical regions, including the hypothalamus in one subject. Correlations between high frequency activity (HFA, 70-170 Hz) and peripheral glucose levels are found across multiple brain regions, notably in the hypothalamus, with correlation magnitude modulated by sleep-wake cycles, circadian coupling, and hypothalamic connectivity. Correlations are further present between non-circadian (ultradian) HFA and glucose levels which are higher during awake periods. Spectro-spatial features of neural activity enable decoding of peripheral glucose levels both in the present and up to hours in the future. Our findings demonstrate proactive encoding of homeostatic glucose dynamics by the CNS.
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Affiliation(s)
- Yuhao Huang
- Department of Neurosurgery, Stanford University Medical Center, Stanford, CA, 94305, USA
| | - Jeffrey B Wang
- Department of Neurosurgery, Stanford University Medical Center, Stanford, CA, 94305, USA
- Medical Scientist Training Program, Stanford School of Medicine, Stanford, CA, 94305, USA
| | - Jonathon J Parker
- Department of Neurosurgery, Stanford University Medical Center, Stanford, CA, 94305, USA
| | - Rajat Shivacharan
- Department of Neurosurgery, Stanford University Medical Center, Stanford, CA, 94305, USA
| | - Rayhan A Lal
- Department of Medicine (Endocrinology), Stanford University Medical Center, Stanford, CA, 94305, USA.
- Department of Pediatrics (Endocrinology), Stanford University Medical Center, Stanford, CA, 94305, USA.
| | - Casey H Halpern
- Department of Neurosurgery, Stanford University Medical Center, Stanford, CA, 94305, USA.
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11
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Sun H, Lin W, Tang Y, Tu H, Chen T, Zhou J, Wang D, Xu Q, Niu J, Dong W, Liu S, Ni X, Yang W, Zhao Y, Ying L, Zhang J, Li X, Mohammadi M, Shen WL, Huang Z. Sustained remission of type 2 diabetes in rodents by centrally administered fibroblast growth factor 4. Cell Metab 2023:S1550-4131(23)00172-9. [PMID: 37167965 DOI: 10.1016/j.cmet.2023.04.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 09/30/2022] [Accepted: 04/21/2023] [Indexed: 05/13/2023]
Abstract
Type 2 diabetes (T2D) is a major health and economic burden worldwide. Despite the availability of multiple drugs for short-term management, sustained remission of T2D is currently not achievable pharmacologically. Intracerebroventricular administration of fibroblast growth factor 1 (icvFGF1) induces sustained remission in T2D rodents, propelling intense research efforts to understand its mechanism of action. Whether other FGFs possess similar therapeutic benefits is currently unknown. Here, we show that icvFGF4 also elicits a sustained antidiabetic effect in both male db/db mice and diet-induced obese mice by activating FGF receptor 1 (FGFR1) expressed in glucose-sensing neurons within the mediobasal hypothalamus. Specifically, FGF4 excites glucose-excited (GE) neurons while inhibiting glucose-inhibited (GI) neurons. Moreover, icvFGF4 restores the percentage of GI neurons in db/db mice. Importantly, intranasal delivery of FGF4 alleviates hyperglycemia in db/db mice, paving the way for non-invasive therapy. We conclude that icvFGF4 holds significant therapeutic potential for achieving sustained remission of T2D.
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Affiliation(s)
- Hongbin Sun
- School of Life Science and Technology & Shanghai Clinical Research and Trial Center, ShanghaiTech University, Shanghai 201210, China
| | - Wei Lin
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yu Tang
- Key Laboratory of Thermoregulation and Inflammation of Sichuan Higher Education Institutes, Department of Physiology, Chengdu Medical College, Chengdu, Sichuan 610500, China
| | - Hongqing Tu
- School of Life Science and Technology & Shanghai Clinical Research and Trial Center, ShanghaiTech University, Shanghai 201210, China
| | - Ting Chen
- School of Life Science and Technology & Shanghai Clinical Research and Trial Center, ShanghaiTech University, Shanghai 201210, China
| | - Jie Zhou
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Dezhong Wang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Qingqing Xu
- Biology Science Institutes, Chongqing Medical University, Chongqing 400016, China
| | - Jianlou Niu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Wenliya Dong
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Sidan Liu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xinyan Ni
- School of Life Science and Technology & Shanghai Clinical Research and Trial Center, ShanghaiTech University, Shanghai 201210, China
| | - Wen Yang
- School of Life Science and Technology & Shanghai Clinical Research and Trial Center, ShanghaiTech University, Shanghai 201210, China
| | - Yingzheng Zhao
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Lei Ying
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jie Zhang
- Key Laboratory of Thermoregulation and Inflammation of Sichuan Higher Education Institutes, Department of Physiology, Chengdu Medical College, Chengdu, Sichuan 610500, China
| | - Xiaokun Li
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Moosa Mohammadi
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Wei L Shen
- School of Life Science and Technology & Shanghai Clinical Research and Trial Center, ShanghaiTech University, Shanghai 201210, China.
| | - Zhifeng Huang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
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12
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Thakkar P, Pauza AG, Murphy D, Paton JFR. Carotid body: an emerging target for cardiometabolic co-morbidities. Exp Physiol 2023; 108:661-671. [PMID: 36999224 PMCID: PMC10988524 DOI: 10.1113/ep090090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 03/03/2023] [Indexed: 04/01/2023]
Abstract
NEW FINDINGS What is the topic of this review? Regarding the global metabolic syndrome crisis, this review focuses on common mechanisms for high blood sugar and high blood pressure. Connections are made between the homeostatic regulation of blood pressure and blood sugar and their dysregulation to reveal signalling mechanisms converging on the carotid body. What advances does it highlight? The carotid body plays a major part in the generation of excessive sympathetic activity in diabetes and also underpins diabetic hypertension. As treatment of diabetic hypertension is notoriously difficult, we propose that novel receptors within the carotid body may provide a novel treatment strategy. ABSTRACT The maintenance of glucose homeostasis is obligatory for health and survival. It relies on peripheral glucose sensing and signalling between the brain and peripheral organs via hormonal and neural responses that restore euglycaemia. Failure of these mechanisms causes hyperglycaemia or diabetes. Current anti-diabetic medications control blood glucose but many patients remain with hyperglycemic condition. Diabetes is often associated with hypertension; the latter is more difficult to control in hyperglycaemic conditions. We ask whether a better understanding of the regulatory mechanisms of glucose control could improve treatment of both diabetes and hypertension when they co-exist. With the involvement of the carotid body (CB) in glucose sensing, metabolic regulation and control of sympathetic nerve activity, we consider the CB as a potential treatment target for both diabetes and hypertension. We provide an update on the role of the CB in glucose sensing and glucose homeostasis. Physiologically, hypoglycaemia stimulates the release of hormones such as glucagon and adrenaline, which mobilize or synthesize glucose; however, these counter-regulatory responses were markedly attenuated after denervation of the CBs in animals. Also, CB denervation prevents and reverses insulin resistance and glucose intolerance. We discuss the CB as a metabolic regulator (not just a sensor of blood gases) and consider recent evidence of novel 'metabolic' receptors within the CB and putative signalling peptides that may control glucose homeostasis via modulation of the sympathetic nervous system. The evidence presented may inform future clinical strategies in the treatment of patients with both diabetes and hypertension, which may include the CB.
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Affiliation(s)
- Pratik Thakkar
- Manaaki Manawa – the Centre for Heart Research, Department of Physiology, Faculty of Medical and Health SciencesUniversity of AucklandAucklandNew Zealand
| | - Audrys G. Pauza
- Manaaki Manawa – the Centre for Heart Research, Department of Physiology, Faculty of Medical and Health SciencesUniversity of AucklandAucklandNew Zealand
| | - David Murphy
- Molecular Neuroendocrinology Research Group, Bristol Medical School: Translational Health SciencesUniversity of BristolBristolUK
| | - Julian F. R. Paton
- Manaaki Manawa – the Centre for Heart Research, Department of Physiology, Faculty of Medical and Health SciencesUniversity of AucklandAucklandNew Zealand
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13
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Wang Y, Sui X, Luo J, Yang G, Fan P, Lu B, Li M, Xu Z, Qu L, Song Y, Li Y, Cai X. A Microelectrode Array Modified by PtNPs/PB Nanocomposites Used for the Detection and Analysis of Glucose-Sensitive Neurons under Different Blood Glucose States. ACS APPLIED BIO MATERIALS 2023; 6:1260-1271. [PMID: 36884222 DOI: 10.1021/acsabm.3c00006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023]
Abstract
Hypoglycemia state damages the organism, and glucose-excited and glucose-inhibited neurons from the ventral medial hypothalamus can regulate this state. Therefore, it is crucial to understand the functional mechanism between blood glucose and electrophysiology of glucose-excited and glucose-inhibited neurons. To better detect and analyze this mechanism, a PtNPs/PB nanomaterials modified 32-channel microelectrode array with low impedance (21.91 ± 6.80 kΩ), slight phase delay (-12.7° ± 2.7°), high double layer capacitance (0.606 μF), and biocompatibility was developed to realize in vivo real-time detection of the electrophysiology activities of glucose-excited and glucose-inhibited neurons. The phase-locking level of some glucose-inhibited neurons elevated during fasting (low blood glucose state) and showed theta rhythms after glucose injection (high blood glucose state). With an independent oscillating ability, glucose-inhibited neurons can provide an essential indicator to prevent severe hypoglycemia. The results reveal a mechanism for glucose-sensitive neurons to respond to blood glucose. Some glucose-inhibited neurons can integrate glucose information input and convert it into theta oscillating or phase lock output. It helps in enhancing the interaction between neurons and glucose. Therefore, the research can provide a basis for further controlling blood glucose by modulating the characteristics of neuronal electrophysiology. This helps reduce the damage of organisms under energy-limiting conditions, such as prolonged manned spaceflight or metabolic disorders.
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Affiliation(s)
- Yiding Wang
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, PR China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Xiukun Sui
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, PR China
| | - Jinping Luo
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, PR China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Gucheng Yang
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, PR China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Penghui Fan
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, PR China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Botao Lu
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, PR China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Ming Li
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, PR China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Zhaojie Xu
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, PR China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Lina Qu
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, PR China
| | - Yilin Song
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, PR China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Yinghui Li
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, PR China
| | - Xinxia Cai
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, PR China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, PR China
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14
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Mendoza-Viveros L, Marmolejo-Gutierrez C, Cid-Castro C, Escalante-Covarrubias Q, Montellier E, Carreño-Vázquez E, Noriega LG, Velázquez-Villegas LA, Tovar AR, Sassone-Corsi P, Aguilar-Arnal L, Orozco-Solis R. Astrocytic circadian clock control of energy expenditure by transcriptional stress responses in the ventromedial hypothalamus. Glia 2023; 71:1626-1647. [PMID: 36919670 DOI: 10.1002/glia.24360] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 02/28/2023] [Accepted: 03/04/2023] [Indexed: 03/16/2023]
Abstract
Hypothalamic circuits compute systemic information to control metabolism. Astrocytes residing within the hypothalamus directly sense nutrients and hormones, integrating metabolic information, and modulating neuronal responses. Nevertheless, the role of the astrocytic circadian clock on the control of energy balance remains unclear. We used mice with a targeted ablation of the core-clock gene Bmal1 within Gfap-expressing astrocytes to gain insight on the role played by this transcription factor in astrocytes. While this mutation does not substantially affect the phenotype in mice fed normo-caloric diet, under high-fat diet we unmasked a thermogenic phenotype consisting of increased energy expenditure, and catabolism in brown adipose and overall metabolic improvement consisting of better glycemia control, and body composition. Transcriptomic analysis in the ventromedial hypothalamus revealed an enhanced response to moderate cellular stress, including ER-stress response, unfolded protein response and autophagy. We identified Xbp1 and Atf1 as two key transcription factors enhancing cellular stress responses. Therefore, we unveiled a previously unknown role of the astrocytic circadian clock modulating energy balance through the regulation of cellular stress responses within the VMH.
