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Leon-Mercado L, Menendez-Montes I, Tao J, Chen B, Olson DP, Mackaaij C, Cleypool CGJ, Gautron L. Hypoxia inducible factor-dependent upregulation of Agrp in glomus type I cells of the carotid body. Mol Metab 2025; 92:102095. [PMID: 39793758 PMCID: PMC11786784 DOI: 10.1016/j.molmet.2025.102095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 12/11/2024] [Accepted: 01/03/2025] [Indexed: 01/13/2025] Open
Abstract
Agouti-related peptide (AgRP) is a well-established potent orexigenic peptide primarily expressed in hypothalamic neurons. Nevertheless, the expression and functional significance of extrahypothalamic AgRP remain poorly understood. In this study, utilizing histological and molecular biology techniques, we have identified a significant expression of Agrp mRNA and AgRP peptide production in glomus type I cells within the mouse carotid body (CB). Furthermore, we have uncovered evidence supporting the expression of the AgRP receptor melanocortin receptor 3 (Mc3r) in adjacent sympathetic neurons, suggesting a potential local paracrine role for AgRP within the CB. Importantly, AgRP immunoreactivity was also identified in glomus type I cells of the human CB. Given the unexpected abundance of AgRP in glomus type I cells, a chemoreceptor cell specialized in oxygen sensing, we proceeded to investigate whether Agrp expression in the CB is regulated by hypoxemia and associated oxygen-sensing molecular mechanisms. In vitro luciferase assays reveal that hypoxia stimulates the human and mouse Agrp promoters in a Hypoxia Inducible Factor (HIF1/2)-dependent manner. Our in vivo experiments further demonstrate that exposure to environmental hypoxia (10%) robustly induces Agrp expression in type I glomus cells of mice. Furthermore, these findings collectively highlight the hitherto unknown source of AgRP in murine and human type I glomus cells and underscore the direct control of Agrp transcription by HIF signaling.
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Affiliation(s)
- Luis Leon-Mercado
- Center for Hypothalamic Research and Department of Internal medicine, UT Southwestern Medical Center, Dallas, TX, USA
| | - Ivan Menendez-Montes
- Division of Cardiology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
| | - Jonathan Tao
- Center for Hypothalamic Research and Department of Internal medicine, UT Southwestern Medical Center, Dallas, TX, USA
| | - Bandy Chen
- Center for Hypothalamic Research and Department of Internal medicine, UT Southwestern Medical Center, Dallas, TX, USA
| | - David P Olson
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - C Mackaaij
- Division of Surgical Specialties, Department of Anatomy, University Medical Center, Utrecht, the Netherlands
| | - C G J Cleypool
- Division of Surgical Specialties, Department of Anatomy, University Medical Center, Utrecht, the Netherlands
| | - Laurent Gautron
- Center for Hypothalamic Research and Department of Internal medicine, UT Southwestern Medical Center, Dallas, TX, USA.
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2
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Valladolid-Acebes I. Hippocampal Leptin Resistance and Cognitive Decline: Mechanisms, Therapeutic Strategies and Clinical Implications. Biomedicines 2024; 12:2422. [PMID: 39594988 PMCID: PMC11591892 DOI: 10.3390/biomedicines12112422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 10/17/2024] [Accepted: 10/17/2024] [Indexed: 11/28/2024] Open
Abstract
Background: Leptin, an adipokine essential for regulating energy balance, exerts important effects on brain function, notably within the hippocampus, a region integral to learning and memory. Leptin resistance, characterized by diminished responsiveness to elevated leptin levels, disrupts hippocampal function and exacerbates both obesity and cognitive impairments. Scope: This review critically examines how leptin resistance impairs hippocampal synaptic plasticity processes, specifically affecting long-term potentiation (LTP) and long-term depression (LTD), which are crucial for cognitive performance. Findings: Recent research highlights that leptin resistance disrupts N-methyl-D-aspartate (NMDA) receptor dynamics and hippocampal structure, leading to deficits in spatial learning and memory. Additionally, high-fat diets (HFDs), which contribute to leptin resistance, further deteriorate hippocampal function. Potential therapeutic strategies, including leptin sensitizers, show promise in mitigating brain disorders associated with leptin resistance. Complementary interventions such as caloric restriction and physical exercise also enhance leptin sensitivity and offer potential benefits to alleviating cognitive impairments. Aims of the review: This review synthesizes recent findings on the molecular pathways underlying leptin resistance and its impact on synaptic transmission and plasticity in the hippocampus. By identifying potential therapeutic targets, this work aims to provide an integrated approach for addressing cognitive deficits in obesity, ultimately improving the quality of life for affected individuals.
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Affiliation(s)
- Ismael Valladolid-Acebes
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden
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3
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Jin H, Yao L, Wang S, Xia P, Hou T, Li B, Li J. Effects of KGM and Degradation Products on Appetite Regulation and Energy Expenditure in High-Fat-Diet Mice via the Adipocyte-Hypothalamus Axis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:15765-15777. [PMID: 38970495 DOI: 10.1021/acs.jafc.4c03819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/08/2024]
Abstract
Konjac glucomannan (KGM), high-viscosity dietary fiber, is utilized in weight management. Previous investigations on the appetite-suppressing effects of KGM have centered on intestinal responses to nutrients and gastric emptying rates, with less focus on downstream hypothalamic neurons of satiety hormones. In our studies, the molecular mechanisms through which KGM and its degradation products influence energy homeostasis via the adipocyte-hypothalamic axis have been examined. It was found that high-viscosity KGM more effectively stimulates enteroendocrine cells to release glucagon-like peptide-1 (GLP-1) and reduces ghrelin production, thereby activating hypothalamic neurons and moderating short-term satiety. Conversely, low-viscosity DKGM has been shown to exhibit stronger anti-inflammatory properties in the hypothalamus, enhancing hormone sensitivity and lowering the satiety threshold. Notably, both KGM and DKGM significantly reduced leptin signaling and fatty acid signaling in adipose tissue and activated brown adipose tissue thermogenesis to suppress pro-opiomelanocortin (POMC) expression and activate agouti-related protein (AgRP) expression, thereby reducing food intake and increasing energy expenditure. Additionally, high-viscosity KGM has been found to activate the adipocyte-hypothalamus axis more effectively than DKGM, thereby promoting greater daily energy expenditure. These findings provide novel insights into the adipocyte-hypothalamic axis for KGM to suppress appetite and reduce weight.
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Affiliation(s)
- Hong Jin
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- Key Laboratory of Environment Correlative Dietology, Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
| | - Lanlan Yao
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- Key Laboratory of Environment Correlative Dietology, Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
| | - Shenwan Wang
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- Key Laboratory of Environment Correlative Dietology, Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
| | - Pengkui Xia
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- Key Laboratory of Environment Correlative Dietology, Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
| | - Tao Hou
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- Key Laboratory of Environment Correlative Dietology, Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
| | - Bin Li
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- Key Laboratory of Environment Correlative Dietology, Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
| | - Jing Li
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- Key Laboratory of Environment Correlative Dietology, Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
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Pena-Leon V, Perez-Lois R, Villalon M, Prida E, Muñoz-Moreno D, Fernø J, Quiñones M, Al-Massadi O, Seoane LM. Novel mechanisms involved in leptin sensitization in obesity. Biochem Pharmacol 2024; 223:116129. [PMID: 38490517 DOI: 10.1016/j.bcp.2024.116129] [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: 11/16/2023] [Revised: 01/21/2024] [Accepted: 03/12/2024] [Indexed: 03/17/2024]
Abstract
Leptin is a hormone that is secreted by adipocytes in proportion to adipose tissue size, and that informs the brain about the energy status of the body. Leptin acts through its receptor LepRb, expressed mainly in the hypothalamus, and induces a negative energy balance by potent inhibition of feeding and activation of energy expenditure. These actions have led to huge expectations for the development of therapeutic targets for metabolic complications based on leptin-derived compounds. However, the majority of patients with obesity presents elevated leptin production, suggesting that in this setting leptin is ineffective in the regulation of energy balance. This resistance to the action of leptin in obesity has led to the development of "leptin sensitizers," which have been tested in preclinical studies. Much research has focused on generating combined treatments that act on multiple levels of the gastrointestinal-brain axis. The gastrointestinal-brain axis secretes a variety of different anorexigenic signals, such as uroguanylin, glucagon-like peptide-1, amylin, or cholecystokinin, which can alleviate the resistance to leptin action. Moreover, alternative mechanism such as pharmacokinetics, proteostasis, the role of specific kinases, chaperones, ER stress and neonatal feeding modifications are also implicated in leptin resistance. This review will cover the current knowledge regarding the interaction of leptin with different endocrine factors from the gastrointestinal-brain axis and other novel mechanisms that improve leptin sensitivity in obesity.
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Affiliation(s)
- Veronica Pena-Leon
- Grupo Fisiopatología Endocrina, Departamento de Endocrinología, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Raquel Perez-Lois
- Grupo Fisiopatología Endocrina, Departamento de Endocrinología, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Maria Villalon
- Grupo Fisiopatología Endocrina, Departamento de Endocrinología, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Eva Prida
- Translational Endocrinology group, Endocrinology Section, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (IDIS/CHUS), Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Diego Muñoz-Moreno
- Translational Endocrinology group, Endocrinology Section, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (IDIS/CHUS), Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Johan Fernø
- Hormone Laboratory, Department of Biochemistry and Pharmacology, Haukeland University Hospital, 5201 Bergen, Norway
| | - Mar Quiñones
- Grupo Fisiopatología Endocrina, Departamento de Endocrinología, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain; CIBER de Fisiopatología de la Obesidad y la Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Omar Al-Massadi
- Translational Endocrinology group, Endocrinology Section, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (IDIS/CHUS), Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain; CIBER de Fisiopatología de la Obesidad y la Nutrición, Instituto de Salud Carlos III, Madrid, Spain.
| | - Luisa M Seoane
- Grupo Fisiopatología Endocrina, Departamento de Endocrinología, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain; CIBER de Fisiopatología de la Obesidad y la Nutrición, Instituto de Salud Carlos III, Madrid, Spain.
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5
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Ousey J, Boktor JC, Mazmanian SK. Gut microbiota suppress feeding induced by palatable foods. Curr Biol 2023; 33:147-157.e7. [PMID: 36450285 PMCID: PMC9839363 DOI: 10.1016/j.cub.2022.10.066] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 08/30/2022] [Accepted: 10/28/2022] [Indexed: 12/03/2022]
Abstract
Feeding behaviors depend on intrinsic and extrinsic factors including genetics, food palatability, and the environment.1,2,3,4,5 The gut microbiota is a major environmental contributor to host physiology and impacts feeding behavior.6,7,8,9,10,11,12 Here, we explored the hypothesis that gut bacteria influence behavioral responses to palatable foods and reveal that antibiotic depletion (ABX) of the gut microbiota in mice results in overconsumption of several palatable foods with conserved effects on feeding dynamics. Gut microbiota restoration via fecal transplant into ABX mice is sufficient to rescue overconsumption of high-sucrose pellets. Operant conditioning tests found that ABX mice exhibit intensified motivation to pursue high-sucrose rewards. Accordingly, neuronal activity in mesolimbic brain regions, which have been linked with motivation and reward-seeking behavior,3 was elevated in ABX mice after consumption of high-sucrose pellets. Differential antibiotic treatment and functional microbiota transplants identified specific gut bacterial taxa from the family S24-7 and the genus Lactobacillus whose abundances associate with suppression of high-sucrose pellet consumption. Indeed, colonization of mice with S24-7 and Lactobacillus johnsonii was sufficient to reduce overconsumption of high-sucrose pellets in an antibiotic-induced model of binge eating. These results demonstrate that extrinsic influences from the gut microbiota can suppress the behavioral response toward palatable foods in mice.
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Affiliation(s)
- James Ousey
- Division of Biology and Biological Engineering, California Institute of Technology, 1200 E California Blvd, Pasadena, CA 91125, USA.
| | - Joseph C Boktor
- Division of Biology and Biological Engineering, California Institute of Technology, 1200 E California Blvd, Pasadena, CA 91125, USA
| | - Sarkis K Mazmanian
- Division of Biology and Biological Engineering, California Institute of Technology, 1200 E California Blvd, Pasadena, CA 91125, USA.
