|
1
|
Xue B, Johnson AK, Bassuk AG. Sex differences in the sensitization of prenatally programmed hypertension. Front Physiol 2025; 16:1589615. [PMID: 40356772 PMCID: PMC12066558 DOI: 10.3389/fphys.2025.1589615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Accepted: 04/18/2025] [Indexed: 05/15/2025] Open
Abstract
Studies have demonstrated that there are sex differences in the timing of onset and severity of prenatally programmed hypertension, with consistently milder phenotypes observed in females relative to male offspring. However, the root cause(s) for these sex-specific effects is unknown. Activation of the renin-angiotensin system (RAS), elevated oxidative stress and inflammation, and sympathetic hyperactivity in the cardiovascular organs and cardiovascular regulatory systems, are all involved in the pathogenesis of hypertension. Sex hormones interact with these prohypertensive systems to modulate blood pressure, and this interaction may lead to a sex-specific development of programmed hypertension. A more complete understanding of the functional capabilities of the sex hormones and their interactions with prohypertensive factors in offspring, from early life to aging, would likely lead to new insights into the basis of sex differences in programmed hypertension. Recently, we have discovered that sex differences also occur in the sensitization of offspring hypertension as programmed by maternal gestational hypertension and that this requires the brain RAS and proinflammatory factors. In this review, we will discuss the possible mechanisms underlying sex differences in sensitization to hypertension in the offspring of mothers exposed to various prenatal insults. These mechanisms operate at various levels from the periphery to the central nervous system (e.g., blood vessel, heart, kidney, and brain). Understanding the sex-specific mechanisms responsible for the sensitized state in offspring can help to develop therapeutic strategies for interrupting the vicious cycle of transgenerational hypertension and for treating hypertension in men and women differentially to maximize efficacy.
Collapse
Affiliation(s)
- Baojian Xue
- Stead Family Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa, IA, United States
| | - Alan Kim Johnson
- Department of Psychological and Brain Sciences, College of Liberal Arts and Sciences, University of Iowa, Iowa, IA, United States
| | - Alexander G. Bassuk
- Stead Family Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa, IA, United States
- The Iowa Neuroscience Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa, IA, United States
- The Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa, IA, United States
| |
Collapse
|
|
2
|
do Carmo JM, Hall JE, Furukawa LNS, Woronik V, Dai X, Ladnier E, Wang Z, Omoto ACM, Mouton A, Li X, Luna-Suarez EM, da Silva AA. Chronic central nervous system leptin administration attenuates kidney dysfunction and injury in a model of ischemia/reperfusion-induced acute kidney injury. Am J Physiol Renal Physiol 2024; 327:F957-F966. [PMID: 39361725 PMCID: PMC11687842 DOI: 10.1152/ajprenal.00158.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 09/30/2024] [Accepted: 09/30/2024] [Indexed: 10/05/2024] Open
Abstract
In the present study, we examined whether chronic intracerebroventricular (ICV) leptin administration protects against ischemia/reperfusion (I/R)-induced acute kidney injury (AKI). Twelve-week-old male rats were implanted with an ICV cannula into the right lateral ventricle, and 8-10 days after surgery, leptin (0.021 µg/h, n = 8) or saline vehicle (0.5 µL/h, n = 8) was infused via osmotic minipump connected to the ICV cannula for 12 days. On day 8 of leptin or vehicle infusion, rats were submitted to unilateral ischemia/reperfusion (UIR) by clamping the left pedicle for 30 min. To control for leptin-induced reductions in food intake, the vehicle-treated group was pair-fed (UIR-PF) to match the same amount of food consumed by leptin-treated (UIR-Leptin) rats. On the 12th day of leptin or vehicle infusion (fourth day after AKI), single-left kidney glomerular filtration rate (GFR) was measured, blood samples were collected to quantify white blood cells, and kidneys were collected for histological assessment of injury. UIR-Leptin-treated rats showed reduced right and left kidney weights (right: 1,040 ± 24 vs. 1,281 ± 36 mg; left: 1,127 ± 71 vs. 1,707 ± 45 mg, for UIR-Leptin and UIR-PF, respectively). ICV leptin infusion improved GFR (0.50 ± 0.06 vs. 0.13 ± 0.03 mL/min/g kidney wt) and reduced kidney injury scores. ICV leptin treatment also attenuated the reduction in circulating adiponectin levels that was observed in UIR-PF rats and increased the circulating white blood cells count compared with UIR-PF rats (16.3 ± 1.3 vs. 9.8 ± 0.6 k/µL). Therefore, we show that leptin, via its actions on the central nervous system, confers significant protection against major kidney dysfunction and injury in a model of ischemia/reperfusion-induced AKI.NEW & NOTEWORTHY A major new finding of this study is that chronic activation of leptin receptors in the CNS markedly attenuates acute kidney injury and protects against severe renal dysfunction after ischemia/reperfusion, independently of leptin's anorexic effects.