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Affiliation(s)
- Lucia Mendoza-Viveros
- Instituto Nacional de Medicina Genómica (INMEGEN), México City, Mexico
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México UNAM, México City, Mexico
- Centro de Investigación sobre el Envejecimiento, Centro de Investigación y de Estudios Avanzados (CIE-CINVESTAV), México City, México
| | | | - Carolina Cid-Castro
- Instituto Nacional de Medicina Genómica (INMEGEN), México City, Mexico
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México UNAM, México City, Mexico
- Centro de Investigación sobre el Envejecimiento, Centro de Investigación y de Estudios Avanzados (CIE-CINVESTAV), México City, México
| | | | | | | | - Lilia G Noriega
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - Armando R Tovar
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - Lorena Aguilar-Arnal
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México UNAM, México City, Mexico
| | - Ricardo Orozco-Solis
- Instituto Nacional de Medicina Genómica (INMEGEN), México City, Mexico
- Centro de Investigación sobre el Envejecimiento, Centro de Investigación y de Estudios Avanzados (CIE-CINVESTAV), México City, México
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15
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Effects of Ventromedial Hypothalamic Nucleus (VMN) Aromatase Gene Knockdown on VMN Glycogen Metabolism and Glucoregulatory Neurotransmission. BIOLOGY 2023; 12:biology12020242. [PMID: 36829519 PMCID: PMC9953379 DOI: 10.3390/biology12020242] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 01/28/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023]
Abstract
The enzyme aromatase is expressed at high levels in the ventromedial hypothalamic nucleus (VMN), a principal component of the brain gluco-regulatory network. Current research utilized selective gene knockdown tools to investigate the premise that VMN neuroestradiol controls glucostasis. Intra-VMN aromatase siRNA administration decreased baseline aromatase protein expression and tissue estradiol concentrations and either reversed or attenuated the hypoglycemic regulation of these profiles in a VMN segment-specific manner. Aromatase gene repression down-regulated protein biomarkers for gluco-stimulatory (nitric oxide; NO) and -inhibitory (gamma-aminobutyric acid; GABA) neurochemical transmitters. Insulin-induced hypoglycemia (IIH) up- or down-regulated neuronal nitric oxide synthase (nNOS) and glutamate decarboxylase65/67 (GAD), respectively, throughout the VMN. Interestingly, IIH caused divergent changes in tissue aromatase and estradiol levels in rostral (diminished) versus middle and caudal (elevated) VMN. Aromatase knockdown prevented hypoglycemic nNOS augmentation in VMN middle and caudal segments, but abolished the GAD inhibitory response to IIH throughout this nucleus. VMN nitrergic and GABAergic neurons monitor stimulus-specific glycogen breakdown. Here, glycogen synthase (GS) and phosphorylase brain- (GPbb; AMP-sensitive) and muscle- (GPmm; noradrenergic -responsive) type isoform responses to aromatase siRNA were evaluated. Aromatase repression reduced GPbb and GPmm content in euglycemic controls and prevented hypoglycemic regulation of GPmm but not GPbb expression while reversing glycogen accumulation. Aromatase siRNA elevated baseline glucagon and corticosterone secretion and abolished hypoglycemic hyperglucagonemia and hypercorticosteronemia. Outcomes document the involvement of VMN neuroestradiol signaling in brain control of glucose homeostasis. Aromatase regulation of VMN gluco-regulatory signaling of hypoglycemia-associated energy imbalance may entail, in part, control of GP variant-mediated glycogen disassembly.
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16
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Ali MH, Alshamrani AA, Napit PR, Briski KP. Single-cell multiplex qPCR evidence for sex-dimorphic glutamate decarboxylase, estrogen receptor, and 5'-AMP-activated protein kinase alpha subunit mRNA expression by ventromedial hypothalamic nucleus GABAergic neurons. J Chem Neuroanat 2022; 124:102132. [PMID: 35772680 PMCID: PMC9474596 DOI: 10.1016/j.jchemneu.2022.102132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 06/20/2022] [Accepted: 06/24/2022] [Indexed: 12/01/2022]
Abstract
The inhibitory amino acid transmitter γ-aminobutryic acid (GABA) acts within the ventromedial hypothalamus to regulate systemic glucose homeostasis, but the issue of whether this neurochemical signal originates locally or is supplied by afferent innervation remains controversial. Here, combinatory in situ immunocytochemistry/laser-catapult microdissection/single-cell multiplex qPCR techniques were used to investigate the premise that ventromedial hypothalamic nucleus ventrolateral (VMNvl) and/or dorsomedial (VMNdm) division neurons contain mRNAs that encode glutamate decarboxylase (GAD)65 or GAD67 and metabolic-sensory biomarkers, and that expression of these genes is sex-dimorphic. In male and female rats, GAD65 mRNA was elevated in VMNvl versus VMNdm GAD65/67-immunopositive (-ir) neurons, yet the female exhibited higher GAD67 transcript content in VMNdm versus VMNvl GABAergic nerve cells. Estrogen receptor (ER)-alpha transcripts were lower in female versus male GABA neurons from either VMN division; ER-beta and G-protein-coupled ER-1 mRNA expression profiles were also comparatively reduced in cells from female versus male VMNvl. VMNvl and VMNdm GAD65/67-ir-positive neurons showed equivalent levels of glucokinase and sulfonylurea receptor-1 mRNA between sexes. 5'-AMP-activated protein kinase-alpha 1 (AMPKα1) and -alpha 2 (AMPKα2) transcripts were lower in female versus male VMNdm GABAergic neurons, yet AMPKα2 mRNA levels were higher in cells acquired from female versus male VMNvl. Current studies document GAD65 and -67 gene expression in VMNvl and VMNdm GAD65/67-ir-positive neurons in each sex. Results infer that GABAergic neurons in each division may exhibit sex differences in receptiveness to estradiol. Outcomes also support the prospect that energy sensory function by this neurotransmitter cell type may predominate in the VMNvl in female versus VMNdm in the male.
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Affiliation(s)
- Md Haider Ali
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Ayed A Alshamrani
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Prabhat R Napit
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Karen P Briski
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA.
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17
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Ahn W, Latremouille J, Harris RBS. Leptin receptor-expressing cells in the ventromedial nucleus of the hypothalamus contribute to enhanced CCK-induced satiety following central leptin injection. Am J Physiol Endocrinol Metab 2022; 323:E267-E280. [PMID: 35830689 PMCID: PMC9448279 DOI: 10.1152/ajpendo.00088.2022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/15/2022] [Accepted: 07/08/2022] [Indexed: 01/27/2023]
Abstract
Others have shown that leptin and cholecystokinin (CCK) act synergistically to suppress food intake. Experiments described here tested whether leptin in the ventromedial hypothalamus (VMH) contributes to the synergy with peripheral CCK in male Sprague Dawley rats. A subthreshold injection of 50-ng leptin into the VMH 1 h before a peripheral injection of 1 µg/kg CCK did not change the response to CCK in rats offered chow or low-fat purified diet, but did exaggerate the reduction in intake of high-fat diet 30 min and 1 h after injection in rats that had been food deprived for 8 h. By contrast, deletion of leptin receptor-expressing cells in the VMH using leptin-conjugated saporin (Lep-Sap) abolished the response to peripheral CCK in chow-fed rats. Lateral ventricle injection of 2-µg leptin combined with peripheral CCK exaggerated the inhibition of chow intake for up to 6 h in control rats treated with Blank-saporin, but not in Lep-Sap rats. Blank-Saporin rats offered low- or high-fat purified diet also demonstrated a dose-response inhibition of intake that reached significance with 1 µg/kg of CCK for both diets. CCK did not inhibit intake of Lep-Sap rats in either low- or high-fat-fed rats. Thus, although basal activation of VMH leptin receptors makes a significant contribution to the synergy with CCK, increased leptin activity in the VMH does not exaggerate the response to CCK in intact rats offered low-fat diets, but does enhance the response in those offered high-fat diet.NEW & NOTEWORTHY Leptin is a feedback signal in the control of energy balance, whereas cholecystokinin (CCK) is a short-term satiety signal that inhibits meal size. The two hormones synergize to promote satiety. We tested whether leptin receptors in the ventromedial nucleus of the hypothalamus (VMH) contribute to the synergy. The results suggest that there is a requirement for a baseline level of activation of leptin receptors in the VMH in order for CCK to promote satiety.
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Affiliation(s)
- WonMo Ahn
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - John Latremouille
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Ruth B S Harris
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia
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18
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Huang YM, Chien WC, Cheng CG, Chang YH, Chung CH, Cheng CA. Females with Diabetes Mellitus Increased the Incidence of Premenstrual Syndrome. Life (Basel) 2022; 12:life12060777. [PMID: 35743808 PMCID: PMC9224876 DOI: 10.3390/life12060777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 05/10/2022] [Accepted: 05/19/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Premenstrual syndrome (PMS) is a multifactorial disorder caused by hormone and autonomic imbalance. In our study, hyperglycemia-induced insulin secretion increased progesterone secretion and progressive autonomic imbalance. The young patients with diabetes mellitus (DM) revealed hypo-parasympathetic function and hypersympathetic function compared with nondiabetic controls. Young female patients with DM with higher blood sugar and autonomic malfunction may be associated with PMS. However, there is a lack of evidence about DM in females related to PMS. We evaluated female patients with DM who subsequently followed PMS in a retrospective cohort study. Methods: We retrieved data from the National Health Insurance Research Database in Taiwan. Female patients with DM between 20 and 50 years old were assessed by the International Classification of Disease, 9 Revision, Clinical Modification (ICD-9-CM) disease code of 250. Patients who were DM-free females were fourfold matched to the control group by age and disease index date. The ICD-9-CM disease code of 625.4 identified the incidence of PMS followed by the index date as events. The possible risk factors associated with PMS were detected with a Cox proportional regression. Results: DM was a significant risk factor for PMS incidence with an adjusted hazard ratio of 1.683 (95% confidence interval: 1.104−2.124, p < 0.001) in females after adjusting for age, other comorbidities, season, urbanization status of patients and the hospital status of visiting. Conclusions: This study noted an association between DM and PMS in female patients. Healthcare providers and female patients with DM must be aware of possible complications of PMS, aggressive glycemic control, decreased hyperglycemia and autonomic dysfunction to prevent this bothersome disorder.
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Affiliation(s)
- Yao-Ming Huang
- Department of Emergency Medicine, Taoyuan Armed Forces General Hospital, National Defense Medical Center, Taoyuan 32549, Taiwan; (Y.-M.H.); (C.-G.C.)
| | - Wu-Chien Chien
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan; (W.-C.C.); (C.-H.C.)
- School of Public Health, National Defense Medical Center, Taipei 11490, Taiwan
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan
| | - Chun-Gu Cheng
- Department of Emergency Medicine, Taoyuan Armed Forces General Hospital, National Defense Medical Center, Taoyuan 32549, Taiwan; (Y.-M.H.); (C.-G.C.)
- Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
- Emergency Department, Department of Emergency and Critical Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
- Department of Emergency, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Yin-Han Chang
- Department of Psychology, National Taiwan University, Taipei 10621, Taiwan;
| | - Chi-Hsiang Chung
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan; (W.-C.C.); (C.-H.C.)