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6
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Gupta R, Wang M, Ma Y, Offermanns S, Whim MD. The β-Hydroxybutyrate-GPR109A Receptor Regulates Fasting-induced Plasticity in the Mouse Adrenal Medulla. Endocrinology 2022; 163:6590010. [PMID: 35595517 PMCID: PMC9188660 DOI: 10.1210/endocr/bqac077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Indexed: 11/19/2022]
Abstract
During fasting, increased sympathoadrenal activity leads to epinephrine release and multiple forms of plasticity within the adrenal medulla including an increase in the strength of the preganglionic → chromaffin cell synapse and elevated levels of agouti-related peptide (AgRP), a peptidergic cotransmitter in chromaffin cells. Although these changes contribute to the sympathetic response, how fasting evokes this plasticity is not known. Here we report these effects involve activation of GPR109A (HCAR2). The endogenous agonist of this G protein-coupled receptor is β-hydroxybutyrate, a ketone body whose levels rise during fasting. In wild-type animals, 24-hour fasting increased AgRP-ir in adrenal chromaffin cells but this effect was absent in GPR109A knockout mice. GPR109A agonists increased AgRP-ir in isolated chromaffin cells through a GPR109A- and pertussis toxin-sensitive pathway. Incubation of adrenal slices in nicotinic acid, a GPR109A agonist, mimicked the fasting-induced increase in the strength of the preganglionic → chromaffin cell synapse. Finally, reverse transcription polymerase chain reaction experiments confirmed the mouse adrenal medulla contains GPR109A messenger RNA. These results are consistent with the activation of a GPR109A signaling pathway located within the adrenal gland. Because fasting evokes epinephrine release, which stimulates lipolysis and the production of β-hydroxybutyrate, our results indicate that chromaffin cells are components of an autonomic-adipose-hepatic feedback circuit. Coupling a change in adrenal physiology to a metabolite whose levels rise during fasting is presumably an efficient way to coordinate the homeostatic response to food deprivation.
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Affiliation(s)
- Rajesh Gupta
- Department of Cell Biology & Anatomy, LSU Health Sciences Center, New Orleans, Louisiana 70112, USA
| | - Manqi Wang
- Department of Cell Biology & Anatomy, LSU Health Sciences Center, New Orleans, Louisiana 70112, USA
| | - Yunbing Ma
- Department of Cell Biology & Anatomy, LSU Health Sciences Center, New Orleans, Louisiana 70112, USA
| | - Stefan Offermanns
- Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
| | - Matthew D Whim
- Correspondence: Matthew D. Whim, PhD, Department of Cell Biology and Anatomy, LSU Health Sciences Center, Medical Education Bldg (MEB 6142), 1901 Perdido St, New Orleans, LA 70112, USA.
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7
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Oliveira LDC, Morais GP, Ropelle ER, de Moura LP, Cintra DE, Pauli JR, de Freitas EC, Rorato R, da Silva ASR. Using Intermittent Fasting as a Non-pharmacological Strategy to Alleviate Obesity-Induced Hypothalamic Molecular Pathway Disruption. Front Nutr 2022; 9:858320. [PMID: 35445066 PMCID: PMC9014844 DOI: 10.3389/fnut.2022.858320] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 02/25/2022] [Indexed: 12/18/2022] Open
Abstract
Intermittent fasting (IF) is a popular intervention used to fight overweight/obesity. This condition is accompanied by hypothalamic inflammation, limiting the proper signaling of molecular pathways, with consequent dysregulation of food intake and energy homeostasis. This mini-review explored the therapeutic modulation potential of IF regarding the disruption of these molecular pathways. IF seems to modulate inflammatory pathways in the brain, which may also be correlated with the brain-microbiota axis, improving hypothalamic signaling of leptin and insulin, and inducing the autophagic pathway in hypothalamic neurons, contributing to weight loss in obesity. Evidence also suggests that when an IF protocol is performed without respecting the circadian cycle, it can lead to dysregulation in the expression of circadian cycle regulatory genes, with potential health damage. In conclusion, IF may have the potential to be an adjuvant treatment to improve the reestablishment of hypothalamic responses in obesity.
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Affiliation(s)
- Luciana da Costa Oliveira
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Gustavo Paroschi Morais
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Eduardo R. Ropelle
- Laboratory of Molecular Biology of Exercise, School of Applied Sciences, University of Campinas, São Paulo, Brazil
| | - Leandro P. de Moura
- Laboratory of Molecular Biology of Exercise, School of Applied Sciences, University of Campinas, São Paulo, Brazil
| | - Dennys E. Cintra
- Laboratory of Molecular Biology of Exercise, School of Applied Sciences, University of Campinas, São Paulo, Brazil
| | - José R. Pauli
- Laboratory of Molecular Biology of Exercise, School of Applied Sciences, University of Campinas, São Paulo, Brazil
| | - Ellen C. de Freitas
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Rodrigo Rorato
- Postgraduate Program in Molecular Biology, Laboratory of Stress Neuroendocrinology, Department of Biophysics, Paulista Medical School, Federal University of São Paulo, São Paulo, Brazil
- Rodrigo Rorato,
| | - Adelino Sanchez R. da Silva
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
- *Correspondence: Adelino Sanchez R. da Silva,
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McClung JA, Levy L, Garcia V, Stec DE, Peterson SJ, Abraham NG. Heme-oxygenase and lipid mediators in obesity and associated cardiometabolic diseases: Therapeutic implications. Pharmacol Ther 2021; 231:107975. [PMID: 34499923 DOI: 10.1016/j.pharmthera.2021.107975] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 07/08/2021] [Accepted: 07/27/2021] [Indexed: 02/08/2023]
Abstract
Obesity-mediated metabolic syndrome remains the leading cause of death worldwide. Among many potential targets for pharmacological intervention, a promising strategy involves the heme oxygenase (HO) system, specifically its inducible form, HO-1. This review collects and updates much of the current knowledge relevant to pharmacology and clinical medicine concerning HO-1 in metabolic diseases and its effect on lipid metabolism. HO-1 has pleotropic effects that collectively reduce inflammation, while increasing vasodilation and insulin and leptin sensitivity. Recent reports indicate that HO-1 with its antioxidants via the effect of bilirubin increases formation of biologically active lipid metabolites such as epoxyeicosatrienoic acid (EET), omega-3 and other polyunsaturated fatty acids (PUFAs). Similarly, HO-1and bilirubin are potential therapeutic targets in the treatment of fat-induced liver diseases. HO-1-mediated upregulation of EET is capable not only of reversing endothelial dysfunction and hypertension, but also of reversing cardiac remodeling, a hallmark of the metabolic syndrome. This process involves browning of white fat tissue (i.e. formation of healthy adipocytes) and reduced lipotoxicity, which otherwise will be toxic to the heart. More importantly, this review examines the activity of EET in biological systems and a series of pathways that explain its mechanism of action and discusses how these might be exploited for potential therapeutic use. We also discuss the link between cardiac ectopic fat deposition and cardiac function in humans, which is similar to that described in obese mice and is regulated by HO-1-EET-PGC1α signaling, a potent negative regulator of the inflammatory adipokine NOV.
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Affiliation(s)
- John A McClung
- Department of Medicine, New York Medical College, Valhalla, NY 10595, United States of America
| | - Lior Levy
- Department of Medicine, New York Medical College, Valhalla, NY 10595, United States of America
| | - Victor Garcia
- Department of Pharmacology, New York Medical College, Valhalla, NY 10595, United States of America
| | - David E Stec
- Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, United States of America.
| | - Stephen J Peterson
- Department of Medicine, Weill Cornell Medicine, New York, NY 10065, United States of America; New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY 11215, United States of America
| | - Nader G Abraham
- Department of Medicine, New York Medical College, Valhalla, NY 10595, United States of America; Department of Pharmacology, New York Medical College, Valhalla, NY 10595, United States of America.
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Hypothalamic regulation of energy homoeostasis when consuming diets of different energy concentrations: comparison between Tibetan and Small-tailed Han sheep. Br J Nutr 2021; 127:1132-1142. [PMID: 34085612 DOI: 10.1017/s0007114521001902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Seasonal energy intake of Tibetan sheep on the harsh Qinghai-Tibetan Plateau (QTP) fluctuates greatly and is often well below maintenance requirements. The aim of this study was to gain insight into how the hypothalamus regulates energy homoeostasis in Tibetan sheep. We compared Tibetan and Small-tailed Han sheep (n 24 of each breed), which were each allocated randomly into four groups and offered one of four diets that differed in digestible energy densities: 8·21, 9·33, 10·45 and 11·57 MJ/kg DM. Sheep were weighed every 2 weeks, and it was assumed that the change in body weight (BW) reflected the change in energy balance. The arcuate nucleus of the hypothalamus in Tibetan sheep had greater protein expressions of neuropeptide Y (NPY) and agouti-related peptide (AgRP) when in negative energy balance, but lesser protein expressions of proopiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) when in positive energy balance than Small-tailed Han sheep. As a result, Tibetan sheep had a lesser BW loss when in negative energy balance and stored more energy and gained more BW when in positive energy balance than Small-tailed Han sheep with the same dietary intake. Moreover, in the hypothalamic adenosine monophosphate-activated protein kinase (AMPK) regulation pathway, Tibetan sheep had greater adenosine monophosphate-activated protein kinase-α 2 protein expression than Small-tailed Han sheep, which supported the premise of a better ability to regulate energy homoeostasis and better growth performance. These differences in the hypothalamic NPY/AgRP, POMC/CART and AMPK pathways between breeds conferred an advantage to the Tibetan over Small-tailed Han sheep to cope with low energy intake on the harsh QTP.
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10
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Deal CK, Volkoff H. Response of the thyroid axis and appetite-regulating peptides to fasting and overfeeding in goldfish (Carassius auratus). Mol Cell Endocrinol 2021; 528:111229. [PMID: 33662475 DOI: 10.1016/j.mce.2021.111229] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 02/24/2021] [Accepted: 02/26/2021] [Indexed: 12/14/2022]
Abstract
The thyroid axis is a major regulator of metabolism and energy homeostasis in vertebrates. There is conclusive evidence in mammals for the involvement of the thyroid axis in the regulation of food intake, but in fish, this link is unclear. In order to assess the effects of nutritional status on the thyroid axis in goldfish, Carassius auratus, we examined brain and peripheral transcripts of genes associated with the thyroid axis [thyrotropin-releasing hormone (TRH), thyrotropin-releasing hormone receptors (TRH-R type 1 and 2), thyroid stimulating hormone beta (TSHβ), deiodinase enzymes (DIO2, DIO3) and UDP-glucoronsyltransferase (UGT)] and appetite regulators [neuropeptide Y (NPY), proopiomelanocortin (POMC), agouti-related peptide (AgRP) and cholecystokinin (CCK)] in fasted and overfed fish for 7 and 14 day periods. We show that the thyroid axis responds to overfeeding, with an increase of brain TRH and TSHβ mRNA expression after 14 days, suggesting that overfeeding might activate the thyroid axis. In fasted fish, hepatic DIO3 and UGT transcripts were downregulated from 7 to 14 days, suggesting a time-dependent inhibition of thyroid hormone degradation pathways. Nutritional status had no effect on circulating levels of thyroid hormone. Central appetite-regulating peptides exhibited temporal changes in mRNA expression, with decreased expression of the appetite-inhibiting peptide POMC from 7 to 14 days for both fasted and overfed fish, with no change in central NPY or AgRP, or intestinal CCK transcript expression. Compared to control fish, fasting increased AgRP mRNA expression at both 7 and 14 days, and POMC expression was higher than controls only at 7 days. Our results indicate that nutritional status time-dependently affects the thyroid axis and appetite regulators, although no clear correlation between thyroid physiology and appetite regulators could be established. Our study helps to fill a knowledge gap in current fish endocrinological research on the effects of energy balance on thyroid metabolism and function.
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Affiliation(s)
- Cole K Deal
- Departments of Biology, Memorial University of Newfoundland, St. John's, NL, A1B 3X9, Canada
| | - Helene Volkoff
- Departments of Biology, Memorial University of Newfoundland, St. John's, NL, A1B 3X9, Canada; Departments of Biochemistry, Memorial University of Newfoundland, St. John's, NL, A1B 3X9, Canada.