- School of Public Health, National Defense Medical Center, Taipei 11490, Taiwan
| | - Chun-An Cheng
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
- Correspondence: ; Tel.: +886-2-87927173
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She QY, Bao JF, Wang HZ, Liang H, Huang W, Wu J, Zhong Y, Ling H, Li A, Qin SL. Fibroblast growth factor 21: A "rheostat" for metabolic regulation? Metabolism 2022; 130:155166. [PMID: 35183545 DOI: 10.1016/j.metabol.2022.155166] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 02/12/2022] [Accepted: 02/14/2022] [Indexed: 01/10/2023]
Abstract
Fibroblast growth factor 21 is an evolutionarily conserved factor that plays multiple important roles in metabolic homeostasis. During the past two decades, extensive investigations have improved our understanding of its delicate metabolic roles and identified its pharmacological potential to mitigate metabolic disorders. However, most clinical trials have failed to obtain the desired results, which raises issues regarding its clinical value. Fibroblast growth factor 21 is dynamically regulated by nutrients derived from food intake and hepatic/adipose release, which in turn act on the central nervous system, liver, and adipose tissues to influence food preference, hepatic glucose, and adipose fatty acid output. Based on this information, we propose that fibroblast growth factor 21 should not be considered merely an anti-hyperglycemia or anti-obesity factor, but rather a means of balancing of nutrient fluctuations to maintain an appropriate energy supply. Hence, the specific functions of fibroblast growth factor 21 in glycometabolism and lipometabolism depend on specific metabolic states, indicating that its pharmacological effects require further consideration.
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Affiliation(s)
- Qin-Ying She
- Department of Endocrinology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510999, China; Department of Nephrology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510999, China
| | - Jing-Fu Bao
- State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510515, China
| | - Hui-Zhen Wang
- State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510515, China
| | - Huixin Liang
- Department of Endocrinology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510999, China
| | - Wentao Huang
- Department of Endocrinology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510999, China
| | - Jing Wu
- Department of Nephrology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510999, China
| | - Yiwen Zhong
- Department of Nephrology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510999, China
| | - Hanxin Ling
- Department of Nephrology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510999, China
| | - Aiqing Li
- State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510515, China.
| | - Shu-Lan Qin
- Department of Endocrinology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510999, China.
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20
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Koracevic G, Micic S, Stojanovic M, Radovanovic RV, Pavlovic MP, Kostic T, Djordjevic D, Antonijevic N, Koracevic M, Atanaskovic V, Dakic S. Beta Blockers can mask not only Hypoglycemia, but also Hypotension. Curr Pharm Des 2022; 28:1660-1668. [DOI: 10.2174/1381612828666220421135523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 02/01/2022] [Indexed: 11/22/2022]
Abstract
Background:
Beta-adrenergic (β-AR) receptor blockers (BBs) are an essential class of drugs as they have numerous indications. On the other hand, they have numerous unwanted effects which decrease the compliance, adherence, and persistence of this very useful group of drugs.
Objective:
The paper aims to analyze the possibility that an unnoticed side effect may contribute to a less favorable pharmacologic profile of BBs, e.g., a diminished reaction to a sudden fall in BP.
Methods:
We searched two medical databases for abstracts and citations (Medline and SCOPUS). Moreover, we searched the internet for drug prescription leaflets (of the individual BBs).
Results:
Whichever cause of stress is considered, the somatic manifestations of stress will be (partially) masked if a patient takes BB. Stress–induced hypercatecholaminemia acts on β-AR of cardiomyocytes; it increases heart rate and contractility, effects suppressed by BBs. The answers of the organism to hypoglycemia and hypotension share the main mechanisms such as sympathetic nervous system activation and hypercatecholaminemia. Thus, there is a striking analogy: BBs can cover up symptoms of both hypoglycemia (which is widely known) and of hypotension (which is not recognized). It is widely known that BBs can cause hypotension. However, they can also complicate recovery by spoiling the defense mechanisms in hypotension as they interfere with the crucial compensatory reflex to increase blood pressure in hypotension.
Conclusion:
Beta blockers can cause hypotension, mask it, and make recovery more difficult. This is clinically important and deserves to be more investigated and probably to be stated as a warning.
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Affiliation(s)
- Goran Koracevic
- Department for Cardiovascular Diseases, University Clinical Centre Nis, Nis, Serbia
| | | | | | | | - Milan Pavlovic Pavlovic
- Department for Cardiovascular Diseases, University Clinical Centre Nis, Nis, Serbia
- Faculty of Medicine, University of Nis, Nis, Serbia
| | - Tomislav Kostic
- Department for Cardiovascular Diseases, University Clinical Centre Nis, Nis, Serbia
- Faculty of Medicine, University of Nis, Nis, Serbia
| | - Dragan Djordjevic
- Faculty of Medicine, University of Nis, Nis, Serbia
- Institute for Treatment and Rehabilitation Niska Banja, Nis, Serbia
| | - Nebojsa Antonijevic
- Clinic for Cardiology, University Clinical Centre of Serbia, Belgrade, Serbia
| | - Maja Koracevic
- Faculty of Medicine, University of Nis, Nis, Serbia
- Innovation Centre, University of Nis, Nis, Serbia
| | - Vesna Atanaskovic
- Department for Cardiovascular Diseases, University Clinical Centre Nis, Nis, Serbia
| | - Sonja Dakic
- Department for Cardiovascular Diseases, University Clinical Centre Nis, Nis, Serbia
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21
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Vipin VA, Blesson CS, Yallampalli C. Maternal low protein diet and fetal programming of lean type 2 diabetes. World J Diabetes 2022; 13:185-202. [PMID: 35432755 PMCID: PMC8984567 DOI: 10.4239/wjd.v13.i3.185] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 12/30/2021] [Accepted: 02/10/2022] [Indexed: 02/06/2023] Open
Abstract
Maternal nutrition is found to be the key factor that determines fetal health in utero and metabolic health during adulthood. Metabolic diseases have been primarily attributed to impaired maternal nutrition during pregnancy, and impaired nutrition has been an immense issue across the globe. In recent years, type 2 diabetes (T2D) has reached epidemic proportion and is a severe public health problem in many countries. Although plenty of research has already been conducted to tackle T2D which is associated with obesity, little is known regarding the etiology and pathophysiology of lean T2D, a variant of T2D. Recent studies have focused on the effects of epigenetic variation on the contribution of in utero origins of lean T2D, although other mechanisms might also contribute to the pathology. Observational studies in humans and experiments in animals strongly suggest an association between maternal low protein diet and lean T2D phenotype. In addition, clear sex-specific disease prevalence was observed in different studies. Consequently, more research is essential for the understanding of the etiology and pathophysiology of lean T2D, which might help to develop better disease prevention and treatment strategies. This review examines the role of protein insufficiency in the maternal diet as the central driver of the developmental programming of lean T2D.
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Affiliation(s)
- Vidyadharan Alukkal Vipin
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, United States
| | - Chellakkan Selvanesan Blesson
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, United States
- Family Fertility Center, Texas Children's Hospital, Houston, TX 77030, United States
| | - Chandra Yallampalli
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, United States
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22
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Thorens B. Neuronal regulation of glucagon secretion and gluconeogenesis. J Diabetes Investig 2022; 13:599-607. [PMID: 34989155 PMCID: PMC9017634 DOI: 10.1111/jdi.13745] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 01/02/2022] [Indexed: 11/29/2022] Open
Abstract
Hypoglycemia almost never develops in healthy individuals because multiple hypoglycemia sensing systems, located in the periphery and in the central nervous system trigger a coordinated counterregulatory hormonal response to restore normoglycemia. This involves not only the secretion of glucagon but also of epinephrine, norepinephrine, cortisol and growth hormone. Increased hepatic glucose production is also stimulated by direct autonomous nervous connections to the liver that stimulate glycogenolysis and gluconeogenesis. This counterregulatory response, however, becomes deregulated in a significant fraction of diabetic patients that receive insulin therapy. This leads to risk of developing hypoglycemic episodes, of increasing severity, which negatively impact the quality of life of the patients. How hypoglycemia is detected by the central nervous system is being actively investigated. Recent studies using novel molecular biological, optogenetic and chemogenetic techniques, allow the characterization of glucose sensing neurons, the mechanisms of hypoglycemia detection, the neuronal circuits in which they are integrated and the physiological responses they control. This review will discuss recent studies aimed at identifying central hypoglycemia sensing neuronal circuits, how neurons are activated by hypoglycemia, and how they restore normoglycemia.
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Affiliation(s)
- Bernard Thorens
- Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland
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23
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Wang Q, Zhang Q, Li Y, Zhao X, Zhang Y. Screening and Identification of Differential Ovarian Proteins before and after Induced Ovulation via Seminal Plasma in Bactrian Camels. Animals (Basel) 2021; 11:ani11123512. [PMID: 34944287 PMCID: PMC8698062 DOI: 10.3390/ani11123512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/16/2021] [Accepted: 12/08/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Camelidae are induced ovulators whose ovulation is tightly regulated by multiple factors. Understanding the biological mechanisms underlying follicular development, hormone secretion, and ovulation requires investigating the potential molecular pathways involved in these mechanisms. However, little is known about these molecular pathways in Bactrian camels. To screen and identify candidate biomarkers after seminal plasma (SP)-induced ovulation in the ovaries, we performed comprehensive proteomic and molecular biological analyses of the ovaries from camels that were intramuscularly injected with either seminal plasma or phosphate-buffered saline. Identification of these candidate biomarkers will enable a better understanding of reproduction in Bactrian camels. Our findings suggest candidate proteins for further studies on the molecular mechanisms of induced ovulation. Abstract Camelidae are induced ovulators whose ovulation is tightly regulated by multiple factors. Understanding the biological mechanisms underlying follicular development, hormone secretion, and ovulation requires investigating the potential molecular pathways involved. However, little is known about these pathways in Bactrian camels. To screen and identify candidate biomarkers after inducing ovulation, this study performed comprehensive proteomic and molecular biological analyses of the ovaries from two camel groups (n = 6). We identified 5075 expressed ovarian proteins, of which 404 were differentially expressed (264 upregulated, 140 downregulated) (p < 0.05 or p < 0.01), in samples from plasma-induced versus control camels. Gene ontology annotation identified the potential functions of the differentially expressed proteins (DEPs). These results validated the differential expression for a subset of these proteins using Western blot (p < 0.05) and immunofluorescence staining. Three DEPs (FST, NR5A1, and PRL) were involved in neurochemical signal transduction, as well as endocrine and reproductive hormone regulatory processes. The Kyoto Encyclopedia of Genes and Genomes analysis indicated the involvement of several pathways, including the calcium, cAMP, gonadotropin-releasing hormone, MAPK, and neuroactive ligand–receptor signaling pathways, suggesting that induced ovulation depends on the hypothalamic–pituitary–ovarian axis. Identifying these candidate biomarkers enables a better understanding of Bactrian camel reproduction. Ovarian proteomic profiling and the measurement of selected proteins using more targeted methods is a promising approach for studying induced-ovulation mechanisms.
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Affiliation(s)
- Qi Wang
- College of Veterinary Medicine, Gansu Agriculture University, Lanzhou 730070, China; (Q.W.); (Y.L.)
| | - Quanwei Zhang
- College of Life Science and Technology, Gansu Agriculture University, Lanzhou 730070, China;
| | - Yina Li
- College of Veterinary Medicine, Gansu Agriculture University, Lanzhou 730070, China; (Q.W.); (Y.L.)
| | - Xingxu Zhao
- College of Veterinary Medicine, Gansu Agriculture University, Lanzhou 730070, China; (Q.W.); (Y.L.)
- College of Life Science and Technology, Gansu Agriculture University, Lanzhou 730070, China;
- Correspondence: (X.Z.); (Y.Z.)
| | - Yong Zhang
- College of Veterinary Medicine, Gansu Agriculture University, Lanzhou 730070, China; (Q.W.); (Y.L.)
- College of Life Science and Technology, Gansu Agriculture University, Lanzhou 730070, China;
- Correspondence: (X.Z.); (Y.Z.)