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Liu H, Du T, Li C, Yang G. STAT3 phosphorylation in central leptin resistance. Nutr Metab (Lond) 2021; 18:39. [PMID: 33849593 PMCID: PMC8045279 DOI: 10.1186/s12986-021-00569-w] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 04/03/2021] [Indexed: 12/20/2022] Open
Abstract
Mechanism exploitation of energy homeostasis is urgently required because of the worldwide prevailing of obesity-related metabolic disorders in human being. Although it is well known that leptin plays a central role in regulating energy balance by suppressing food intake and promoting energy expenditure, the existence of leptin resistance in majority of obese individuals hampers the utilization of leptin therapy against these disorders. However, the mechanism of leptin resistance is largely unknown in spite of the globally enormous endeavors. Current theories to interpret leptin resistance include the impairment of leptin transport, attenuation of leptin signaling, chronic inflammation, ER tress, deficiency of autophagy, as well as leptin itself. Leptin-activated leptin receptor (LepRb) signals in hypothalamus via several pathways, in which JAK2-STAT3 pathway, the most extensively investigated one, is considered to mediate the major action of leptin in energy regulation. Upon leptin stimulation the phosphorylation of STAT3 is one of the key events in JAK2-STAT3 pathway, followed by the dimerization and nuclear translocation of this molecule. Phosphorylated STAT3 (p-STAT3), as a transcription factor, binds to and regulates its target gene such as POMC gene, playing the physiological function of leptin. Regarding POMC gene in hypothalamus however little is known about the detail of its interaction with STAT3. Moreover the status of p-STAT3 and its significance in hypothalamus of DIO mice needs to be well elucidated. This review comprehends literatures on leptin and leptin resistance and especially discusses what STAT3 phosphorylation would contribute to central leptin resistance.
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Affiliation(s)
- Huimin Liu
- College of Life Science, Henan Agricultural University, 95 Wen Hua Road, Zhengzhou, 450002, China
| | - Tianxin Du
- College of Life Science, Henan Agricultural University, 95 Wen Hua Road, Zhengzhou, 450002, China
| | - Chen Li
- College of Life Science, Henan Agricultural University, 95 Wen Hua Road, Zhengzhou, 450002, China
| | - Guoqing Yang
- College of Life Science, Henan Agricultural University, 95 Wen Hua Road, Zhengzhou, 450002, China.
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12
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Neuroendocrine control of appetite and metabolism. Exp Mol Med 2021; 53:505-516. [PMID: 33837263 PMCID: PMC8102538 DOI: 10.1038/s12276-021-00597-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 02/11/2021] [Accepted: 02/17/2021] [Indexed: 02/02/2023] Open
Abstract
Body homeostasis is predominantly controlled by hormones secreted by endocrine organs. The central nervous system contains several important endocrine structures, including the hypothalamic-pituitary axis. Conventionally, neurohormones released by the hypothalamus and the pituitary gland (hypophysis) have received much attention owing to the unique functions of the end hormones released by their target peripheral organs (e.g., glucocorticoids released by the adrenal glands). Recent advances in mouse genetics have revealed several important metabolic functions of hypothalamic neurohormone-expressing cells, many of which are not readily explained by the action of the corresponding classical downstream hormones. Notably, the newly identified functions are better explained by the action of conventional neurotransmitters (e.g., glutamate and GABA) that constitute a neuronal circuit. In this review, we discuss the regulation of appetite and metabolism by hypothalamic neurohormone-expressing cells, with a focus on the distinct contributions of neurohormones and neurotransmitters released by these neurons.
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13
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Yang Y, Xu Y. The central melanocortin system and human obesity. J Mol Cell Biol 2020; 12:785-797. [PMID: 32976556 PMCID: PMC7816681 DOI: 10.1093/jmcb/mjaa048] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/04/2020] [Accepted: 08/14/2020] [Indexed: 12/13/2022] Open
Abstract
The prevalence of obesity and the associated comorbidities highlight the importance of understanding the regulation of energy homeostasis. The central melanocortin system plays a critical role in controlling body weight balance. Melanocortin neurons sense and integrate the neuronal and hormonal signals, and then send regulatory projections, releasing anorexigenic or orexigenic melanocortin neuropeptides, to downstream neurons to regulate the food intake and energy expenditure. This review summarizes the latest progress in our understanding of the role of the melanocortin pathway in energy homeostasis. We also review the advances in the identification of human genetic variants that cause obesity via mechanisms that affect the central melanocortin system, which have provided rational targets for treatment of genetically susceptible patients.
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Affiliation(s)
- Yongjie Yang
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - Yong Xu
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.,Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
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14
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Cardoso RC, West SM, Maia TS, Alves BRC, Williams GL. Nutritional control of puberty in the bovine female: prenatal and early postnatal regulation of the neuroendocrine system. Domest Anim Endocrinol 2020; 73:106434. [PMID: 32115309 DOI: 10.1016/j.domaniend.2020.106434] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 01/02/2020] [Accepted: 01/03/2020] [Indexed: 01/25/2023]
Abstract
Puberty is a complex biological event that requires maturation of the reproductive neuroendocrine axis and subsequent initiation of high-frequency, episodic release of GnRH and LH. Nutrition is a critical factor affecting the neuroendocrine control of puberty. Although nutrient restriction during juvenile development delays puberty, elevated rates of body weight gain during this period facilitate pubertal maturation by programming hypothalamic centers that underlie the pubertal process. Recent findings suggest that maternal nutrition during gestation can also modulate the development of the fetal neuroendocrine axis, thus influencing puberty and subsequent reproductive function. Among the several metabolic signals, leptin plays a critical role in conveying metabolic information to the brain and, consequently, controlling puberty. The effects of leptin on GnRH secretion are mediated via an upstream neuronal network because GnRH neurons do not express the leptin receptor. Two neuronal populations located in the arcuate nucleus that express the orexigenic peptide neuropeptide Y (NPY), and the anorexigenic peptide alpha melanocyte-stimulating hormone (αMSH), are key components of the neurocircuitry that conveys inhibitory (NPY) and excitatory (αMSH) inputs to GnRH neurons. In addition, neurons in the arcuate nucleus that coexpress kisspeptin, neurokinin B, and dynorphin (termed KNDy neurons) are also involved in the metabolic control of puberty. Our studies in the bovine female demonstrate that increased planes of nutrition during juvenile development lead to organizational and functional changes in hypothalamic pathways comprising NPY, proopiomelanocortin (POMC, the precursor of αMSH), and kisspeptin neurons. Changes include alterations in the abundance of NPY, POMC, and Kiss1 mRNA and in plasticity of the neuronal projections to GnRH neurons. Our studies also indicate that epigenetic mechanisms, such as modifications in the DNA methylation pattern, are involved in this process. Finally, our most recent data demonstrate that maternal nutrition during gestation can also induce morphological and functional changes in the hypothalamic NPY system in the heifer offspring that are likely to persist long after birth. These organizational changes occurring during fetal development have the potential to not only impact puberty but also influence reproductive performance throughout adulthood in the bovine female.
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Affiliation(s)
- R C Cardoso
- Department of Animal Science, Texas A&M University, College Station, TX, USA.
| | - S M West
- Department of Animal Science, Texas A&M University, College Station, TX, USA
| | - T S Maia
- Department of Animal Science, Texas A&M University, College Station, TX, USA; Animal Reproduction Laboratory, Texas A&M AgriLife Research, Beeville, TX, USA
| | - B R C Alves
- Department of Animal Science, Texas A&M University, College Station, TX, USA
| | - G L Williams
- Department of Animal Science, Texas A&M University, College Station, TX, USA; Animal Reproduction Laboratory, Texas A&M AgriLife Research, Beeville, TX, USA
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15
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Hypothalamic and Cell-Specific Transcriptomes Unravel a Dynamic Neuropil Remodeling in Leptin-Induced and Typical Pubertal Transition in Female Mice. iScience 2020; 23:101563. [PMID: 33083731 PMCID: PMC7522126 DOI: 10.1016/j.isci.2020.101563] [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: 06/18/2020] [Revised: 08/16/2020] [Accepted: 09/10/2020] [Indexed: 01/01/2023] Open
Abstract
Epidemiological and genome-wide association studies (GWAS) have shown high correlation between childhood obesity and advance in puberty. Early age at menarche is associated with a series of morbidities, including breast cancer, cardiovascular diseases, type 2 diabetes, and obesity. The adipocyte hormone leptin signals the amount of fat stores to the neuroendocrine reproductive axis via direct actions in the brain. Using mouse genetics, we and others have identified the hypothalamic ventral premammillary nucleus (PMv) and the agouti-related protein (AgRP) neurons in the arcuate nucleus (Arc) as primary targets of leptin action in pubertal maturation. However, the molecular mechanisms underlying leptin's effects remain unknown. Here we assessed changes in the PMv and Arc transcriptional program during leptin-stimulated and typical pubertal development using overlapping analysis of bulk RNA sequecing, TRAP sequencing, and the published database. Our findings demonstrate that dynamic somatodendritic remodeling and extracellular space organization underlie leptin-induced and typical pubertal maturation in female mice.
MBH DEGs between lean and Lepob mice are highly represented in development Short-term leptin to Lepob mice alters MBH DEGs associated with reproduction PMv/Arc LepRb DEGs between lean and Lepob mice are abundant in extracellular space DEGs in developing PMv/Arc are conspicuous in extracellular and neuropil remodeling
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16
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Hanlon C, Ramachandran R, Zuidhof MJ, Bédécarrats GY. Should I Lay or Should I Grow: Photoperiodic Versus Metabolic Cues in Chickens. Front Physiol 2020; 11:707. [PMID: 32670092 PMCID: PMC7332832 DOI: 10.3389/fphys.2020.00707] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 05/29/2020] [Indexed: 12/11/2022] Open
Abstract
While photoperiod has been generally accepted as the primary if not the exclusive cue to stimulate reproduction in photoperiodic breeders such as the laying hen, current knowledge suggests that metabolism, and/or body composition can also play an influential role to control the hypothalamic-pituitary gonadal (HPG)-axis. This review thus intends to first describe how photoperiodic and metabolic cues can impact the HPG axis, then explore and propose potential common pathways and mechanisms through which both cues could be integrated. Photostimulation refers to a perceived increase in day-length resulting in the stimulation of the HPG. While photoreceptors are present in the retina of the eye and the pineal gland, it is the deep brain photoreceptors (DBPs) located in the hypothalamus that have been identified as the potential mediators of photostimulation, including melanopsin (OPN4), neuropsin (OPN5), and vertebrate-ancient opsin (VA-Opsin). Here, we present the current state of knowledge surrounding these DBPs, along with their individual and relative importance and, their possible downstream mechanisms of action to initiate the activation of the HPG axis. On the metabolic side, specific attention is placed on the hypothalamic integration of appetite control with the stimulatory (Gonadotropin Releasing Hormone; GnRH) and inhibitory (Gonadotropin Inhibitory Hormone; GnIH) neuropeptides involved in the control of the HPG axis. Specifically, the impact of orexigenic peptides agouti-related peptide (AgRP), and neuropeptide Y (NPY), as well as the anorexigenic peptides pro-opiomelanocortin (POMC), and cocaine-and amphetamine regulated transcript (CART) is reviewed. Furthermore, beyond hypothalamic control, several metabolic factors involved in the control of body weight and composition are also presented as possible modulators of reproduction at all three levels of the HPG axis. These include peroxisome proliferator-activated receptor gamma (PPAR-γ) for its impact in liver metabolism during the switch from growth to reproduction, adiponectin as a potential modulator of ovarian development and follicular maturation, as well as growth hormone (GH), and leptin (LEP).
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Affiliation(s)
- Charlene Hanlon
- Department of Animal Biosciences, University of Guelph, Guelph, ON, Canada
| | - Ramesh Ramachandran
- Center for Reproductive Biology and Health, Department of Animal Science, Pennsylvania State University, University Park, PA, United States
| | - Martin J. Zuidhof
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, Canada
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17
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Plaisier F, Hume C, Menzies J. Neural connectivity between the hypothalamic supramammillary nucleus and appetite- and motivation-related regions of the rat brain. J Neuroendocrinol 2020; 32:e12829. [PMID: 31925973 PMCID: PMC7065010 DOI: 10.1111/jne.12829] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 12/06/2019] [Accepted: 01/08/2020] [Indexed: 12/20/2022]
Abstract
The supramammillary nucleus (SuM) has an emerging role in appetite control. We have shown that the rat SuM is activated during hunger or food anticipation, or by ghrelin administration. In the present study, we characterised the connectivity between the SuM and key appetite- and motivation-related nuclei in the rat. In adult wild-type rats, or rats expressing Cre recombinase under the control of the tyrosine hydroxylase (TH) promoter (TH-Cre rats), we used c-Fos immunohistochemistry to visualise and correlate the activation of medial SuM (SuMM) with activation in the lateral hypothalamic area (LH), the dorsomedial hypothalamus (DMH) or the ventral tegmental area (VTA) after voluntary consumption of a high-sugar, high-fat food. To determine neuroanatomical connectivity, we used retrograde and anterograde tracing methods to specifically investigate the neuronal inputs and outputs of the SuMM. After consumption of the food there were positive correlations between c-Fos expression in the SuMM and the LH, DMH and VTA (P = 0.0001, 0.01 and 0.004). Using Fluoro-Ruby as a retrograde tracer, we demonstrate the existence of inputs from the LH, DMH, VTA and ventromedial hypothalamus (VMH) to the SuMM. The SuMM showed reciprocal inputs to the LH and DMH, and we identified a TH-positive output from SuMM to DMH. We co-labelled retrogradely-labelled sections for TH in the VMH, or for TH, orexin and melanin-concentrating hormone in the LH and DMH. However, we did not observe any colocalisation of immunoreactivity with any retrogradely-labelled cells. Viral mapping in TH-Cre rats confirms the existence of a reciprocal SuMM-DMH connection and shows that TH-positive cells project from the SuMM and VTA to the lateral septal area and cingulate cortex, respectively. These data provide evidence for the connectivity of the SuMM to brain regions involved in appetite control, and form the foundation for functional and behavioural studies aiming to further characterise the brain circuitry controlling eating behaviours.
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Affiliation(s)
- Fabrice Plaisier
- Centre for Discovery Brain SciencesEdinburgh Medical School: Biomedical SciencesUniversity of EdinburghEdinburghUK
| | - Catherine Hume
- Centre for Discovery Brain SciencesEdinburgh Medical School: Biomedical SciencesUniversity of EdinburghEdinburghUK
| | - John Menzies
- Centre for Discovery Brain SciencesEdinburgh Medical School: Biomedical SciencesUniversity of EdinburghEdinburghUK
- ZJU‐UoE InstituteZhejiang University School of Medicine, Zhejiang University International CampusHainingZhejiangChina
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18
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Coutinho EA, Prescott M, Hessler S, Marshall CJ, Herbison AE, Campbell RE. Activation of a Classic Hunger Circuit Slows Luteinizing Hormone Pulsatility. Neuroendocrinology 2020; 110:671-687. [PMID: 31630145 DOI: 10.1159/000504225] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 10/11/2019] [Indexed: 11/19/2022]
Abstract
INTRODUCTION The central regulation of fertility is carefully coordinated with energy homeostasis, and infertility is frequently the outcome of energy imbalance. Neurons in the hypothalamus expressing neuropeptide Y and agouti-related peptide (NPY/AgRP neurons) are strongly implicated in linking metabolic cues with fertility regulation. OBJECTIVE We aimed here to determine the impact of selectively activating NPY/AgRP neurons, critical regulators of metabolism, on the activity of luteinizing hormone (LH) pulse generation. METHODS We employed a suite of in vivo optogenetic and chemogenetic approaches with serial measurements of LH to determine the impact of selectively activating NPY/AgRP neurons on dynamic LH secretion. In addition, electrophysiological studies in ex vivo brain slices were employed to ascertain the functional impact of activating NPY/AgRP neurons on gonadotropin-releasing hormone (GnRH) neurons. RESULTS Selective activation of NPY/AgRP neurons significantly decreased post-castration LH secretion. This was observed in males and females, as well as in prenatally androgenized females that recapitulate the persistently elevated LH pulse frequency characteristic of polycystic ovary syndrome (PCOS). Reduced LH pulse frequency was also observed when optogenetic stimulation was restricted to NPY/AgRP fiber projections surrounding GnRH neuron cell bodies in the rostral preoptic area. However, electrophysiological studies in ex vivo brain slices indicated these effects were likely to be indirect. CONCLUSIONS These data demonstrate the ability of NPY/AgRP neuronal signaling to modulate and, specifically, reduce GnRH/LH pulse generation. The findings suggest a mechanism by which increased activity of this hunger circuit, in response to negative energy balance, mediates impaired fertility in otherwise reproductively fit states, and highlight a potential mechanism to slow LH pulsatility in female infertility disorders, such as PCOS, that are associated with hyperactive LH secretion.
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Affiliation(s)
- Eulalia A Coutinho
- Department of Physiology and Centre for Neuroendocrinology, Otago School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Melanie Prescott
- Department of Physiology and Centre for Neuroendocrinology, Otago School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Sabine Hessler
- Department of Physiology and Centre for Neuroendocrinology, Otago School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Christopher J Marshall
- Department of Physiology and Centre for Neuroendocrinology, Otago School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Allan E Herbison
- Department of Physiology and Centre for Neuroendocrinology, Otago School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Rebecca E Campbell
- Department of Physiology and Centre for Neuroendocrinology, Otago School of Biomedical Sciences, University of Otago, Dunedin, New Zealand,
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19
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Ahi EP, Brunel M, Tsakoumis E, Schmitz M. Transcriptional study of appetite regulating genes in the brain of zebrafish (Danio rerio) with impaired leptin signalling. Sci Rep 2019; 9:20166. [PMID: 31882937 PMCID: PMC6934527 DOI: 10.1038/s41598-019-56779-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 12/10/2019] [Indexed: 12/26/2022] Open
Abstract
The hormone leptin is a key regulator of body weight, food intake and metabolism. In mammals, leptin acts as an anorexigen and inhibits food intake centrally by affecting the appetite centres in the hypothalamus. In teleost fish, the regulatory connections between leptin and other appetite-regulating genes are largely unknown. In the present study, we used a zebrafish mutant with a loss of function leptin receptor to investigate brain expression patterns of 12 orexigenic and 24 anorexigenic genes under different feeding conditions (normal feeding, 7-day fasting, 2 and 6-hours refeeding). Expression patterns were compared to wild-type zebrafish, in order to identify leptin-dependent differentially expressed genes under different feeding conditions. We provide evidence that the transcription of certain orexigenic and anorexigenic genes is influenced by leptin signalling in the zebrafish brain. We found that the expression of orexigenic genes was not affected by impaired leptin signalling under normal feeding conditions; however, several orexigenic genes showed increased transcription during fasting and refeeding, including agrp, apln, galr1a and cnr1. This suggests an inhibitory effect of leptin signal on the transcription of these orexigenic genes during short-term fasting and refeeding in functional zebrafish. Most pronounced effects were observed in the group of anorexigenic genes, where the impairment of leptin signalling resulted in reduced gene expression in several genes, including cart family, crhb, gnrh2, mc4r, pomc and spx, in the control group. This suggests a stimulatory effect of leptin signal on the transcription of these anorexigenic genes under normal feeding condition. In addition, we found multiple gain and loss in expression correlations between the appetite-regulating genes, in zebrafish with impaired leptin signal, suggesting the presence of gene regulatory networks downstream of leptin signal in zebrafish brain. The results provide the first evidence for the effects of leptin signal on the transcription of various appetite-regulating genes in zebrafish brain, under different feeding conditions. Altogether, these transcriptional changes suggest an anorexigenic role for leptin signal, which is likely to be mediated through distinct set of appetite-regulating genes under different feeding conditions.
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Affiliation(s)
- Ehsan Pashay Ahi
- Department of Organismal Biology, Comparative Physiology, Evolutionary Biology Centre, Uppsala University, Norbyvägen 18A, SE-752 36, Uppsala, Sweden
| | - Mathilde Brunel
- Department of Molecular Sciences, Swedish University of Agricultural Sciences, BioCentrum, Allmas Allé 5, SE-750 07 Uppsala, Sweden
| | - Emmanouil Tsakoumis
- Department of Organismal Biology, Comparative Physiology, Evolutionary Biology Centre, Uppsala University, Norbyvägen 18A, SE-752 36, Uppsala, Sweden
| | - Monika Schmitz
- Department of Organismal Biology, Comparative Physiology, Evolutionary Biology Centre, Uppsala University, Norbyvägen 18A, SE-752 36, Uppsala, Sweden.
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20
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Razolli DS, Moura-Assis A, Bombassaro B, Velloso LA. Hypothalamic neuronal cellular and subcellular abnormalities in experimental obesity. Int J Obes (Lond) 2019; 43:2361-2369. [PMID: 31548571 DOI: 10.1038/s41366-019-0451-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 06/27/2019] [Accepted: 07/18/2019] [Indexed: 01/15/2023]
Abstract
The characterization of the hypothalamic neuronal network, that controls food intake and energy expenditure, has provided great advances in the understanding of the pathophysiology of obesity. Most of the advances in this field were obtained thanks to the development of a number of genetic and nongenetic animal models that, at least in part, overtook the anatomical constraints that impair the study of the human hypothalamus. Despite the undisputed differences between human and rodent physiology, most seminal studies undertaken in rodents that have unveiled details of the neural regulation of energy homeostasis were eventually confirmed in humans; thus, placing experimental studies in the forefront of obesity research. During the last 15 years, researchers have provided extensive experimental proof that supports the existence of hypothalamic dysfunction, which leads to a progressive whole-body positive energy balance, and thus, to obesity. Here, we review the experimental work that unveiled the mechanisms behind hypothalamic dysfunction in obesity.
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Affiliation(s)
- Daniela S Razolli
- Laboratory of Cell Signaling, Obesity and Comorbidities Center University of Campinas, Campinas, São Paulo, 13084-970, Brazil
| | - Alexandre Moura-Assis
- Laboratory of Cell Signaling, Obesity and Comorbidities Center University of Campinas, Campinas, São Paulo, 13084-970, Brazil
| | - Bruna Bombassaro
- Laboratory of Cell Signaling, Obesity and Comorbidities Center University of Campinas, Campinas, São Paulo, 13084-970, Brazil
| | - Licio A Velloso
- Laboratory of Cell Signaling, Obesity and Comorbidities Center University of Campinas, Campinas, São Paulo, 13084-970, Brazil.
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21
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Patkar PP, Hao Z, Mumphrey MB, Townsend RL, Berthoud HR, Shin AC. Unlike calorie restriction, Roux-en-Y gastric bypass surgery does not increase hypothalamic AgRP and NPY in mice on a high-fat diet. Int J Obes (Lond) 2019; 43:2143-2150. [PMID: 30718818 PMCID: PMC6679822 DOI: 10.1038/s41366-019-0328-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 12/05/2018] [Accepted: 12/26/2018] [Indexed: 01/02/2023]
Abstract
OBJECTIVES Dieting often fails because weight loss triggers strong counter-regulatory biological responses such as increased hunger and hypometabolism that are thought to be critically dependent on the master fuel sensor in the mediobasal hypothalamus (MBH). Because prolonged starvation has been shown to increase AgRP and NPY, the expression level of these two orexigenic genes has been taken as an experimental readout for the presence or absence of hunger. Roux-en-Y gastric bypass (RYGB) surgery leads to a significant weight loss without inducing the associated hunger, indicating possible changes in hypothalamic neuropeptides and/or signaling. Our goal was to assess key genes in the MBH involved in regulating body weight, appetite, and inflammation/oxidative stress after RYGB surgery in mice. METHODS Obese mice on a high-fat diet were subjected to either sham or RYGB surgery, or caloric restriction to match the weight of RYGB group. Chow-fed mice without surgery served as an additional control group. After 2 or 12 weeks post-surgery, hypothalamic genes were analyzed by real-time qPCR. RESULTS During the rapid weight loss phase at 2 weeks after RYGB surgery, hypothalamic AgRP and NPY gene expression was not increased compared to mice with sham surgery, indicating that the mice are not hungry. In contrast, the same weight loss induced by caloric restriction promptly triggered increased AgRP and NPY expression. This differential effect of RYGB and caloric restriction was no longer observed during the weight-maintenance phase at 12 weeks after surgery. A similar differential effect was observed for ObRb, but not for POMC and CART expression. Furthermore, RAGE and IBA-1, two markers for inflammation/oxidative stress, were significantly suppressed after RYGB compared to caloric restriction at 2 weeks post-surgery. CONCLUSIONS These findings suggest that RYGB prevents the biologically adaptive hunger response triggered by undernutrition and weight loss, and suppresses weight loss-induced hypothalamic inflammation markers.
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Affiliation(s)
- Presheet P Patkar
- Department of Nutritional Sciences, College of Human Sciences, Texas Tech University, Lubbock, TX, 79409, USA
| | - Zheng Hao
- Neurobiology of Nutrition Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, 70808, USA
| | - Michael B Mumphrey
- Neurobiology of Nutrition Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, 70808, USA
| | - R Leigh Townsend
- Neurobiology of Nutrition Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, 70808, USA
| | - Hans-Rudolf Berthoud
- Neurobiology of Nutrition Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, 70808, USA
| | - Andrew C Shin
- Department of Nutritional Sciences, College of Human Sciences, Texas Tech University, Lubbock, TX, 79409, USA.