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24
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Claflin KE, Flippo KH, Sullivan AI, Naber MC, Zhou B, Neff TJ, Jensen-Cody SO, Potthoff MJ. Conditional gene targeting using UCP1-Cre mice directly targets the central nervous system beyond thermogenic adipose tissues. Mol Metab 2021; 55:101405. [PMID: 34844020 PMCID: PMC8683614 DOI: 10.1016/j.molmet.2021.101405] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022] Open
Abstract
Objective Uncoupling protein 1 (UCP1) is a mitochondrial protein critical for adaptive thermogenesis in adipose tissues, and it is typically believed to be restricted to thermogenic adipose tissues. UCP1-Cre transgenic mice are utilized in numerous studies to provide “brown adipose-specific” conditional gene targeting. Here, we examined the distribution of Cre and UCP1 throughout the body in UCP1-Cre reporter mice. Methods UCP1-Cre mice crossed to Ai14-tdTomato and Ai9-tdTomato reporter mice were used to explore the tissue distribution of Cre recombinase and Ucp1 mRNA in various tissues. UCP1-Cre mice were independently infected with either a Cre-dependent PHP.eB-tdTomato virus or a Cre-dependent AAV-tdTomato virus to determine whether and where UCP1 is actively expressed in the adult central nervous system. In situ analysis of the deposited single cell RNA sequencing data was used to evaluate Ucp1 expression in the hypothalamus. Results As expected, Ucp1 expression was detected in both brown and inguinal adipose tissues. Ucp1 expression was also detected in the kidney, adrenal glands, thymus, and hypothalamus. Consistent with detectable Ucp1 expression, tdTomato expression was also observed in brown adipose tissue, inguinal white adipose tissue, kidney, adrenal glands, and hypothalamus of both male and female UCP1-Cre; Ai14-tdTomato and UCP1-Cre; Ai9-tdTomato mice by fluorescent imaging and qPCR. Critically, expression of tdTomato, and thus UCP1, within the central nervous system was observed in regions of the brain critical for the regulation of energy homeostasis, including the ventromedial hypothalamus (VMH). Conclusions TdTomato expression in UCP1-Cre; tdTomato mice is not restricted to thermogenic adipose tissues. TdTomato was also expressed in the kidneys, adrenal glands, and throughout the brain, including brain regions and cell types that are critical for multiple aspects of central regulation of energy homeostasis. Collectively, these data have important implications for the utility of UCP1-Cre mice as genetic tools to investigate gene function specifically in brown adipose tissue.
UCP1-Cre transgenic mice express Cre in tissues beyond thermogenic adipose tissues. UCP1-Cre; tdTomato reporter mice show that Cre is also expressed throughout the brain, kidney, and adrenal glands. Ucp1 mRNA is actively expressed in the central nervous system of adult mice.
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Affiliation(s)
- Kristin E Claflin
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Kyle H Flippo
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Andrew I Sullivan
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Meghan C Naber
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Bolu Zhou
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Tate J Neff
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Sharon O Jensen-Cody
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Matthew J Potthoff
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Department of Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
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25
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Imoto D, Yamamoto I, Matsunaga H, Yonekura T, Lee ML, Kato KX, Yamasaki T, Xu S, Ishimoto T, Yamagata S, Otsuguro KI, Horiuchi M, Iijima N, Kimura K, Toda C. Refeeding activates neurons in the dorsomedial hypothalamus to inhibit food intake and promote positive valence. Mol Metab 2021; 54:101366. [PMID: 34728342 PMCID: PMC8609163 DOI: 10.1016/j.molmet.2021.101366] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 10/26/2021] [Indexed: 11/17/2022] Open
Abstract
Objective The regulation of food intake is a major research area in the study of obesity, which plays a key role in the development of metabolic syndrome. Gene targeting studies have clarified the roles of hypothalamic neurons in feeding behavior, but the deletion of a gene has a long-term effect on neurophysiology. Our understanding of short-term changes such as appetite under physiological conditions is therefore still limited. Methods Targeted recombination in active populations (TRAP) is a newly developed method for labeling active neurons by using tamoxifen-inducible Cre recombination controlled by the promoter of activity-regulated cytoskeleton-associated protein (Arc/Arg3.1), a member of immediate early genes. Transgenic mice for TRAP were fasted overnight, re-fed with normal diet, and injected with 4-hydroxytamoxifen 1 h after the refeeding to label the active neurons. The role of labeled neurons was examined by expressing excitatory or inhibitory designer receptors exclusively activated by designer drugs (DREADDs). The labeled neurons were extracted and RNA sequencing was performed to identify genes that are specifically expressed in these neurons. Results Fasting-refeeding activated and labeled neurons in the compact part of the dorsomedial hypothalamus (DMH) that project to the paraventricular hypothalamic nucleus. Chemogenetic activation of the labeled DMH neurons decreased food intake and developed place preference, an indicator of positive valence. Chemogenetic activation or inhibition of these neurons had no influence on the whole-body glucose metabolism. The labeled DMH neurons expressed prodynorphin (pdyn), gastrin-releasing peptide (GRP), cholecystokinin (CCK), and thyrotropin-releasing hormone receptor (Trhr) genes. Conclusions We identified a novel cell type of DMH neurons that can inhibit food intake and promote feeding-induced positive valence. Our study provides insight into the role of DMH and its molecular mechanism in the regulation of appetite and emotion.
Fasting-refeeding activates a subset of neurons in the dorsomedial hypothalamus (DMH). Chemogenetic inhibition of the DMH neurons increases food intake. Chemogenetic activation of the DMH neurons inhibits food intake and promotes positive valence. The DMH neurons express pdyn, GRP, CCK and Trhr genes.
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Affiliation(s)
- Daigo Imoto
- Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan
| | - Izumi Yamamoto
- Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan
| | - Hirokazu Matsunaga
- Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan
| | - Toya Yonekura
- Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan
| | - Ming-Liang Lee
- Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan
| | - Kan X Kato
- Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan
| | - Takeshi Yamasaki
- Laboratory of Animal Experiment, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan
| | - Shucheng Xu
- Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan
| | - Taiga Ishimoto
- Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan
| | - Satoshi Yamagata
- Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan
| | - Ken-Ichi Otsuguro
- Laboratory of Pharmacology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan
| | - Motohiro Horiuchi
- Laboratory of Veterinary Hygiene, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan
| | - Norifumi Iijima
- National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, 567-0085, Japan; Immunology Frontier Research Center, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Kazuhiro Kimura
- Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan
| | - Chitoku Toda
- Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan.
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26
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Gallon CW, Ferreira CF, Henz A, Oderich CL, Conzatti M, Ritondale Sodré de Castro J, Parmegiani Jahn M, da Silva K, Wender MCO. Leptin, ghrelin, & insulin levels and food intake in premenstrual syndrome: A case-control study. Appetite 2021; 168:105750. [PMID: 34648911 DOI: 10.1016/j.appet.2021.105750] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 09/06/2021] [Accepted: 10/08/2021] [Indexed: 01/10/2023]
Abstract
OBJECTIVES The objective of this study was to evaluate the relationship between food intake and serum levels of leptin and ghrelin in the luteal (LP) and follicular (FP) phases of the MC (menstrual cycle) in participants with and without PMS (premenstrual syndrome). METHODS This was a case-control study with healthy participants aged 20-45 years with regular menstrual cycles (24-35 days) with and without PMS. After the Daily Record of Severity of Problems (DRSP) was filled out for two months (PMS diagnosis), a nutritional assessment was carried out based on twelve food intake records (for two menstrual cycles) to quantify food intake. RESULTS Of the 69 participants analyzed, 35 experienced PMS and 34 did not experience PMS. For participants with PMS, calorie and carbohydrate intake was higher during LP than in FP (p = 0.004 and p = 0.003, respectively), whereas these changes were not observed in participants without PMS (p > 0.05). There were interactions between the groups and the MC phases (LP and FP) for the intake of calories (p = 0.028) and carbohydrates (p = 0.001). There was a marginal negative relationship between the levels of ghrelin and calorie intake in FP (rS = -0.314, p = 0.066) in the PMS group and a negative relationship between the levels of ghrelin and leptin in LP (rS = -0.490, p = 0.004) in the group without PMS. CONCLUSIONS These results indicated a higher calorie and carbohydrate intake during LP in participants with PMS, in addition to the hypothesis that the roles of ghrelin and leptin in energy regulation may be different in participants with PMS compared to those without PMS.
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Affiliation(s)
- Carin Weirich Gallon
- Postgraduate Program in Health Sciences: Gynaecology and Obstetrics (PPGGO), Menopause Research Group. Department of Gynaecology and Obstetrics, Clinical Hospital of Porto Alegre (HCPA), School of Medicine (FAMED), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; University of Caxias do Sul (UCS). Caxias do Sul, RS, Brazil.
| | - Charles Francisco Ferreira
- Postgraduate Program in Health Sciences: Gynaecology and Obstetrics (PPGGO), Menopause Research Group. Department of Gynaecology and Obstetrics, Clinical Hospital of Porto Alegre (HCPA), School of Medicine (FAMED), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Aline Henz
- Postgraduate Program in Health Sciences: Gynaecology and Obstetrics (PPGGO), Menopause Research Group. Department of Gynaecology and Obstetrics, Clinical Hospital of Porto Alegre (HCPA), School of Medicine (FAMED), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Carolina Leão Oderich
- Postgraduate Program in Health Sciences: Gynaecology and Obstetrics (PPGGO), Menopause Research Group. Department of Gynaecology and Obstetrics, Clinical Hospital of Porto Alegre (HCPA), School of Medicine (FAMED), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Maiara Conzatti
- Postgraduate Program in Health Sciences: Gynaecology and Obstetrics (PPGGO), Menopause Research Group. Department of Gynaecology and Obstetrics, Clinical Hospital of Porto Alegre (HCPA), School of Medicine (FAMED), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Juliana Ritondale Sodré de Castro
- Postgraduate Program in Health Sciences: Gynaecology and Obstetrics (PPGGO), Menopause Research Group. Department of Gynaecology and Obstetrics, Clinical Hospital of Porto Alegre (HCPA), School of Medicine (FAMED), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | | | - Keoma da Silva
- University of Caxias do Sul (UCS). Caxias do Sul, RS, Brazil
| | - Maria Celeste Osório Wender
- Postgraduate Program in Health Sciences: Gynaecology and Obstetrics (PPGGO), Menopause Research Group. Department of Gynaecology and Obstetrics, Clinical Hospital of Porto Alegre (HCPA), School of Medicine (FAMED), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
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27
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Uddin MM, Ibrahim MMH, Briski KP. Glycogen Phosphorylase Isoform Regulation of Ventromedial Hypothalamic Nucleus Gluco-Regulatory Neuron 5'-AMP-Activated Protein Kinase and Transmitter Marker Protein Expression. ASN Neuro 2021; 13:17590914211035020. [PMID: 34596459 PMCID: PMC8495507 DOI: 10.1177/17590914211035020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Brain glycogen is remodeled during metabolic homeostasis and provides oxidizable
L-lactate equivalents. Brain glycogen phosphorylase (GP)-brain (GPbb;
AMP-sensitive) and -muscle (GPmm; norepinephrine-sensitive) type isoforms
facilitate stimulus-specific control of glycogen disassembly. Here, a whole
animal model involving stereotactic-targeted delivery of GPmm or GPbb siRNA to
the ventromedial hypothalamic nucleus (VMN) was used to investigate the premise
that these variants impose differential control of gluco-regulatory
transmission. Intra-VMN GPmm or GPbb siRNA administration inhibited glutamate
decarboxylate65/67 (GAD), a protein marker for the
gluco-inhibitory transmitter γ--aminobutyric acid (GABA), in the caudal VMN.
GPbb knockdown, respectively overturned or exacerbated hypoglycemia-associated
GAD suppression in rostral and caudal VMN. GPmm siRNA caused a segment-specific
reversal of hypoglycemic augmentation of the gluco-stimulatory transmitter
indicator, neuronal nitric oxide synthase (nNOS). In both cell types, GP siRNA
down-regulated 5′-AMP-activated protein kinase (AMPK) during euglycemia, but
hypoglycemic suppression of AMPK was reversed by GPmm targeting. GP knockdown
elevated baseline GABA neuron phosphoAMPK (pAMKP) content, and amplified
hypoglycemic augmentation of pAMPK expression in each neuron type. GPbb
knockdown increased corticosterone secretion in eu- and hypoglycemic rats.