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22
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Saygı Bacanak M, Aydın B, Cabadak H, Nurten A, Gören MZ, Enginar N. Contribution of M 1 and M 2 muscarinic receptor subtypes to convulsions in fasted mice treated with scopolamine and given food. Behav Brain Res 2019; 364:423-430. [PMID: 29158113 DOI: 10.1016/j.bbr.2017.11.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 11/14/2017] [Accepted: 11/16/2017] [Indexed: 01/24/2023]
Abstract
Treatment of fasted mice and rats with the nonselective muscarinic antagonist, scopolamine or atropine, causes convulsions after food intake. This study evaluated the effect of fasting on the expression of M1 and M2 muscarinic receptors in the brain regions, the relationship between receptor expression and seizure stages, and the muscarinic receptor subtype which plays a role in the occurrence of convulsions. Mice were grouped as allowed to eat ad lib (fed) and deprived of food for 24h (fasted). Fasted animals developed convulsions after being treated with scopolamine (60%) or the selective M1 receptor antagonist pirenzepine (10mg/kg; 20% and 60mg/kg; 70%) and given food. Fasting increased expression of M1 receptors in the frontal cortex and M2 receptors in the hippocampus, but produced no change in the expression of both receptors in the amygdaloid complex. Food intake after fasting decreased M1 receptor expression in the frontal cortex and M1 and M2 receptor expression in the hippocampus. Seizure severity was uncorrelated with muscarinic receptor expression in the brain regions. Taken together, these findings provide evidence for the role of M1 muscarinic receptor antagonism and fasting-induced increases in M1 and M2 expression possible underlying mechanism in the occurrence of convulsions in fasted animals.
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Affiliation(s)
- Merve Saygı Bacanak
- Department of Medical Pharmacology, Istanbul Faculty of Medicine, Istanbul University, Turkey
| | - Banu Aydın
- Department of Biophysics, School of Medicine, Marmara University, Turkey
| | - Hülya Cabadak
- Department of Biophysics, School of Medicine, Marmara University, Turkey
| | - Asiye Nurten
- Department of Physiology, Faculty of Medicine, Istanbul Yeni Yuzyil University, Turkey
| | - Mehmet Zafer Gören
- Department of Medical Pharmacology, School of Medicine, Marmara University Istanbul, Turkey
| | - Nurhan Enginar
- Department of Medical Pharmacology, Istanbul Faculty of Medicine, Istanbul University, Turkey.
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23
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Garcia-Galiano D, Borges BC, Allen SJ, Elias CF. PI3K signalling in leptin receptor cells: Role in growth and reproduction. J Neuroendocrinol 2019; 31:e12685. [PMID: 30618188 PMCID: PMC6533139 DOI: 10.1111/jne.12685] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 01/04/2019] [Accepted: 01/04/2019] [Indexed: 12/15/2022]
Abstract
Nutrition and growth are important signals for pubertal development, although how they are perceived and integrated in brain circuits has not been well defined. Growth hormones and metabolic cues both recruit phosphatidylinositol 3-kinase (PI3K) signalling in hypothalamic sites, although whether they converge into the same neuronal population(s) is also not known. In this review, we discuss recent findings from our laboratory showing the role of PI3K subunits in cells directly responsive to the adipocyte-derived hormone leptin in the coordination of growth, pubertal development and fertility. Mice with deletion of PI3K p110α and p110β catalytic subunits in leptin receptor cells (LRΔα+β ) have a lean phenotype associated with increased energy expenditure, locomotor activity and thermogenesis. The LRΔα+β mice also show deficient growth and delayed puberty. Deletion of a single subunit (ie, p110α) in LR cells (LRΔα ) causes a similar phenotype of increased energy expenditure, deficient growth and delayed pubertal development, indicating that these functions are preferably controlled by p110α. The LRΔα mice show enhanced leptin sensitivity in metabolic regulation but, remarkably, these mice are unresponsive to the effects of leptin on growth and puberty. PI3K is also recruited by insulin and a subpopulation of LR neurones is responsive to i.c.v. insulin administration. Deletion of insulin receptor in LR cells causes no changes in body weight or linear growth and induces only a mild delay in pubertal completion. Our findings demonstrate that PI3K in LR cells plays an essential role in growth and reproduction. We will also discuss the potential neural pathways underlying these effects.
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Affiliation(s)
- David Garcia-Galiano
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Beatriz C. Borges
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
- Kresge Hearing Research Institute and Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Susan J. Allen
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Carol F. Elias
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
- Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA
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24
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Oussaada SM, van Galen KA, Cooiman MI, Kleinendorst L, Hazebroek EJ, van Haelst MM, Ter Horst KW, Serlie MJ. The pathogenesis of obesity. Metabolism 2019; 92:26-36. [PMID: 30639246 DOI: 10.1016/j.metabol.2018.12.012] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 12/28/2018] [Accepted: 12/30/2018] [Indexed: 12/14/2022]
Abstract
Body fat mass increases when energy intake exceeds energy expenditure. In the long term, a positive energy balance will result in obesity. The worldwide prevalence of obesity has increased dramatically, posing a serious threat to human health. Therefore, insight in the pathogenesis of obesity is important to identify novel prevention and treatment strategies. This review describes the physiology of energy expenditure and energy intake in the context of body weight gain in humans. We focus on the components of energy expenditure and the regulation of energy intake. Finally, we describe rare monogenetic causes leading to an impairment in central regulation of food intake and obesity.
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Affiliation(s)
- Sabrina M Oussaada
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, the Netherlands
| | - Katy A van Galen
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, the Netherlands
| | - Mellody I Cooiman
- Department of Bariatric Surgery, Rijnstate Hospital, Arnhem, the Netherlands
| | - Lotte Kleinendorst
- Department of Clinical Genetics, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, the Netherlands
| | - Eric J Hazebroek
- Department of Bariatric Surgery, Rijnstate Hospital, Arnhem, the Netherlands
| | - Mieke M van Haelst
- Department of Clinical Genetics, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, the Netherlands
| | - Kasper W Ter Horst
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, the Netherlands
| | - Mireille J Serlie
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, the Netherlands.
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25
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Papathanasiou AE, Nolen-Doerr E, Farr OM, Mantzoros CS. GEOFFREY HARRIS PRIZE LECTURE 2018: Novel pathways regulating neuroendocrine function, energy homeostasis and metabolism in humans. Eur J Endocrinol 2019; 180:R59-R71. [PMID: 30475221 PMCID: PMC6378110 DOI: 10.1530/eje-18-0847] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 11/05/2018] [Indexed: 12/12/2022]
Abstract
The discovery of leptin, an adipocyte-secreted hormone, set the stage for unraveling the mechanisms dictating energy homeostasis, revealing adipose tissue as an endocrine system that regulates appetite and body weight. Fluctuating leptin levels provide molecular signals to the brain regarding available energy reserves modulating energy homeostasis and neuroendocrine response in states of leptin deficiency and to a lesser extent in hyperleptinemic states. While leptin replacement therapy fails to provide substantial benefit in common obesity, it is an effective treatment for congenital leptin deficiency and states of acquired leptin deficiency such as lipodystrophy. Current evidence suggests that regulation of eating behavior in humans is not limited to homeostatic mechanisms and that the reward, attention, memory and emotion systems are involved, participating in a complex central nervous system network. It is critical to study these systems for the treatment of typical obesity. Although progress has been made, further studies are required to unravel the physiology, pathophysiology and neurobehavioral mechanisms underlying potential treatments for weight-related problems in humans.
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Affiliation(s)
| | - Eric Nolen-Doerr
- Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215
| | - Olivia M. Farr
- Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215
| | - Christos S. Mantzoros
- Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215
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26
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Gaspar JM, Velloso LA. Hypoxia Inducible Factor as a Central Regulator of Metabolism - Implications for the Development of Obesity. Front Neurosci 2018; 12:813. [PMID: 30443205 PMCID: PMC6221908 DOI: 10.3389/fnins.2018.00813] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 10/18/2018] [Indexed: 12/19/2022] Open
Abstract
The hypothalamus plays a major role in the regulation of food intake and energy expenditure. In the last decade, it was demonstrated that consumption of high-fat diets triggers the activation of an inflammatory process in the hypothalamus, inducing neurofunctional alterations and contributing to the development of obesity. Hypoxia-inducible factors (HIFs) are key molecules that regulate cellular responses to inflammation and hypoxia, being essential for the normal cell function and survival. Currently, evidence points to a role of HIF pathway in metabolic regulation that could also be involved in the progression of obesity and metabolic diseases. The challenge is to understand how HIF modulation impacts body mass gain and metabolic disorders such as insulin resistance. Distinct animal models with tissue-specific knocking-out or overexpression of hypoxia signaling pathway genes revealed a cell-specificity in the activation of HIF pathways, and some of them have opposite phenotypes among the various HIFs gain- and loss-of-function mouse models. In this review, we discuss the major findings that provide support for a role of HIF pathway involvement in the regulation of metabolism, especially in glucose and energy homeostasis.
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Affiliation(s)
- Joana M Gaspar
- Post-Graduation in Biochemistry, Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, Brazil.,Laboratório de Bioenergética e Estresse Oxidativo, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - Lício A Velloso
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil.,National Institute of Science and Technology on Neuroimmunomodulation, Rio de Janeiro, Brazil
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27
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Anderson JE, Zhu A, Mizuno TM. Nitric oxide treatment attenuates muscle atrophy during hind limb suspension in mice. Free Radic Biol Med 2018; 115:458-470. [PMID: 29277394 DOI: 10.1016/j.freeradbiomed.2017.12.021] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Revised: 12/09/2017] [Accepted: 12/15/2017] [Indexed: 02/07/2023]
Abstract
UNLABELLED Debilitating muscle-disuse atrophy in aging or obesity has huge socioeconomic impact. Since nitric oxide (NO) mediates muscle satellite cell activation and induces hypertrophy with exercise in old mice, we tested whether treatment with the NO donor, isosorbide dinitrate (ISDN), during hind limb suspension would reduce atrophy. Mice were suspended 18 days, with or without daily ISDN (66mg/kg). Muscles were examined for atrophy (weight, fiber diameter); regulatory changes in atrogin-1 (a negative regulator of muscle mass), myostatin (inhibits myogenesis), and satellite cell proliferation; and metabolic responses in myosin heavy chains (MyHCs), liver lipid, and hypothalamic gene expression. Suspension decreased muscle weight and weight relative to body weight between 25-55%, and gastrocnemius fiber diameter vs. CONTROLS In young-adult mice, ISDN attenuated atrophy by half or more. In quadriceps, ISDN completely prevented the suspension-induced rise in atrogin-1 and drop in myostatin precursor, and attenuated the changes in MyHCs 1 and 2b observed in unloaded muscles without treatment. Fatty liver in suspended young-adult mice was also reduced by ISDN; suspended young mice had higher hypothalamic expression of the orexigenic agouti-related protein, Agrp than controls. Notably, a suspension-induced drop in muscle satellite cell proliferation by 25-58% was completely prevented (young mice) or attenuated (halved, in young-adult mice) by ISDN. NO-donor treatment has potential to attenuate atrophy and metabolic changes, and prevent regulatory changes during disuse and offset/prevent wasting in age-related sarcopenia or space travel. Increases in precursor proliferation resulting from NO treatment would also amplify benefits of physical therapy and exercise.
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Affiliation(s)
- Judy E Anderson
- Department of Biological Sciences, University of Manitoba, 50 Sifton Road, Winnipeg, MB, Canada R3T 2N2.
| | - Antonia Zhu
- Department of Biological Sciences, University of Manitoba, 50 Sifton Road, Winnipeg, MB, Canada R3T 2N2
| | - Tooru M Mizuno
- Department of Physiology and Pathophysiology, Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, 727 McDermott Avenue, Winnipeg, MB, Canada R3E 3P5
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28
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Khan AM, Grant AH, Martinez A, Burns GAPC, Thatcher BS, Anekonda VT, Thompson BW, Roberts ZS, Moralejo DH, Blevins JE. Mapping Molecular Datasets Back to the Brain Regions They are Extracted from: Remembering the Native Countries of Hypothalamic Expatriates and Refugees. ADVANCES IN NEUROBIOLOGY 2018; 21:101-193. [PMID: 30334222 PMCID: PMC6310046 DOI: 10.1007/978-3-319-94593-4_6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
This article focuses on approaches to link transcriptomic, proteomic, and peptidomic datasets mined from brain tissue to the original locations within the brain that they are derived from using digital atlas mapping techniques. We use, as an example, the transcriptomic, proteomic and peptidomic analyses conducted in the mammalian hypothalamus. Following a brief historical overview, we highlight studies that have mined biochemical and molecular information from the hypothalamus and then lay out a strategy for how these data can be linked spatially to the mapped locations in a canonical brain atlas where the data come from, thereby allowing researchers to integrate these data with other datasets across multiple scales. A key methodology that enables atlas-based mapping of extracted datasets-laser-capture microdissection-is discussed in detail, with a view of how this technology is a bridge between systems biology and systems neuroscience.