Outcomes validate efficacy of GP siRNA delivery for manipulation of glycogen
breakdown in discrete brain structures in vivo, and document VMN GPbb control of
local GPmm expression. Results document GPmm and/or -bb regulation of GABAergic
and nitrergic transmission in discrete rostro-caudal VMN segments. Contrary
effects of glycogenolysis on metabolic-sensory AMPK protein during eu- versus
hypoglycemia may reflect energy state-specific astrocyte signaling. Amplifying
effects of GPbb knockdown on hypoglycemic stimulation of pAMPK infer that
glycogen mobilization by GPbb limits neuronal energy instability during
hypoglycemia.
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Affiliation(s)
- Md Main Uddin
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, 15512University of Louisiana Monroe, Monroe, LA, USA
| | - Mostafa M H Ibrahim
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, 15512University of Louisiana Monroe, Monroe, LA, USA
| | - Karen P Briski
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, 15512University of Louisiana Monroe, Monroe, LA, USA
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28
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Abstract
The ventromedial nucleus of the hypothalamus (VMH) is a complex brain structure that is integral to many neuroendocrine functions, including glucose regulation, thermogenesis, and appetitive, social, and sexual behaviors. As such, it is of little surprise that the nucleus is under intensive investigation to decipher the mechanisms which underlie these diverse roles. Developments in genetic and investigative tools, for example the targeting of steroidogenic factor-1-expressing neurons, have allowed us to take a closer look at the VMH, its connections, and how it affects competing behaviors. In the current review, we aim to integrate recent findings into the literature and contemplate the conclusions that can be drawn.
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Affiliation(s)
- Tansi Khodai
- Faculty of Biology, Medicine and Health, The University of Manchester, Oxford Road, Manchester, UK
| | - Simon M Luckman
- Faculty of Biology, Medicine and Health, The University of Manchester, Oxford Road, Manchester, UK
- Correspondence: Simon M. Luckman, Faculty of Biology, Medicine and Health, The University of Manchester, Oxford Road, Manchester, UK.
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29
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De Rosa MC, Glover HJ, Stratigopoulos G, LeDuc CA, Su Q, Shen Y, Sleeman MW, Chung WK, Leibel RL, Altarejos JY, Doege CA. Gene expression atlas of energy balance brain regions. JCI Insight 2021; 6:e149137. [PMID: 34283813 PMCID: PMC8409984 DOI: 10.1172/jci.insight.149137] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Energy balance is controlled by interconnected brain regions in the hypothalamus, brainstem, cortex, and limbic system. Gene expression signatures of these regions can help elucidate the pathophysiology underlying obesity. RNA sequencing was conducted on P56 C57BL/6NTac male mice and E14.5 C57BL/6NTac embryo punch biopsies in 16 obesity-relevant brain regions. The expression of 190 known obesity-associated genes (monogenic, rare, and low-frequency coding variants; GWAS; syndromic) was analyzed in each anatomical region. Genes associated with these genetic categories of obesity had localized expression patterns across brain regions. Known monogenic obesity causal genes were highly enriched in the arcuate nucleus of the hypothalamus and developing hypothalamus. The obesity-associated genes clustered into distinct “modules” of similar expression profile, and these were distinct from expression modules formed by similar analysis with genes known to be associated with other disease phenotypes (type 1 and type 2 diabetes, autism, breast cancer) in the same energy balance–relevant brain regions.
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Affiliation(s)
- Maria Caterina De Rosa
- Department of Pediatrics and Molecular Genetics.,Naomi Berrie Diabetes Center, College of Physicians and Surgeons.,Columbia Stem Cell Initiative, and
| | - Hannah J Glover
- Department of Pediatrics and Molecular Genetics.,Naomi Berrie Diabetes Center, College of Physicians and Surgeons.,Columbia Stem Cell Initiative, and
| | - George Stratigopoulos
- Department of Pediatrics and Molecular Genetics.,Naomi Berrie Diabetes Center, College of Physicians and Surgeons
| | - Charles A LeDuc
- Department of Pediatrics and Molecular Genetics.,Naomi Berrie Diabetes Center, College of Physicians and Surgeons.,New York Obesity Nutrition Research Center, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Qi Su
- Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA
| | - Yufeng Shen
- Department of Systems Biology.,Department of Biomedical Informatics
| | - Mark W Sleeman
- Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA
| | - Wendy K Chung
- Department of Pediatrics and Molecular Genetics.,Naomi Berrie Diabetes Center, College of Physicians and Surgeons.,Department of Medicine.,Herbert Irving Comprehensive Cancer Center.,Institute of Human Nutrition
| | - Rudolph L Leibel
- Department of Pediatrics and Molecular Genetics.,Naomi Berrie Diabetes Center, College of Physicians and Surgeons.,New York Obesity Nutrition Research Center, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.,Institute of Human Nutrition
| | | | - Claudia A Doege
- Naomi Berrie Diabetes Center, College of Physicians and Surgeons.,Columbia Stem Cell Initiative, and.,New York Obesity Nutrition Research Center, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.,Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA
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30
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Okamoto T, Shimada T, Matsumura C, Minoshima H, Ban T, Itotani M, Shinohara T, Fujita S, Matsuda S, Sato S, Kanemoto N. New Approach to Drug Discovery of a Safe Mitochondrial Uncoupler: OPC-163493. ACS OMEGA 2021; 6:16980-16988. [PMID: 34250356 PMCID: PMC8264940 DOI: 10.1021/acsomega.1c01993] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 05/18/2021] [Indexed: 05/10/2023]
Abstract
We serendipitously found a mitochondrial uncoupler (mUncoupler), compound 1, in the process of screening for inhibitors of a gene product related to calorie restriction (CR) and longevity. Compound 1 has a unique 4-cyano-1,2,3-triazole structure which is different from any known mUncoupler and ameliorated HbA1c in Zucker diabetic fatty (ZDF) rats. However, its administration at high doses was not tolerated in an acute toxicity test in rats. We therefore tried to optimize cyanotriazole compound 1 and convert it into an agent that could be safely administered to patients with diabetes mellitus (DM) or metabolic disorders. Considering pharmacokinetic (PK) profiles, especially organ distribution targeting the liver and avoiding the brain, as well as acute toxicities and pharmacological effects of the derivatives, various conversions and substitutions at the 5-position on the cyanotriazole ring were carried out. These optimizing processes improved PK profiles and effectiveness, and acute toxicities became negligible even at high doses. We finally succeeded in developing an optimized compound, OPC-163493, as a liver-localized/targeted mUncoupler.
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Affiliation(s)
- Takashi Okamoto
- Department
of Lead Discovery Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Takahiro Shimada
- Department
of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center,
Tokushima Research Institute, Otsuka Pharmaceutical
Co., Ltd., Tokushima, Japan
| | - Chiharu Matsumura
- Medicinal
Chemistry Research Laboratories, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Hitomi Minoshima
- Pharmaceutical
Planning Group, Otsuka Pharmaceutical Co.,
Ltd., Tokyo, Japan
| | - Takashi Ban
- Department
of Renal and Cardiovascular Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Motohiro Itotani
- Quality Assurance
Section (Tokushima Wajiki Factory), Quality Assurance Department,
Headquarters for Product Safety and Quality Assurance, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Toshio Shinohara
- Medicinal
Chemistry Research Laboratories, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Shigekazu Fujita
- Human
Resources Department, Otsuka Pharmaceutical
Co., Ltd., Tokushima, Japan
| | - Satoshi Matsuda
- Administration
Department, Diagnostic Division, Otsuka
Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Seiji Sato
- Medicinal
Chemistry Research Laboratories, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Naohide Kanemoto
- Department
of Lead Discovery Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
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31
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Castorena CM, Caron A, Michael NJ, Ahmed NI, Arnold AG, Lee J, Lee C, Limboy C, Tinajero AS, Granier M, Wang S, Horton JD, Holland WL, Lee S, Liu C, Fujikawa T, Elmquist JK. CB1Rs in VMH neurons regulate glucose homeostasis but not body weight. Am J Physiol Endocrinol Metab 2021; 321:E146-E155. [PMID: 34097543 PMCID: PMC8321828 DOI: 10.1152/ajpendo.00044.2021] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Cannabinoid 1 receptor (CB1R) inverse agonists reduce body weight and improve several parameters of glucose homeostasis. However, these drugs have also been associated with deleterious side effects. CB1R expression is widespread in the brain and in peripheral tissues, but whether specific sites of expression can mediate the beneficial metabolic effects of CB1R drugs, while avoiding the untoward side effects, remains unclear. Evidence suggests inverse agonists may act on key sites within the central nervous system to improve metabolism. The ventromedial hypothalamus (VMH) is a critical node regulating energy balance and glucose homeostasis. To determine the contributions of CB1Rs expressed in VMH neurons in regulating metabolic homeostasis, we generated mice lacking CB1Rs in the VMH. We found that the deletion of CB1Rs in the VMH did not affect body weight in chow- and high-fat diet-fed male and female mice. We also found that deletion of CB1Rs in the VMH did not alter weight loss responses induced by the CB1R inverse agonist SR141716. However, we did find that CB1Rs of the VMH regulate parameters of glucose homeostasis independent of body weight in diet-induced obese male mice.NEW & NOTEWORTHY Cannabinoid 1 receptors (CB1Rs) regulate metabolic homeostasis, and CB1R inverse agonists reduce body weight and improve parameters of glucose metabolism. However, the cell populations expressing CB1Rs that regulate metabolic homeostasis remain unclear. CB1Rs are highly expressed in the ventromedial hypothalamic nucleus (VMH), which is a crucial node that regulates metabolism. With CRISPR/Cas9, we generated mice lacking CB1Rs specifically in VMH neurons and found that CB1Rs in VMH neurons are essential for the regulation of glucose metabolism independent of body weight regulation.
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Affiliation(s)
- Carlos M Castorena
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Alexandre Caron
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Natalie J Michael
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Newaz I Ahmed
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Amanda G Arnold
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jiwon Lee
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Charlotte Lee
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Chelsea Limboy
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Arely Salazar Tinajero
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Madison Granier
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Simeng Wang
- Department of Molecular Genetics, University of Utah, Salt Lake City, Utah
| | - Jay D Horton
- Department of Molecular Genetics, University of Utah, Salt Lake City, Utah
| | - William L Holland
- Department of Biochemistry, Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah
| | - Syann Lee
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Chen Liu
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Teppei Fujikawa
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Joel K Elmquist
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas
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32
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Myers MG, Affinati AH, Richardson N, Schwartz MW. Central nervous system regulation of organismal energy and glucose homeostasis. Nat Metab 2021; 3:737-750. [PMID: 34158655 DOI: 10.1038/s42255-021-00408-5] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 05/12/2021] [Indexed: 02/05/2023]
Abstract
Growing evidence implicates the brain in the regulation of both immediate fuel availability (for example, circulating glucose) and long-term energy stores (that is, adipose tissue mass). Rather than viewing the adipose tissue and glucose control systems separately, we suggest that the brain systems that control them are components of a larger, highly integrated, 'fuel homeostasis' control system. This conceptual framework, along with new insights into the organization and function of distinct neuronal systems, provides a context within which to understand how metabolic homeostasis is achieved in both basal and postprandial states. We also review evidence that dysfunction of the central fuel homeostasis system contributes to the close association between obesity and type 2 diabetes, with the goal of identifying more effective treatment options for these common metabolic disorders.
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Affiliation(s)
- Martin G Myers
- Departments of Medicine and Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Alison H Affinati
- Departments of Medicine and Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Nicole Richardson
- UW Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Michael W Schwartz
- UW Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA, USA.
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33
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Lee ML, Matsunaga H, Sugiura Y, Hayasaka T, Yamamoto I, Ishimoto T, Imoto D, Suematsu M, Iijima N, Kimura K, Diano S, Toda C. Prostaglandin in the ventromedial hypothalamus regulates peripheral glucose metabolism. Nat Commun 2021; 12:2330. [PMID: 33879780 PMCID: PMC8058102 DOI: 10.1038/s41467-021-22431-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Accepted: 03/12/2021] [Indexed: 11/24/2022] Open
Abstract
The hypothalamus plays a central role in monitoring and regulating systemic glucose metabolism. The brain is enriched with phospholipids containing poly-unsaturated fatty acids, which are biologically active in physiological regulation. Here, we show that intraperitoneal glucose injection induces changes in hypothalamic distribution and amounts of phospholipids, especially arachidonic-acid-containing phospholipids, that are then metabolized to produce prostaglandins. Knockdown of cytosolic phospholipase A2 (cPLA2), a key enzyme for generating arachidonic acid from phospholipids, in the hypothalamic ventromedial nucleus (VMH), lowers insulin sensitivity in muscles during regular chow diet (RCD) feeding. Conversely, the down-regulation of glucose metabolism by high fat diet (HFD) feeding is improved by knockdown of cPLA2 in the VMH through changing hepatic insulin sensitivity and hypothalamic inflammation. Our data suggest that cPLA2-mediated hypothalamic phospholipid metabolism is critical for controlling systemic glucose metabolism during RCD, while continuous activation of the same pathway to produce prostaglandins during HFD deteriorates glucose metabolism. The ventromedial hypothalamus regulates systemic glucose metabolism. Here the authors show that cytosolic phospholipase A2 mediated phospholipid metabolism contributes to this regulation in healthy animals but exert deteriorating effects on glucose homeostasis under high-fat-diet feeding.
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Affiliation(s)
- Ming-Liang Lee
- Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Hirokazu Matsunaga
- Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Yuki Sugiura
- Department of Biochemistry, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Takahiro Hayasaka
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Izumi Yamamoto
- Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Taiga Ishimoto
- Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Daigo Imoto
- Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Makoto Suematsu
- Department of Biochemistry, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Norifumi Iijima
- National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.,Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
| | - Kazuhiro Kimura
- Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Sabrina Diano
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, USA.,Department of Cellular and Molecular Physiology, Yale School of Medicine, Yale University, New Haven, CT, USA
| | - Chitoku Toda
- Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
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34
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Zeigerer A, Sekar R, Kleinert M, Nason S, Habegger KM, Müller TD. Glucagon's Metabolic Action in Health and Disease. Compr Physiol 2021; 11:1759-1783. [PMID: 33792899 PMCID: PMC8513137 DOI: 10.1002/cphy.c200013] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Discovered almost simultaneously with insulin, glucagon is a pleiotropic hormone with metabolic action that goes far beyond its classical role to increase blood glucose. Albeit best known for its ability to directly act on the liver to increase de novo glucose production and to inhibit glycogen breakdown, glucagon lowers body weight by decreasing food intake and by increasing metabolic rate. Glucagon further promotes lipolysis and lipid oxidation and has positive chronotropic and inotropic effects in the heart. Interestingly, recent decades have witnessed a remarkable renaissance of glucagon's biology with the acknowledgment that glucagon has pharmacological value beyond its classical use as rescue medication to treat severe hypoglycemia. In this article, we summarize the multifaceted nature of glucagon with a special focus on its hepatic action and discuss the pharmacological potential of either agonizing or antagonizing the glucagon receptor for health and disease. © 2021 American Physiological Society. Compr Physiol 11:1759-1783, 2021.
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Affiliation(s)
- Anja Zeigerer
- Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Revathi Sekar
- Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Maximilian Kleinert
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Diabetes and Obesity, Helmholtz Center Munich, Neuherberg, Germany
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Shelly Nason
- Comprehensive Diabetes Center, Department of Medicine - Endocrinology, Diabetes & Metabolism, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Kirk M. Habegger
- Comprehensive Diabetes Center, Department of Medicine - Endocrinology, Diabetes & Metabolism, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Timo D. Müller
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Diabetes and Obesity, Helmholtz Center Munich, Neuherberg, Germany
- Department of Pharmacology, Experimental Therapy and Toxicology, Institute of Experimental and Clinical Pharmacology and Pharmacogenomics, Eberhard Karls University Hospitals and Clinics, Tübingen, Germany
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35
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Nedoboy PE, Houlahan CB, Farnham MMJ. Pentobarbital Anesthesia Suppresses the Glucose Response to Acute Intermittent Hypoxia in Rat. Front Physiol 2021; 12:645392. [PMID: 33746780 PMCID: PMC7973217 DOI: 10.3389/fphys.2021.645392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 02/17/2021] [Indexed: 11/17/2022] Open
Abstract
A key feature of sleep disordered breathing syndromes, such as obstructive sleep apnea is intermittent hypoxia. Intermittent hypoxia is well accepted to drive the sympathoexcitation that is frequently associated with hypertension and diabetes, with measurable effects after just 1 h. The aim of this study was to directly measure the glucose response to 1 h of acute intermittent hypoxia in pentobarbital anesthetized rats, compared to conscious rats. However, we found that while a glucose response is measurable in conscious rats exposed to intermittent hypoxia, it is suppressed in anesthetized rats. Intermittent hypoxia for 1, 2, or 8 h increased blood glucose by 0.7 ± 0.1 mmol/L in conscious rats but had no effect in anesthetized rats (-0.1 ± 0.2 mmol/L). These results were independent of the frequency of the hypoxia challenges, fasting state, vagotomy, or paralytic agents. A supraphysiological challenge of 3 min of hypoxia was able to induce a glycemic response indicating that the reflex response is not abolished under pentobarbital anesthesia. We conclude that pentobarbital anesthesia is unsuitable for investigations into glycemic response pathways in response to intermittent hypoxia in rats.
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Affiliation(s)
- Polina E. Nedoboy
- Cardiovascular Neuroscience Unit, Heart Research Institute, Newtown, NSW, Australia
- Department of Physiology, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Callum B. Houlahan
- Cardiovascular Neuroscience Unit, Heart Research Institute, Newtown, NSW, Australia
- Department of Physiology, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Melissa M. J. Farnham
- Cardiovascular Neuroscience Unit, Heart Research Institute, Newtown, NSW, Australia
- Department of Physiology, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
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36
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Han JC, Weiss R. Obesity, Metabolic Syndrome and Disorders of Energy Balance. SPERLING PEDIATRIC ENDOCRINOLOGY 2021:939-1003. [DOI: 10.1016/b978-0-323-62520-3.00024-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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37
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Bheemanapally K, Ibrahim MMH, Briski KP. Ultra-High-Performance Liquid Chromatography-Electrospray Ionization-Mass Spectrometry for High-Neuroanatomical Resolution Quantification of Brain Estradiol Concentrations. J Pharm Biomed Anal 2020; 191:113606. [PMID: 32966939 DOI: 10.1016/j.jpba.2020.113606] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/27/2020] [Accepted: 08/28/2020] [Indexed: 12/21/2022]
Abstract
Ventromedial hypothalamic nucleus (VMN) control of glucostasis is estradiol (E-2)-dependent. E-2 regulation of VMN reactivity to hypoglycemia may involve changes in signal volume due to altered aromatase expression. Here, high-resolution micropunch dissection tools for isolation of segmental VMN tissue were used with Design of Experiments-refined uHPLC-electrospray ionization-mass spectrometry (LC-ESI-MS) methodology to investigate the premise that effects of acute and/or recurring hypoglycemia on VMN E-2 content are sex-dimorphic. Relationships among multiple independent mass spectrometric operational variables were assessed by Central Composite Design (CCD) to amplify E-2 chromatogram area. Combinations of spectrometric temperature and gas pressure variable combinations were screened by Akaike Information Criterion correction modeling. A Fibonacci Sequence design using CCD minimum and maximal variable limits produced a small-run model that replicated maximal response from CCD. E-2 chromatographic response was further enhanced by optimization of solid phase extraction and instrument source and collision-induced dissociation voltages. In male rats, acute and chronic hypoglycemia respectively elevated or diminished E-2 concentrations relative to baseline in both rostral and caudal VMN. However, females exhibited regional variability in tissue E-2 profiles during acute (increased, rostral VMN; no change, caudal VMN) and recurring (no change, rostral VMN; increased, caudal VMN) hypoglycemia. Outcomes demonstrate requisite LC-ESI-MS sensitivity for E-2 quantification in small-volume brain tissue samples acquired with high-neuroanatomical specificity. Current methodology will facilitate efforts to investigate physiological consequences of VMN rostro-caudal segment-specific acclimation of E-2 profiles to recurring hypoglycemia, including effects on gluco-regulatory function, in each sex.
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Affiliation(s)
- Khaggeswar Bheemanapally
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, United States
| | - Mostafa M H Ibrahim
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, United States
| | - Karen P Briski
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, United States.
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Błaszczyk JW. Energy Metabolism Decline in the Aging Brain-Pathogenesis of Neurodegenerative Disorders. Metabolites 2020; 10:metabo10110450. [PMID: 33171879 PMCID: PMC7695180 DOI: 10.3390/metabo10110450] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/31/2020] [Accepted: 11/04/2020] [Indexed: 12/14/2022] Open
Abstract
There is a growing body of evidencethat indicates that the aging of the brain results from the decline of energy metabolism. In particular, the neuronal metabolism of glucose declines steadily, resulting in a growing deficit of adenosine triphosphate (ATP) production-which, in turn, limits glucose access. This vicious circle of energy metabolism at the cellular level is evoked by a rising deficiency of nicotinamide adenine dinucleotide (NAD) in the mitochondrial salvage pathway and subsequent impairment of the Krebs cycle. A decreasing NAD level also impoverishes the activity of NAD-dependent enzymes that augments genetic errors and initiate processes of neuronal degeneration and death.This sequence of events is characteristic of several brain structures in which neurons have the highest energy metabolism. Neurons of the cerebral cortex and basal ganglia with long unmyelinated axons and these with numerous synaptic junctions are particularly prone to senescence and neurodegeneration. Unfortunately, functional deficits of neurodegeneration are initially well-compensated, therefore, clinical symptoms are recognized too late when the damages to the brain structures are already irreversible. Therefore, future treatment strategies in neurodegenerative disorders should focus on energy metabolism and compensation age-related NAD deficit in neurons. This review summarizes the complex interrelationships between metabolic processes on the systemic and cellular levels and provides directions on how to reduce the risk of neurodegeneration and protect the elderly against neurodegenerative diseases.
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Affiliation(s)
- Janusz Wiesław Błaszczyk
- Department of Human Motor Behavior, Jerzy Kukuczka Academy of Physical Education, 40-065 Katowice, Poland
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Mens Sana in Corpore Sano: Does the Glycemic Index Have a Role to Play? Nutrients 2020; 12:nu12102989. [PMID: 33003562 PMCID: PMC7599769 DOI: 10.3390/nu12102989] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 09/25/2020] [Accepted: 09/27/2020] [Indexed: 12/20/2022] Open
Abstract
Although diet interventions are mostly related to metabolic disorders, nowadays they are used in a wide variety of pathologies. From diabetes and obesity to cardiovascular diseases, to cancer or neurological disorders and stroke, nutritional recommendations are applied to almost all diseases. Among such disorders, metabolic disturbances and brain function and/or diseases have recently been shown to be linked. Indeed, numerous neurological functions are often associated with perturbations of whole-body energy homeostasis. In this regard, specific diets are used in various neurological conditions, such as epilepsy, stroke, or seizure recovery. In addition, Alzheimer’s disease and Autism Spectrum Disorders are also considered to be putatively improved by diet interventions. Glycemic index diets are a novel developed indicator expected to anticipate the changes in blood glucose induced by specific foods and how they can affect various physiological functions. Several results have provided indications of the efficiency of low-glycemic index diets in weight management and insulin sensitivity, but also cognitive function, epilepsy treatment, stroke, and neurodegenerative diseases. Overall, studies involving the glycemic index can provide new insights into the relationship between energy homeostasis regulation and brain function or related disorders. Therefore, in this review, we will summarize the main evidence on glycemic index involvement in brain mechanisms of energy homeostasis regulation.