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Affiliation(s)
- Arshad M Khan
- UTEP Systems Neuroscience Laboratory, University of Texas at El Paso, El Paso, TX, USA.
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX, USA.
- Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX, USA.
| | - Alice H Grant
- UTEP Systems Neuroscience Laboratory, University of Texas at El Paso, El Paso, TX, USA
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX, USA
- Graduate Program in Pathobiology, University of Texas at El Paso, El Paso, TX, USA
| | - Anais Martinez
- UTEP Systems Neuroscience Laboratory, University of Texas at El Paso, El Paso, TX, USA
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX, USA
- Graduate Program in Pathobiology, University of Texas at El Paso, El Paso, TX, USA
| | - Gully A P C Burns
- Information Sciences Institute, Viterbi School of Engineering, University of Southern California, Marina del Rey, CA, USA
| | - Brendan S Thatcher
- VA Puget Sound Health Care System, Office of Research and Development Medical Research Service, Department of Veterans Affairs Medical Center, Seattle, WA, USA
| | - Vishwanath T Anekonda
- VA Puget Sound Health Care System, Office of Research and Development Medical Research Service, Department of Veterans Affairs Medical Center, Seattle, WA, USA
| | - Benjamin W Thompson
- VA Puget Sound Health Care System, Office of Research and Development Medical Research Service, Department of Veterans Affairs Medical Center, Seattle, WA, USA
| | - Zachary S Roberts
- VA Puget Sound Health Care System, Office of Research and Development Medical Research Service, Department of Veterans Affairs Medical Center, Seattle, WA, USA
| | - Daniel H Moralejo
- Division of Neonatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA
| | - James E Blevins
- VA Puget Sound Health Care System, Office of Research and Development Medical Research Service, Department of Veterans Affairs Medical Center, Seattle, WA, USA
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
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29
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Suyama S, Ralevski A, Liu ZW, Dietrich MO, Yada T, Simonds SE, Cowley MA, Gao XB, Diano S, Horvath TL. Plasticity of calcium-permeable AMPA glutamate receptors in Pro-opiomelanocortin neurons. eLife 2017; 6. [PMID: 28762946 PMCID: PMC5538821 DOI: 10.7554/elife.25755] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Accepted: 06/17/2017] [Indexed: 11/13/2022] Open
Abstract
POMC neurons integrate metabolic signals from the periphery. Here, we show in mice that food deprivation induces a linear current-voltage relationship of AMPAR-mediated excitatory postsynaptic currents (EPSCs) in POMC neurons. Inhibition of EPSCs by IEM-1460, an antagonist of calcium-permeable (Cp) AMPARs, diminished EPSC amplitude in the fed but not in the fasted state, suggesting entry of GluR2 subunits into the AMPA receptor complex during food deprivation. Accordingly, removal of extracellular calcium from ACSF decreased the amplitude of mEPSCs in the fed but not the fasted state. Ten days of high-fat diet exposure, which was accompanied by elevated leptin levels and increased POMC neuronal activity, resulted in increased expression of Cp-AMPARs on POMC neurons. Altogether, our results show that entry of calcium via Cp-AMPARs is inherent to activation of POMC neurons, which may underlie a vulnerability of these neurons to calcium overload while activated in a sustained manner during over-nutrition. DOI:http://dx.doi.org/10.7554/eLife.25755.001
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Affiliation(s)
- Shigetomo Suyama
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, United States.,Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Tochigi, Japan
| | - Alexandra Ralevski
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, United States
| | - Zhong-Wu Liu
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, United States
| | - Marcelo O Dietrich
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, United States
| | - Toshihiko Yada
- Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Tochigi, Japan
| | - Stephanie E Simonds
- Biomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, Australia
| | - Michael A Cowley
- Biomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, Australia
| | - Xiao-Bing Gao
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, United States
| | - Sabrina Diano
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, United States.,Departments of Ob/Gyn and Reproductive Sciences, Yale University School of Medicine, New Haven, United States.,Department of Neurobiology, Yale University School of Medicine, New Haven, United States
| | - Tamas L Horvath
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, United States.,Departments of Ob/Gyn and Reproductive Sciences, Yale University School of Medicine, New Haven, United States.,Department of Neurobiology, Yale University School of Medicine, New Haven, United States.,Department of Anatomy and Histology, University of Veterinary Medicine, Budapest, Hungary
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30
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Wanlong Z, Di Z, Dongmin H, Guang Y. Roles of hypothalamic neuropeptide gene expression in body mass regulation in Eothenomys miletus (Mammalia: Rodentia: Cricetidae). THE EUROPEAN ZOOLOGICAL JOURNAL 2017. [DOI: 10.1080/24750263.2017.1334840] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Affiliation(s)
- Z. Wanlong
- Key Laboratory of Adaptive Evolution and Ecological Conservation on Plants and Animals in Southwest Mountain Ecosystem of Yunnan Higher Education Institutes, School of Life Sciences, Yunnan Normal University, Kunming, People’s Republic of China
| | - Z. Di
- School of Life Sciences, Kunming, People’s Republic of China
| | - H. Dongmin
- Key Laboratory of Adaptive Evolution and Ecological Conservation on Plants and Animals in Southwest Mountain Ecosystem of Yunnan Higher Education Institutes, School of Life Sciences, Yunnan Normal University, Kunming, People’s Republic of China
| | - Y. Guang
- College of Life Sciences, Nanjing Normal University, Nanjing, People’s Republic of China
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31
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Morales FE, Tinsley GM, Gordon PM. Acute and Long-Term Impact of High-Protein Diets on Endocrine and Metabolic Function, Body Composition, and Exercise-Induced Adaptations. J Am Coll Nutr 2017; 36:295-305. [PMID: 28443785 DOI: 10.1080/07315724.2016.1274691] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND High-protein diets have been shown to improve body composition through alterations in satiety, muscle protein synthesis, and the thermic effect of food. AIM Given these findings, the purpose of this review is to discuss the integration of the specific hormonal and metabolic effects of high-protein diets following both acute and long-term usage, especially with regard to body composition. METHODS Full-text articles were obtained through PubMed by using the terms "high-protein diet and body composition," "high-protein diet and exercise," "high-protein diet risk," "high-protein diet side effects," "protein quality PDCAAS," "RDA for protein," and "daily protein recommendation." Articles were initially screened according to their title and abstract; careful evaluation of the full manuscripts was then used to identify relevant articles. RESULTS The higher satiety exerted by high-protein diets is generated through increments in anorexigenic, as well as decrements in orexigenic hormones. Improvements in muscle mass are achieved by activation of muscle protein synthesis acting through the mTOR pathway. High thermic effect of food is caused due to necessary deamination, gluconeogenesis, and urea synthesis caused by high-protein diets. Interestingly, high-protein diets in both hypo- and normocaloric conditions have shown to improve body composition, whereas in combination with hypercaloric conditions does not seem to increase fat mass, when the excess energy comes from protein. CONCLUSIONS High protein diets effectively improve body composition by acting through different pathways.
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Affiliation(s)
- Flor E Morales
- a Department of Health , Human Performance, and Recreation, Baylor University , Waco , Texas , USA
| | - Grant M Tinsley
- b Department of Kinesiology and Sport Management , Texas Tech University , Lubbock , Texas , USA
| | - Paul M Gordon
- a Department of Health , Human Performance, and Recreation, Baylor University , Waco , Texas , USA
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32
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Mahú I, Domingos AI. The sympathetic neuro-adipose connection and the control of body weight. Exp Cell Res 2017; 360:27-30. [PMID: 28342901 DOI: 10.1016/j.yexcr.2017.03.047] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 03/21/2017] [Indexed: 02/08/2023]
Abstract
In recent decades, obesity has become a global public health crisis irrespective of age or gender [20]. But according to historic records, concerns over appropriate maintenance of body size have been long established. For more than to 2 millennia, the main therapeutic approach to curb excess weight has been to recommend dietary restrictions and regular exercise (Haslam, 2016). Nevertheless, more contemporary studies indicate that the employment of such approaches in the treatment of severely obese patients causes metabolic adaptions which impair their long-term success in weight management [8]. These evidences highlight thus, the urgency in the search for a more comprehensive knowledge of the mechanisms that underlie the control of body weight, which would be essential for the development of effective strategies for the treatment of obesity and its comorbidities. Importantly, the discovery of the hormone leptin [33]and the use of novel techniques in targeted transgenesis [32] have enabled progress in defining some of the key players and the molecular mechanisms that are involved in the processes that control body size homeostasis and energy balance, and how obesity may disrupt leptin's feedback loop and lead to the pathology of metabolic syndrome. On the light of such findings, here we review how the sympathetic nervous system modulates adipose tissue metabolism downstream of leptin's action on the CNS, with particular focus on how this system may be disrupted in the context of excess adiposity, plus highlight the potential clinical implications arising from a better understanding of the physiologic control of the sympathetic neuro-adipose connection.
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Affiliation(s)
- Inês Mahú
- Obesity Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
| | - Ana I Domingos
- Obesity Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal.
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33
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Zhang L, Yang F, Wang ZK, Zhu WL. Role of thermal physiology and bioenergetics on adaptation in tree shrew (Tupaia belangeri): the experiment test. Sci Rep 2017; 7:41352. [PMID: 28145515 PMCID: PMC5286505 DOI: 10.1038/srep41352] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 12/19/2016] [Indexed: 12/27/2022] Open
Abstract
Ambient conditions, as temperature and photoperiod, play a key role in animals’ physiology and behaviors. To test the hypothesis that the maximum thermal physiological and bioenergetics tolerances are induced by extreme environments in Tupaia belangeri. We integrated the acclimatized and acclimated data in several physiological, hormonal, and biochemical markers of thermogenic capacity and bioenergetics in T. belangeri. Results showed that T. belangeri increased body mass, thermogenesis capacity, protein contents and cytochrome c oxidase (COX) activity of liver and brown adipose tissue in winter-like environments, which indicated that temperature was the primary signal for T. belangeri to regulate several physiological capacities. The associated photoperiod signal also elevated the physiological capacities. The regulations of critical physiological traits play a primary role in meeting the survival challenges of winter-like condition in T. belangeri. Together, to cope with cold, leptin may play a potential role in thermogenesis and body mass regulation, as this hormonal signal is associated with other hormones. The strategies of thermal physiology and bioenergetics differs between typical Palearctic species and the local species. However, the maximum thermal physiology and bioenergetic tolerance maybe is an important strategy to cope with winter-like condition of T. belangeri.
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Affiliation(s)
- Lin Zhang
- Key Laboratory of Ecological Adaptive Evolution and Conservation on Animals-Plants in Southwest Mountain Ecosystem of Yunnan Province Higher Institutes College, School of Life Sciences, Yunnan Normal University, Kunming 650500, China
| | - Fang Yang
- School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Zheng-Kun Wang
- Key Laboratory of Ecological Adaptive Evolution and Conservation on Animals-Plants in Southwest Mountain Ecosystem of Yunnan Province Higher Institutes College, School of Life Sciences, Yunnan Normal University, Kunming 650500, China
| | - Wan-Long Zhu
- Key Laboratory of Ecological Adaptive Evolution and Conservation on Animals-Plants in Southwest Mountain Ecosystem of Yunnan Province Higher Institutes College, School of Life Sciences, Yunnan Normal University, Kunming 650500, China
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34
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Neuropeptides and Microglial Activation in Inflammation, Pain, and Neurodegenerative Diseases. Mediators Inflamm 2017; 2017:5048616. [PMID: 28154473 PMCID: PMC5244030 DOI: 10.1155/2017/5048616] [Citation(s) in RCA: 143] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 11/26/2016] [Accepted: 12/05/2016] [Indexed: 12/15/2022] Open
Abstract
Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity.