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Sohn JW, Ho WK. Cellular and systemic mechanisms for glucose sensing and homeostasis. Pflugers Arch 2020; 472:1547-1561. [PMID: 32960363 DOI: 10.1007/s00424-020-02466-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 08/14/2020] [Accepted: 09/14/2020] [Indexed: 12/25/2022]
Abstract
Glucose is a major source of energy in animals. Maintaining blood glucose levels within a physiological range is important for facilitating glucose uptake by cells, as required for optimal functioning. Glucose homeostasis relies on multiple glucose-sensing cells in the body that constantly monitor blood glucose levels and respond accordingly to adjust its glycemia. These include not only pancreatic β-cells and α-cells that secrete insulin and glucagon, but also central and peripheral neurons regulating pancreatic endocrine function. Different types of cells respond distinctively to changes in blood glucose levels, and the mechanisms involved in glucose sensing are diverse. Notably, recent studies have challenged the currently held views regarding glucose-sensing mechanisms. Furthermore, peripheral and central glucose-sensing cells appear to work in concert to control blood glucose level and maintain glucose and energy homeostasis in organisms. In this review, we summarize the established concepts and recent advances in the understanding of cellular and systemic mechanisms that regulate glucose sensing and its homeostasis.
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Affiliation(s)
- Jong-Woo Sohn
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, South Korea.
| | - Won-Kyung Ho
- Department of Physiology, Seoul National University College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul, 03080, South Korea.
- Department of Brain and Cognitive Sciences, Seoul National University College of Natural Sciences, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, South Korea.
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Jensen-Cody SO, Flippo KH, Claflin KE, Yavuz Y, Sapouckey SA, Walters GC, Usachev YM, Atasoy D, Gillum MP, Potthoff MJ. FGF21 Signals to Glutamatergic Neurons in the Ventromedial Hypothalamus to Suppress Carbohydrate Intake. Cell Metab 2020; 32:273-286.e6. [PMID: 32640184 PMCID: PMC7734879 DOI: 10.1016/j.cmet.2020.06.008] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 04/02/2020] [Accepted: 06/10/2020] [Indexed: 12/20/2022]
Abstract
Fibroblast growth factor 21 (FGF21) is an endocrine hormone produced by the liver that regulates nutrient and metabolic homeostasis. FGF21 production is increased in response to macronutrient imbalance and signals to the brain to suppress sugar intake and sweet-taste preference. However, the central targets mediating these effects have been unclear. Here, we identify FGF21 target cells in the hypothalamus and reveal that FGF21 signaling to glutamatergic neurons is both necessary and sufficient to mediate FGF21-induced sugar suppression and sweet-taste preference. Moreover, we show that FGF21 acts directly in the ventromedial hypothalamus (VMH) to specifically regulate sucrose intake, but not non-nutritive sweet-taste preference, body weight, or energy expenditure. Finally, our data demonstrate that FGF21 affects neuronal activity by increasing activation and excitability of neurons in the VMH. Thus, FGF21 signaling to glutamatergic neurons in the VMH is an important component of the neurocircuitry that functions to regulate sucrose intake.
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Affiliation(s)
- Sharon O Jensen-Cody
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Kyle H Flippo
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Kristin E Claflin
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Yavuz Yavuz
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Sarah A Sapouckey
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Grant C Walters
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Yuriy M Usachev
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Deniz Atasoy
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Matthew P Gillum
- Section for Nutrient and Metabolite Sensing, the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark.
| | - Matthew J Potthoff
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Department of Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
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Kirlioglu SS, Balcioglu YH. Chronobiology Revisited in Psychiatric Disorders: From a Translational Perspective. Psychiatry Investig 2020; 17:725-743. [PMID: 32750762 PMCID: PMC7449842 DOI: 10.30773/pi.2020.0129] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 05/15/2020] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE Several lines of evidence support a relationship between circadian rhythms disruption in the onset, course, and maintenance of mental disorders. Despite the study of circadian phenotypes promising a decent understanding of the pathophysiologic or etiologic mechanisms of psychiatric entities, several questions still need to be addressed. In this review, we aimed to synthesize the literature investigating chronobiologic theories and their associations with psychiatric entities. METHODS The Medline, Embase, PsycInfo, and Scopus databases were comprehensively and systematically searched and articles published between January 1990 and October 2019 were reviewed. Different combinations of the relevant keywords were polled. We first introduced molecular elements and mechanisms of the circadian system to promote a better understanding of the chronobiologic implications of mental disorders. Then, we comprehensively and systematically reviewed circadian system studies in mood disorders, schizophrenia, and anxiety disorders. RESULTS Although subject characteristics and study designs vary across studies, current research has demonstrated that circadian pathologies, including genetic and neurohumoral alterations, represent the neural substrates of the pathophysiology of many psychiatric disorders. Impaired HPA-axis function-related glucocorticoid rhythm and disrupted melatonin homeostasis have been prominently demonstrated in schizophrenia and other psychotic disorders, while alterations of molecular expressions of circadian rhythm genes including CLOCK, PER, and CRY have been reported to be involved in the pathogenesis of mood disorders. CONCLUSION Further translational work is needed to identify the causal relationship between circadian physiology abnormalities and mental disorders and related psychopathology, and to develop sound pharmacologic interventions.
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Affiliation(s)
- Simge Seren Kirlioglu
- Department of Psychiatry, Bakirkoy Prof Mazhar Osman Training and Research Hospital for Psychiatry, Neurology and Neurosurgery, Istanbul, Turkey
| | - Yasin Hasan Balcioglu
- Department of Psychiatry, Bakirkoy Prof Mazhar Osman Training and Research Hospital for Psychiatry, Neurology and Neurosurgery, Istanbul, Turkey
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Stoelzel CR, Zhang Y, Cincotta AH. Circadian-timed dopamine agonist treatment reverses high-fat diet-induced diabetogenic shift in ventromedial hypothalamic glucose sensing. Endocrinol Diabetes Metab 2020; 3:e00139. [PMID: 32704560 PMCID: PMC7375120 DOI: 10.1002/edm2.139] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 03/28/2020] [Indexed: 12/19/2022] Open
Abstract
INTRODUCTION Within the ventromedial hypothalamus (VMH), glucose inhibitory (GI) neurons sense hypoglycaemia while glucose excitatory (GE) neurons sense hyperglycaemia to initiate counter control mechanisms under normal conditions. However, potential electrophysiological alterations of these two neuronal types in vivo in insulin-resistant states have never been simultaneously fully documented. Further, the anti-diabetic effect of dopamine agonism on this VMH system under insulin resistance has not been studied. METHODS This study examined the impact of a high-fat diet (HFD) on in vivo electrophysiological recordings from VMH GE and GI neurons and the ability of circadian-timed dopamine agonist therapy to reverse any adverse effect of the HFD on such VMH activities and peripheral glucose metabolism. RESULTS HFD significantly inhibited VMH GE neuronal electrophysiological response to local hyperglycaemia (36.3%) and augmented GI neuronal excitation response to local hypoglycaemia (47.0%). Bromocriptine (dopamine agonist) administration at onset of daily activity (but not during the daily sleep phase) completely reversed both VMH GE and GI neuronal aberrations induced by HFD. Such timed treatment also normalized glucose intolerance and insulin resistance. These VMH and peripheral glucose metabolism effects of circadian-timed bromocriptine may involve its known effect to reduce elevated VMH noradrenergic activity in insulin-resistant states as local VMH administration of norepinephrine was observed to significantly inhibit VMH GE neuronal sensing of local hyperglycaemia in insulin-sensitive animals on regular chow diet (52.4%). CONCLUSIONS HFD alters VMH glucose sensing in a manner that potentiates hyperglycaemia and this effect on the VMH can be reversed by appropriately circadian-timed dopamine agonist administration.
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Aslanpour S, Rosin JM, Balakrishnan A, Klenin N, Blot F, Gradwohl G, Schuurmans C, Kurrasch DM. Ascl1 is required to specify a subset of ventromedial hypothalamic neurons. Development 2020; 147:dev180067. [PMID: 32253239 DOI: 10.1242/dev.180067] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 03/23/2020] [Indexed: 03/01/2024]
Abstract
Despite clear physiological roles, the ventromedial hypothalamus (VMH) developmental programs are poorly understood. Here, we asked whether the proneural gene achaete-scute homolog 1 (Ascl1) contributes to VMH development. Ascl1 transcripts were detected in embryonic day (E) 10.5 to postnatal day 0 VMH neural progenitors. The elimination of Ascl1 reduced the number of VMH neurons at E12.5 and E15.5, particularly within the VMH-central (VMHC) and -dorsomedial (VMHDM) subdomains, and resulted in a VMH cell fate change from glutamatergic to GABAergic. We observed a loss of Neurog3 expression in Ascl1-/- hypothalamic progenitors and an upregulation of Neurog3 when Ascl1 was overexpressed. We also demonstrated a glutamatergic to GABAergic fate switch in Neurog3-null mutant mice, suggesting that Ascl1 might act via Neurog3 to drive VMH cell fate decisions. We also showed a concomitant increase in expression of the central GABAergic fate determinant Dlx1/2 in the Ascl1-null hypothalamus. However, Ascl1 was not sufficient to induce an ectopic VMH fate when overexpressed outside the normal window of competency. Combined, Ascl1 is required but not sufficient to specify the neurotransmitter identity of VMH neurons, acting in a transcriptional cascade with Neurog3.
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Affiliation(s)
- Shaghayegh Aslanpour
- Department of Neuroscience, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
- Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Jessica M Rosin
- Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
- Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Anjali Balakrishnan
- Sunnybrook Research Institute, Department of Biochemistry, University of Toronto, ON M4N 3M5, Canada
| | - Natalia Klenin
- Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
- Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Florence Blot
- Department of Development and Stem Cells, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM, Universite de Strasbourg, Illkirch 67400, France
| | - Gerard Gradwohl
- Department of Development and Stem Cells, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM, Universite de Strasbourg, Illkirch 67400, France
| | - Carol Schuurmans
- Sunnybrook Research Institute, Department of Biochemistry, University of Toronto, ON M4N 3M5, Canada
| | - Deborah M Kurrasch
- Department of Neuroscience, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
- Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
- Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
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Schwartsburd P. A View on Pathogenesis of ≪Vicious Cancer Progression Cycle≫. Front Oncol 2020; 10:690. [PMID: 32426290 PMCID: PMC7204907 DOI: 10.3389/fonc.2020.00690] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 04/14/2020] [Indexed: 12/19/2022] Open
Abstract
Unrestricted tumor growth requires a permanent supply of glucose that can be obtained from cancer-stimulated hepatic glucose production and/or glucose redirecting from host insulin resistant tissues to cancer cells. This study proposes a mechanism based on metabolic and hormonal changes that may provoke glucose delivery to cancer cells through two interconnected "vicious cycles" whose continuous activity drives cancer progression. As follows from the proposed here feedback model, these "vicious cycles" result from cancer-mediated manipulation of host glucose sensors. The derived conclusions contribute to a better understanding of cancer pathogenesis and identifying potential therapeutic targets.
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Affiliation(s)
- Polina Schwartsburd
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia
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Hanna L, Kawalek TJ, Beall C, Ellacott KLJ. Changes in neuronal activity across the mouse ventromedial nucleus of the hypothalamus in response to low glucose: Evaluation using an extracellular multi-electrode array approach. J Neuroendocrinol 2020; 32:e12824. [PMID: 31880369 PMCID: PMC7064989 DOI: 10.1111/jne.12824] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 12/04/2019] [Accepted: 12/23/2019] [Indexed: 01/01/2023]
Abstract
The hypothalamic ventromedial nucleus (VMN) is involved in maintaining systemic glucose homeostasis. Neurophysiological studies in rodent brain slices have identified populations of VMN glucose-sensing neurones: glucose-excited (GE) neurones, cells which increased their firing rate in response to increases in glucose concentration, and glucose-inhibited (GI) neurones, which show a reduced firing frequency in response to increasing glucose concentrations. To date, most slice electrophysiological studies characterising VMN glucose-sensing neurones in rodents have utilised the patch clamp technique. Multi-electrode arrays (MEAs) are a state-of-the-art electrophysiological tool enabling the electrical activity of many cells to be recorded across multiple electrode sites (channels) simultaneously. We used a perforated MEA (pMEA) system to evaluate electrical activity changes across the dorsal-ventral extent of the mouse VMN region in response to alterations in glucose concentration. Because intrinsic (ie, direct postsynaptic sensing) and extrinsic (ie, presynaptically modulated) glucosensation were not discriminated, we use the terminology 'GE/presynaptically excited by an increase (PER)' and 'GI/presynaptically excited by a decrease (PED)' in the present study to describe responsiveness to changes in extracellular glucose across the mouse VMN. We observed that 15%-60% of channels were GE/PER, whereas 2%-7% were GI/PED channels. Within the dorsomedial portion of the VMN (DM-VMN), significantly more channels were GE/PER compared to the ventrolateral portion of the VMN (VL-VMN). However, GE/PER channels within the VL-VMN showed a significantly higher basal firing rate in 2.5 mmol l-1 glucose than DM-VMN GE/PER channels. No significant difference in the distribution of GI/PED channels was observed between the VMN subregions. The results of the present study demonstrate the utility of the pMEA approach for evaluating glucose responsivity across the mouse VMN. pMEA studies could be used to refine our understanding of other neuroendocrine systems by examining population level changes in electrical activity across brain nuclei, thus providing key functional neuroanatomical information to complement and inform the design of single-cell neurophysiological studies.
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Affiliation(s)
- Lydia Hanna
- Reading School of PharmacyUniversity of ReadingReadingUK
- Institute of Biomedical & Clinical SciencesUniversity of Exeter Medical SchoolExeterUK
- Present address:
Department of Biological SciencesCentre for Biomedical SciencesRoyal Holloway University of LondonEghamUK
| | - Tristan J. Kawalek
- Institute of Biomedical & Clinical SciencesUniversity of Exeter Medical SchoolExeterUK
| | - Craig Beall
- Institute of Biomedical & Clinical SciencesUniversity of Exeter Medical SchoolExeterUK
| | - Kate L. J. Ellacott
- Institute of Biomedical & Clinical SciencesUniversity of Exeter Medical SchoolExeterUK
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Hirschberg PR, Sarkar P, Teegala SB, Routh VH. Ventromedial hypothalamus glucose-inhibited neurones: A role in glucose and energy homeostasis? J Neuroendocrinol 2020; 32:e12773. [PMID: 31329314 PMCID: PMC7074896 DOI: 10.1111/jne.12773] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 06/18/2019] [Accepted: 07/14/2019] [Indexed: 12/20/2022]
Abstract
The ventromedial hypothalamus (VMH) plays a complex role in glucose and energy homeostasis. The VMH is necessary for the counter-regulatory response to hypoglycaemia (CRR) that increases hepatic gluconeogenesis to restore euglycaemia. On the other hand, the VMH also restrains hepatic glucose production during euglycaemia and stimulates peripheral glucose uptake. The VMH is also important for the ability of oestrogen to increase energy expenditure. This latter function is mediated by VMH modulation of the lateral/perifornical hypothalamic area (lateral/perifornical hypothalamus) orexin neurones. Activation of VMH AMP-activated protein kinase (AMPK) is necessary for the CRR. By contrast, VMH AMPK inhibition favours decreased basal glucose levels and is required for oestrogen to increase energy expenditure. Specialised VMH glucose-sensing neurones confer the ability to sense and respond to changes in blood glucose levels. Glucose-excited (GE) neurones increase and glucose-inhibited (GI) neurones decrease their activity as glucose levels rise. VMH GI neurones, in particular, appear to be important in the CRR, although a role for GE neurones cannot be discounted. AMPK mediates glucose sensing in VMH GI neurones suggesting that, although activation of these neurones is important for the CRR, it is necessary to silence them to lower basal glucose levels and enable oestrogen to increase energy expenditure. In support of this, we found that oestrogen reduces activation of VMH GI neurones in low glucose by inhibiting AMPK. In this review, we present the evidence underlying the role of the VMH in glucose and energy homeostasis. We then discuss the role of VMH glucose-sensing neurones in mediating these effects, with a strong emphasis on oestrogenic regulation of glucose sensing and how this may affect glucose and energy homeostasis.
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Affiliation(s)
- Pamela R Hirschberg
- Department of Pharmacology, Physiology and Neurosciences, Rutgers New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
| | - Pallabi Sarkar
- Department of Pharmacology, Physiology and Neurosciences, Rutgers New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
| | - Suraj B Teegala
- Department of Pharmacology, Physiology and Neurosciences, Rutgers New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
| | - Vanessa H Routh
- Department of Pharmacology, Physiology and Neurosciences, Rutgers New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
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Yeh SHH, Shie FS, Liu HK, Yao HH, Kao PC, Lee YH, Chen LM, Hsu SM, Chao LJ, Wu KW, Shiao YJ, Tsay HJ. A high-sucrose diet aggravates Alzheimer's disease pathology, attenuates hypothalamic leptin signaling, and impairs food-anticipatory activity in APPswe/PS1dE9 mice. Neurobiol Aging 2019; 90:60-74. [PMID: 31879131 DOI: 10.1016/j.neurobiolaging.2019.11.018] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 11/19/2019] [Accepted: 11/22/2019] [Indexed: 12/14/2022]
Abstract
High-fat and high-sugar diets contribute to the prevalence of type 2 diabetes and Alzheimer's disease (AD). Although the impact of high-fat diets on AD pathogenesis has been established, the effect of high-sucrose diets (HSDs) on AD pathogenesis remains unclear. This study sought to determine the impact of HSDs on AD-related pathologies. Male APPswe/PS1dE9 (APP/PS1) transgenic and wild-type mice were provided with HSD and their cognitive and hypothalamus-related noncognitive parameters, including feeding behaviors and glycemic regulation, were compared. HSD-fed APP/PS1 mice showed increased neuroinflammation, as well as increased cortical and serum levels of amyloid-β. HSD-fed APP/PS1 mice showed aggravated obesity, hyperinsulinemia, insulin resistance, and leptin resistance, but there was no induction of hyperphagia or hyperleptinemia. Leptin-induced phosphorylation of signal transducer and activator of transcription 3 in the dorsomedial and ventromedial hypothalamus was reduced in HSD-fed APP/PS1 mice, which might be associated with attenuated food-anticipatory activity, glycemic dysregulation, and AD-related noncognitive symptoms. Our study demonstrates that HSD aggravates metabolic stresses, increases AD-related pathologies, and attenuates hypothalamic leptin signaling in APP/PS1 mice.
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Affiliation(s)
| | - Feng-Shiun Shie
- Center for Neuropsychiatric Research, National Health Research Institutes, Taiwan, Miaoli, Taiwan, R.O.C
| | - Hui-Kang Liu
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan; Ph.D. Program in Clinical Drug Development of Chinese Herbal Medicine, Taipei Medical University, Taipei, Taiwan, R.O.C
| | - Heng-Hsiang Yao
- Institute of Neuroscience, School of Life Science, National Yang-Ming University, Taipei, Taiwan, R.O.C
| | - Pei-Chen Kao
- Center for Neuropsychiatric Research, National Health Research Institutes, Taiwan, Miaoli, Taiwan, R.O.C
| | - Yi-Heng Lee
- Institute of Neuroscience, School of Life Science, National Yang-Ming University, Taipei, Taiwan, R.O.C.; Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Yang-Ming University and Academia Sinica, Taipei, Taiwan, R.O.C
| | - Li-Min Chen
- Institute of Neuroscience, School of Life Science, National Yang-Ming University, Taipei, Taiwan, R.O.C
| | - Shu-Meng Hsu
- Center for Neuropsychiatric Research, National Health Research Institutes, Taiwan, Miaoli, Taiwan, R.O.C.; Institute of Neuroscience, School of Life Science, National Yang-Ming University, Taipei, Taiwan, R.O.C
| | - Li-Jung Chao
- Brain Research Center, National Yang-Ming University, Taipei, Taiwan, R.O.C
| | - Kuan-Wei Wu
- Institute of Biopharmaceutical Science, National Yang-Ming University, Taipei, Taiwan, R.O.C
| | - Young-Ji Shiao
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan; Ph.D. Program in Clinical Drug Development of Chinese Herbal Medicine, Taipei Medical University, Taipei, Taiwan, R.O.C.; Institute of Biopharmaceutical Science, National Yang-Ming University, Taipei, Taiwan, R.O.C..
| | - Huey-Jen Tsay
- Institute of Neuroscience, School of Life Science, National Yang-Ming University, Taipei, Taiwan, R.O.C..
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Effects of Feeding-Related Peptides on Neuronal Oscillation in the Ventromedial Hypothalamus. J Clin Med 2019; 8:jcm8030292. [PMID: 30832213 PMCID: PMC6463148 DOI: 10.3390/jcm8030292] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 02/23/2019] [Accepted: 02/27/2019] [Indexed: 11/18/2022] Open
Abstract
The ventromedial hypothalamus (VMH) plays an important role in feeding behavior, obesity, and thermoregulation. The VMH contains glucose-sensing neurons, the firing of which depends on the level of extracellular glucose and which are involved in maintaining the blood glucose level via the sympathetic nervous system. The VMH also expresses various receptors of the peptides related to feeding. However, it is not well-understood whether the action of feeding-related peptides mediates the activity of glucose-sensing neurons in the VMH. In the present study, we examined the effects of feeding-related peptides on the burst-generating property of the VMH. Superfusion with insulin, pituitary adenylate cyclase-activating polypeptide, corticotropin-releasing factor, and orexin increased the frequency of the VMH oscillation. In contrast, superfusion with leptin, cholecystokinin, cocaine- and amphetamine-regulated transcript, galanin, ghrelin, and neuropeptide Y decreased the frequency of the oscillation. Our findings indicated that the frequency changes of VMH oscillation in response to the application of feeding-related peptides showed a tendency similar to changes of sympathetic nerve activity in response to the application of these substances to the brain.
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Buijs RM, Guzmán Ruiz MA, Méndez Hernández R, Rodríguez Cortés B. The suprachiasmatic nucleus; a responsive clock regulating homeostasis by daily changing the setpoints of physiological parameters. Auton Neurosci 2019; 218:43-50. [PMID: 30890347 DOI: 10.1016/j.autneu.2019.02.001] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 02/05/2019] [Accepted: 02/06/2019] [Indexed: 12/13/2022]
Abstract
The suprachiasmatic nucleus (SCN) is responsible for determining circadian variations in physiological setpoints. The SCN achieves such control through projections to different target structures within and outside the hypothalamus. Thus the SCN prepares the physiology of the body every 24 h via hormones and autonomic nervous system (ANS), to coming changes in behavior. Resulting rhythms in hormones and ANS activity transmit a precise message to selective organs, adapting their sensitivity to coming hormones, metabolites or other essentials. Thus the SCN as autonomous clock gives rhythm to physiological processes. However when the body is challenged by infections, low or high temperature, food shortage or excess: physiological setpoints need to be changed. For example, under fasting conditions, setpoints for body temperature and glucose levels are lowered at the beginning of the sleep (inactive) phase. However, starting the active phase, a normal increase in glucose and temperature levels take place to support activities associated with the acquisition of food. Thus, the SCN adjusts physiological setpoints in agreement with time of the day and according to challenges faced by the body. The SCN is enabled to do this by receiving extensive input from brain areas involved in sensing the condition of the body. Therefore, when the body receives stimuli contradicting normal physiology, such as eating or activity during the inactive period, this information reaches the SCN, adapting its output to correct this disbalance. As consequence frequent violations of the SCN message, such as by shift work or night eating, will result in development of disease.
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Affiliation(s)
- Ruud M Buijs
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, PC 04510 Mexico D.F., Mexico.
| | - Mara A Guzmán Ruiz
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, PC 04510 Mexico D.F., Mexico
| | - Rebeca Méndez Hernández
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, PC 04510 Mexico D.F., Mexico
| | - Betty Rodríguez Cortés
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, PC 04510 Mexico D.F., Mexico
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