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35
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Barateiro A, Mahú I, Domingos AI. Leptin Resistance and the Neuro-Adipose Connection. Front Endocrinol (Lausanne) 2017; 8:45. [PMID: 28321206 PMCID: PMC5337508 DOI: 10.3389/fendo.2017.00045] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 02/20/2017] [Indexed: 01/30/2023] Open
Affiliation(s)
- Andreia Barateiro
- Obesity Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
- Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, Lisbon, Portugal
| | - Ines Mahú
- Obesity Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
| | - Ana I. Domingos
- Obesity Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
- *Correspondence: Ana I. Domingos,
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Contribution of adaptive thermogenesis to the hypothalamic regulation of energy balance. Biochem J 2016; 473:4063-4082. [DOI: 10.1042/bcj20160012] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 08/13/2016] [Accepted: 08/30/2016] [Indexed: 12/12/2022]
Abstract
Obesity and its related disorders are among the most pervasive diseases in contemporary societies, and there is an urgent need for new therapies and preventive approaches. Given (i) our poor social capacity to correct unhealthy habits, and (ii) our evolutionarily genetic predisposition to store excess energy as fat, the current environment of caloric surplus makes the treatment of obesity extremely difficult. During the last few decades, an increasing number of methodological approaches have increased our knowledge of the neuroanatomical basis of the control of energy balance. Compelling evidence underlines the role of the hypothalamus as a homeostatic integrator of metabolic information and its ability to adjust energy balance. A greater understanding of the neural basis of the hypothalamic regulation of energy balance might indeed pave the way for new therapeutic targets. In this regard, it has been shown that several important peripheral signals, such as leptin, thyroid hormones, oestrogens and bone morphogenetic protein 8B, converge on common energy sensors, such as AMP-activated protein kinase to modulate sympathetic tone on brown adipose tissue. This knowledge may open new ways to counteract the chronic imbalance underlying obesity. Here, we review the current state of the art on the role of hypothalamus in the regulation of energy balance with particular focus on thermogenesis.
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Ladyman SR, Augustine RA, Scherf E, Phillipps HR, Brown CH, Grattan DR. Attenuated hypothalamic responses to α-melanocyte stimulating hormone during pregnancy in the rat. J Physiol 2016; 594:1087-101. [PMID: 26613967 DOI: 10.1113/jp271605] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 11/23/2015] [Indexed: 11/08/2022] Open
Abstract
KEY POINTS Increased appetite and weight gain occurs during pregnancy, associated with development of leptin resistance, and satiety responses to the anorectic peptide α-melanocyte stimulating hormone (α-MSH) are suppressed. This study investigated hypothalamic responses to α-MSH during pregnancy, using c-fos expression in specific hypothalamic nuclei as a marker of neuronal signalling, and in vivo electrophysiology in supraoptic nucleus (SON) oxytocin neurons, as a representative α-MSH-responsive neuronal population that shows a well-characterised α-MSH-induced inhibition of firing. While icv injection of α-MSH significantly increased the number of c-fos-positive cells in the paraventricular, supraoptic, arcuate and ventromedial hypothalamic nuclei in non-pregnant rats, this response was suppressed in pregnant rats. Similarly, SON oxytocin neurons in pregnant rats did not demonstrate characteristic α-MSH-induced inhibition of firing that was observed in non-pregnant animals. Given the known functions of α-MSH in the hypothalamus, the attenuated responses are likely to facilitate adaptive changes in appetite regulation and oxytocin secretion during pregnancy. ABSTRACT During pregnancy, a state of positive energy balance develops to support the growing fetus and to deposit fat in preparation for the subsequent metabolic demands of lactation. As part of this maternal adaptation, the satiety response to the anorectic peptide α-melanocyte stimulating hormone (α-MSH) is suppressed. To investigate whether pregnancy is associated with changes in the response of hypothalamic α-MSH target neurons, non-pregnant and pregnant rats were treated with α-MSH or vehicle and c-fos expression in hypothalamic nuclei was then examined. Furthermore, the firing rate of supraoptic nucleus (SON) oxytocin neurons, a known α-MSH responsive neuronal population, was examined in non-pregnant and pregnant rats following α-MSH treatment. Intracerebroventricular injection of α-MSH significantly increased the number of c-fos-positive cells in the paraventricular, arcuate and ventromedial hypothalamic nuclei in non-pregnant rats, but no significant increase was observed in any of these regions in pregnant rats. In the SON, α-MSH did induce expression of c-fos during pregnancy, but this was significantly reduced compared to that observed in the non-pregnant group. Furthermore, during pregnancy, SON oxytocin neurons did not demonstrate the characteristic α-MSH-induced inhibition of firing rate that was observed in non-pregnant animals. Melanocortin receptor mRNA levels during pregnancy were similar to non-pregnant animals, suggesting that receptor down-regulation is unlikely to be a mechanism underlying the attenuated responses to α-MSH during pregnancy. Given the known functions of α-MSH in the hypothalamus, the attenuated responses will facilitate adaptive changes in appetite regulation and oxytocin secretion during pregnancy.
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Affiliation(s)
- S R Ladyman
- Department of Anatomy and Centre for Neuroendocrinology, School of Medical Sciences, University of Otago, Dunedin, New Zealand
| | - R A Augustine
- Department of Physiology and Centre for Neuroendocrinology, School of Medical Sciences, University of Otago, Dunedin, New Zealand
| | - E Scherf
- Department of Anatomy and Centre for Neuroendocrinology, School of Medical Sciences, University of Otago, Dunedin, New Zealand
| | - H R Phillipps
- Department of Anatomy and Centre for Neuroendocrinology, School of Medical Sciences, University of Otago, Dunedin, New Zealand
| | - C H Brown
- Department of Physiology and Centre for Neuroendocrinology, School of Medical Sciences, University of Otago, Dunedin, New Zealand
| | - D R Grattan
- Department of Anatomy and Centre for Neuroendocrinology, School of Medical Sciences, University of Otago, Dunedin, New Zealand
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Côté I, Sakarya Y, Kirichenko N, Morgan D, Carter CS, Tümer N, Scarpace PJ. Activation of the central melanocortin system chronically reduces body mass without the necessity of long-term caloric restriction. Can J Physiol Pharmacol 2016; 95:206-214. [PMID: 28051332 DOI: 10.1139/cjpp-2016-0290] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Melanotan II (MTII) is a potent appetite suppressor that rapidly reduces body mass. Given the rapid loss of anorexic response upon chronic MTII treatment, most investigations have focused on the initial physiological adaptations. However, other evidence supports MTII as a long-term modulator of energy balance that remains to be established. Therefore, we examined the chronic effects of MTII on energy homeostasis. MTII (high or low dose) or artificial cerebrospinal fluid (aCSF) was infused into the lateral ventricle of the brain of 6-month-old F344BN rats (6-7/group) over 40 days. MTII suppressed appetite in a dose-dependent manner (P < 0.05). Although food intake promptly rose back to control level, body mass was persistently reduced in both MTII groups (P < 0.01). At day 40, both MTII groups displayed lower adiposity than the aCSF animals (P < 0.01). These results show that MTII chronically reduces body mass without the requirement of long-term caloric restriction. Our study proposes that food restriction helps initiate mass loss; however, combined with a secondary pharmacological approach preserving a negative energy balance state over time may help combat obesity.
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Affiliation(s)
- I Côté
- a Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA
| | - Y Sakarya
- a Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.,b Geriatric Research, Education, and Clinical Center, North Florida/South Georgia Veterans Health System, Gainesville, FL, USA
| | - N Kirichenko
- a Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.,b Geriatric Research, Education, and Clinical Center, North Florida/South Georgia Veterans Health System, Gainesville, FL, USA
| | - D Morgan
- c Department of Psychiatry, University of Florida, Gainesville, FL, USA
| | - C S Carter
- d Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA
| | - N Tümer
- a Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.,b Geriatric Research, Education, and Clinical Center, North Florida/South Georgia Veterans Health System, Gainesville, FL, USA
| | - P J Scarpace
- a Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA
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Leptin receptor-positive and leptin receptor-negative proopiomelanocortin neurons innervate an identical set of brain structures. Brain Res 2016; 1646:366-376. [DOI: 10.1016/j.brainres.2016.06.024] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 06/01/2016] [Accepted: 06/15/2016] [Indexed: 11/21/2022]
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Abstract
Leptin, a 167 amino acid adipokine, plays a major role in human energy homeostasis. Its actions are mediated through binding to leptin receptor and activating JAK-STAT3 signal transduction pathway. It is expressed mainly in adipocytes, and its circulating levels reflect the body's energy stores in adipose tissue. Recombinant methionyl human leptin has been FDA approved for patients with generalized non-HIV lipodystrophy and for compassionate use in subjects with congenital leptin deficiency. The purpose of this review is to outline the role of leptin in energy homeostasis, as well as its interaction with other hormones.
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Affiliation(s)
- Georgios A Triantafyllou
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, ST 820, Boston, MA 02215, USA
| | - Stavroula A Paschou
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, ST 820, Boston, MA 02215, USA
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, ST 820, Boston, MA 02215, USA.
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Lee B, Lee S, Lee SK, Lee JW. The LIM-homeobox transcription factor Isl1 plays crucial roles in the development of multiple arcuate nucleus neurons. Development 2016; 143:3763-3773. [PMID: 27578785 DOI: 10.1242/dev.133967] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 08/22/2016] [Indexed: 12/24/2022]
Abstract
Neurons in the hypothalamic arcuate nucleus relay and translate important cues from the periphery into the central nervous system. However, the gene regulatory program directing their development remains poorly understood. Here, we report that the LIM-homeodomain transcription factor Isl1 is expressed in several subpopulations of developing arcuate neurons and plays crucial roles in their fate specification. Mice with conditional deletion of the Isl1 gene in developing hypothalamus display severe deficits in both feeding and linear growth. Consistent with these results, their arcuate nucleus fails to express key fate markers of Isl1-expressing neurons that regulate feeding and growth. These include the orexigenic neuropeptides AgRP and NPY for specifying AgRP-neurons, the anorexigenic neuropeptide αMSH for POMC-neurons, and two growth-stimulatory peptides, growth hormone-releasing hormone (GHRH) for GHRH-neurons and somatostatin (Sst) for Sst-neurons. Finally, we show that Isl1 directly enhances the expression of AgRP by cooperating with the key orexigenic transcription factors glucocorticoid receptor and brain-specific homeobox factor. Our results identify Isl1 as a crucial transcription factor that plays essential roles in the gene regulatory program directing development of multiple arcuate neuronal subpopulations.
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Affiliation(s)
- Bora Lee
- Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.,Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA
| | - Seunghee Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Soo-Kyung Lee
- Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.,Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA.,Vollum Institute, Oregon Health & Science University, Portland, OR, USA
| | - Jae W Lee
- Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA .,Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA
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Mercer JG, Adam CL, Morgan PJ. Towards an Understanding of Physiological Body Mass Regulation: Seasonal Animal Models. Nutr Neurosci 2016; 3:307-20. [DOI: 10.1080/1028415x.2000.11747328] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Kim JS, Rizwan MZ, Clegg DJ, Anderson GM. Leptin Signaling Is Not Required for Anorexigenic Estradiol Effects in Female Mice. Endocrinology 2016; 157:1991-2001. [PMID: 26937712 DOI: 10.1210/en.2015-1594] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Estradiol and leptin are critical hormones in the regulation of body weight. The aim of this study was to determine whether this cross talk between leptin receptor (LepRb) and estrogen receptor-α (ERα) signaling is critical for estradiol's anorexigenic effects. Leprb-Cre mice were crossed with Cre-dependent Tau-green fluorescent protein (GFP) reporter, Stat3-flox or Erα-flox mice to generate female mice with GFP expression, signal transducer and activator of transcription 3 (STAT3) knockout (KO), or ERα KO, specifically in LepRb-expressing cells. The proportion of Leprb-GFP cells colocalizing ERα was high (∼80%) in the preoptic area but low (∼10%) in the mediobasal hypothalamus, suggesting that intracellular cross talk between these receptors is minimal for metabolic regulation. To test whether estradiol enhanced arcuate leptin sensitivity, ovarectomized mice received varying levels of estradiol replacement. Increasing estrogenic states did not increase the degree of leptin-induced STAT3 phosphorylation. LepRb-specific STAT3 KO mice and controls were ovarectomized and given either chronic estradiol or vehicle treatment to test whether STAT3 is required for estrogen-induced body weight suppression. Both groups of estradiol-treated mice showed an equivalent reduction in body weight and fat content compared with vehicle controls. Finally, mice lacking ERα specifically in LepRb-expressing neurons also showed no increase in body weight or impairments in metabolic function compared with controls, indicating that estradiol acts independently of leptin-responsive cells to regulate body weight. However, fecundity was impaired in in Leprb-ERα KO females. Contrary to the current dogma, we report that estradiol has minimal direct actions on LepRb cells in the mediodasal hypothalamus and that its anorexigenic effects can occur entirely independently of LepRb-STAT3 signaling in female mice.
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Affiliation(s)
- Joon S Kim
- Centre for Neuroendocrinology and Department of Anatomy (J.S.K, M.Z.R, G.M.A.), University of Otago School of Medical Sciences, Dunedin 9054, New Zealand; and Cedars-Sinai Diabetes and Obesity Research Institute, Department of Biomedical Research (D.J.C.), Los Angeles, California 90048
| | - Mohammed Z Rizwan
- Centre for Neuroendocrinology and Department of Anatomy (J.S.K, M.Z.R, G.M.A.), University of Otago School of Medical Sciences, Dunedin 9054, New Zealand; and Cedars-Sinai Diabetes and Obesity Research Institute, Department of Biomedical Research (D.J.C.), Los Angeles, California 90048
| | - Deborah J Clegg
- Centre for Neuroendocrinology and Department of Anatomy (J.S.K, M.Z.R, G.M.A.), University of Otago School of Medical Sciences, Dunedin 9054, New Zealand; and Cedars-Sinai Diabetes and Obesity Research Institute, Department of Biomedical Research (D.J.C.), Los Angeles, California 90048
| | - Greg M Anderson
- Centre for Neuroendocrinology and Department of Anatomy (J.S.K, M.Z.R, G.M.A.), University of Otago School of Medical Sciences, Dunedin 9054, New Zealand; and Cedars-Sinai Diabetes and Obesity Research Institute, Department of Biomedical Research (D.J.C.), Los Angeles, California 90048
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Chowen JA, Argente-Arizón P, Freire-Regatillo A, Frago LM, Horvath TL, Argente J. The role of astrocytes in the hypothalamic response and adaptation to metabolic signals. Prog Neurobiol 2016; 144:68-87. [PMID: 27000556 DOI: 10.1016/j.pneurobio.2016.03.001] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 02/09/2016] [Accepted: 03/04/2016] [Indexed: 12/19/2022]
Abstract
The hypothalamus is crucial in the regulation of homeostatic functions in mammals, with the disruption of hypothalamic circuits contributing to chronic conditions such as obesity, diabetes mellitus, hypertension, and infertility. Metabolic signals and hormonal inputs drive functional and morphological changes in the hypothalamus in attempt to maintain metabolic homeostasis. However, the dramatic increase in the incidence of obesity and its secondary complications, such as type 2 diabetes, have evidenced the need to better understand how this system functions and how it can go awry. Growing evidence points to a critical role of astrocytes in orchestrating the hypothalamic response to metabolic cues by participating in processes of synaptic transmission, synaptic plasticity and nutrient sensing. These glial cells express receptors for important metabolic signals, such as the anorexigenic hormone leptin, and determine the type and quantity of nutrients reaching their neighboring neurons. Understanding the mechanisms by which astrocytes participate in hypothalamic adaptations to changes in dietary and metabolic signals is fundamental for understanding the neuroendocrine control of metabolism and key in the search for adequate treatments of metabolic diseases.
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Affiliation(s)
- Julie A Chowen
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación la Princesa, CIBER de Obesidad Fisiopatología de la Obesidad y Nutrición (CIBEROBN). Instituto de Salud Carlos III, Madrid, Spain.
| | - Pilar Argente-Arizón
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación la Princesa, CIBER de Obesidad Fisiopatología de la Obesidad y Nutrición (CIBEROBN). Instituto de Salud Carlos III, Madrid, Spain; Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
| | - Alejandra Freire-Regatillo
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación la Princesa, CIBER de Obesidad Fisiopatología de la Obesidad y Nutrición (CIBEROBN). Instituto de Salud Carlos III, Madrid, Spain; Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
| | - Laura M Frago
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación la Princesa, CIBER de Obesidad Fisiopatología de la Obesidad y Nutrición (CIBEROBN). Instituto de Salud Carlos III, Madrid, Spain; Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
| | - Tamas L Horvath
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Jesús Argente
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación la Princesa, CIBER de Obesidad Fisiopatología de la Obesidad y Nutrición (CIBEROBN). Instituto de Salud Carlos III, Madrid, Spain; Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
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Juan De Solis A, Baquero AF, Bennett CM, Grove KL, Zeltser LM. Postnatal undernutrition delays a key step in the maturation of hypothalamic feeding circuits. Mol Metab 2016; 5:198-209. [PMID: 26977392 PMCID: PMC4770263 DOI: 10.1016/j.molmet.2016.01.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 01/06/2016] [Accepted: 01/11/2016] [Indexed: 01/20/2023] Open
Abstract
OBJECTIVE Humans and animals exposed to undernutrition (UN) during development often experience accelerated "catch-up" growth when food supplies are plentiful. Little is known about the mechanisms regulating early growth rates. We previously reported that actions of leptin and presynaptic inputs to orexigenic NPY/AgRP/GABA (NAG) neurons in the arcuate nucleus of the hypothalamus are almost exclusively excitatory during the lactation period, since neuronal and humoral inhibitory systems do not develop until after weaning. Moreover, we identified a critical step that regulates the maturation of electrophysiological responses of NAG neurons at weaning - the onset of genes encoding ATP-dependent potassium (KATP) channel subunits. We explored the possibility that UN promotes subsequent catch-up growth, in part, by delaying the maturation of negative feedback systems to neuronal circuits driving food intake. METHODS We used the large litter (LL) size model to study the impacts of postnatal UN followed by catch-up growth. We evaluated the maturation of presynaptic and postsynaptic inhibitory systems in NAG neurons using a combination of electrophysiological and molecular criteria, in conjunction with leptin's ability to suppress fasting-induced hyperphagia. RESULTS The onset of KATP channel subunit expression and function, the switch in leptin's effect on NAG neurons, the ingrowth of inhibitory inputs to NAG neurons, and the development of homeostatic feedback to feeding circuits were delayed in LL offspring relative to controls. The development of functional KATP channels and the establishment of leptin-mediated suppression of food intake in the peri-weaning period were tightly linked and were not initiated until growth and adiposity of LL offspring caught up to controls. CONCLUSIONS Our data support the idea that initiation of KATP channel subunit expression in NAG neurons serves as a molecular gatekeeper for the maturation of homeostatic feeding circuits.
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Key Words
- ARH, arcuate nucleus of the hypothalamus
- AgRP
- AgRP, agouti-related peptide
- EPSC, excitatory postsynaptic current
- Feeding circuits
- GABA, gamma-aminobutyric acid
- IPSC, inhibitory postsynaptic current
- KATP channel
- KATP, ATP-sensitive potassium channel
- Kir, potassium inward rectifiying channel subunit
- LL, large litter
- Lepr, leptin receptor
- Leptin
- NAG, NPY, AgRP, GABA, NPY, neuropeptide Y
- NPY
- P, postnatal day
- PVH, paraventricular nucleus of the hypothalamus
- Pomc, pro-opiomelanocortin
- SUR, sulfonylurea receptor
- UN, undernutrition
- Undernutrition
- pSTAT3, phosphorylated signal transducer and activator of transcription 3
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Affiliation(s)
- Alain Juan De Solis
- Division of Molecular Genetics, Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA.
| | - Arian F Baquero
- Division of Diabetes, Obesity & Metabolism, Oregon National Primate Research Center, Beaverton, OR 97006, USA.
| | - Camdin M Bennett
- Division of Diabetes, Obesity & Metabolism, Oregon National Primate Research Center, Beaverton, OR 97006, USA.
| | - Kevin L Grove
- Division of Diabetes, Obesity & Metabolism, Oregon National Primate Research Center, Beaverton, OR 97006, USA.
| | - Lori M Zeltser
- Division of Molecular Genetics, Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
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Morales Fénero CI, Colombo Flores AA, Câmara NOS. Inflammatory diseases modelling in zebrafish. World J Exp Med 2016; 6:9-20. [PMID: 26929916 PMCID: PMC4759353 DOI: 10.5493/wjem.v6.i1.9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 10/20/2015] [Accepted: 12/18/2015] [Indexed: 02/06/2023] Open
Abstract
The ingest of diets with high content of fats and carbohydrates, low or no physical exercise and a stressful routine are part of the everyday lifestyle of most people in the western world. These conditions are triggers for different diseases with complex interactions between the host genetics, the metabolism, the immune system and the microbiota, including inflammatory bowel diseases (IBD), obesity and diabetes. The incidence of these disorders is growing worldwide; therefore, new strategies for its study are needed. Nowadays, the majority of researches are in use of murine models for understand the genetics, physiopathology and interaction between cells and signaling pathways to find therapeutic solutions to these diseases. The zebrafish, a little tropical water fish, shares 70% of our genes and conserves anatomic and physiological characteristics, as well as metabolical pathways, with mammals, and is rising as a new complementary model for the study of metabolic and inflammatory diseases. Its high fecundity, fast development, transparency, versatility and low cost of maintenance makes the zebrafish an interesting option for new researches. In this review, we offer a discussion of the existing genetic and induced zebrafish models of two important Western diseases that have a strong inflammatory component, the IBD and the obesity.
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Interacting Neural Processes of Feeding, Hyperactivity, Stress, Reward, and the Utility of the Activity-Based Anorexia Model of Anorexia Nervosa. Harv Rev Psychiatry 2016; 24:416-436. [PMID: 27824637 PMCID: PMC5485261 DOI: 10.1097/hrp.0000000000000111] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Anorexia nervosa (AN) is a psychiatric illness with minimal effective treatments and a very high rate of mortality. Understanding the neurobiological underpinnings of the disease is imperative for improving outcomes and can be aided by the study of animal models. The activity-based anorexia rodent model (ABA) is the current best parallel for the study of AN. This review describes the basic neurobiology of feeding and hyperactivity seen in both ABA and AN, and compiles the research on the role that stress-response and reward pathways play in modulating the homeostatic drive to eat and to expend energy, which become dysfunctional in ABA and AN.
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48
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Pimentel GD, Contreras C, López M. Fatty Acids and Hypothalamic Dysfunction in Obesity. HANDBOOK OF LIPIDS IN HUMAN FUNCTION 2016:557-582. [DOI: 10.1016/b978-1-63067-036-8.00021-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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49
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Roseberry AG, Stuhrman K, Dunigan AI. Regulation of the mesocorticolimbic and mesostriatal dopamine systems by α-melanocyte stimulating hormone and agouti-related protein. Neurosci Biobehav Rev 2015; 56:15-25. [DOI: 10.1016/j.neubiorev.2015.06.020] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 06/15/2015] [Accepted: 06/21/2015] [Indexed: 11/24/2022]
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Graebner AK, Iyer M, Carter ME. Understanding how discrete populations of hypothalamic neurons orchestrate complicated behavioral states. Front Syst Neurosci 2015; 9:111. [PMID: 26300745 PMCID: PMC4523943 DOI: 10.3389/fnsys.2015.00111] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2014] [Accepted: 07/16/2015] [Indexed: 01/01/2023] Open
Abstract
A major question in systems neuroscience is how a single population of neurons can interact with the rest of the brain to orchestrate complex behavioral states. The hypothalamus contains many such discrete neuronal populations that individually regulate arousal, feeding, and drinking. For example, hypothalamic neurons that express hypocretin (Hcrt) neuropeptides can sense homeostatic and metabolic factors affecting wakefulness and orchestrate organismal arousal. Neurons that express agouti-related protein (AgRP) can sense the metabolic needs of the body and orchestrate a state of hunger. The organum vasculosum of the lamina terminalis (OVLT) can detect the hypertonicity of blood and orchestrate a state of thirst. Each hypothalamic population is sufficient to generate complicated behavioral states through the combined efforts of distinct efferent projections. The principal challenge to understanding these brain systems is therefore to determine the individual roles of each downstream projection for each behavioral state. In recent years, the development and application of temporally precise, genetically encoded tools has greatly improved our understanding of the structure and function of these neural systems. This review will survey recent advances in our understanding of how these individual hypothalamic populations can orchestrate complicated behavioral states due to the combined efforts of individual downstream projections.
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Affiliation(s)
- Allison K Graebner
- Program in Neuroscience, Department of Biology, Williams College Williamstown, MA, USA
| | - Manasi Iyer
- Program in Neuroscience, Department of Biology, Williams College Williamstown, MA, USA
| | - Matthew E Carter
- Program in Neuroscience, Department of Biology, Williams College Williamstown, MA, USA
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