Collapse
Affiliation(s)
- Jussara M do Carmo
- Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi, United States
| | - John E Hall
- Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi, United States
| | - Luzia N S Furukawa
- Laboratory of Renal Pathophysiology, Department of Internal Medicine, University of Sao Paulo, Sao Paulo, Brazil
| | - Viktoria Woronik
- Laboratory of Renal Pathophysiology, Department of Internal Medicine, University of Sao Paulo, Sao Paulo, Brazil
| | - Xuemei Dai
- Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi, United States
| | - Emily Ladnier
- Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi, United States
| | - Zhen Wang
- Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi, United States
| | - Ana C M Omoto
- Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi, United States
| | - Alan Mouton
- Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi, United States
| | - Xuan Li
- Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi, United States
| | - Emilio M Luna-Suarez
- Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi, United States
| | - Alexandre A da Silva
- Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi, United States
| |
Collapse
|
|
3
|
Lawton SB, Wagner VA, Nakagawa P, Segar JL, Sigmund CD, Morselli LL, Grobe JL. Angiotensin in the Arcuate: Mechanisms Integrating Cardiometabolic Control: The 2022 COH Mid-Career Award for Research Excellence. Hypertension 2024; 81:2209-2217. [PMID: 39315447 PMCID: PMC11483214 DOI: 10.1161/hypertensionaha.124.20524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
The American Heart Association has identified obesity as a primary impediment to ongoing improvements in cardiovascular diseases, including hypertension. Although drugs, exercise, diets, and surgeries can each cause weight loss, few subjects maintain a reduced weight over the long term. Dysfunctional integrative control (ie, adaptation) of resting metabolic rate (RMR) appears to underlie this failed weight maintenance, yet the neurobiology of physiological and pathophysiological RMR control is poorly understood. Here, we review recent insights into the cellular and molecular control of RMR by Ang-II (angiotensin II) signaling within the arcuate nucleus of the hypothalamus. Within a unique subset of agouti-related peptide neurons, AT1R (Ang-II type 1 receptors) are implicated in the integrative control of RMR. Furthermore, a spontaneous G protein signal switch of AT1R within this neuron type appears to underlie the pathogenesis of RMR adaptation by qualitatively changing the cellular response to AT1R activation from a β-arrestin-1/Gαi (heterotrimeric G protein, α i subtype)-mediated inhibitory response to a Gαq (heterotrimeric G protein, α q subtype)-mediated stimulatory response. We conclude that therapeutic approaches to obesity are likely hampered by the plasticity of the signaling mechanisms that mediate the normal integrative control of energy balance. The same stimulus that would increase RMR in the normal physiological state may decrease RMR during obesity due to qualitative changes in second-messenger coupling. Understanding the mechanisms that regulate interactions between receptors such as AT1R and its various second messenger signaling cascades will provide novel insights into the pathogenesis of RMR adaptation and potentially point toward new therapeutic approaches for obesity and hypertension.
Collapse
Affiliation(s)
- Samuel B.R. Lawton
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226
- Medical Scientist Training Program, Medical College of Wisconsin, Milwaukee, WI 53226
| | - Valerie A. Wagner
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226
| | - Pablo Nakagawa
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226
- Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226
| | - Jeffrey L. Segar
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226
| | - Curt D. Sigmund
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226
- Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226
| | - Lisa L. Morselli
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226
- Department of Medicine, Division of Endocrinology and Molecular Medicine, Medical College of Wisconsin, Milwaukee, WI
| | - Justin L. Grobe
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226
- Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226
- Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, WI 53226
- Comprehensive Rodent Metabolic Phenotyping Core, Medical College of Wisconsin, Milwaukee, WI 53226
| |
Collapse
|
|
4
|
Cincotta AH. Brain Dopamine-Clock Interactions Regulate Cardiometabolic Physiology: Mechanisms of the Observed Cardioprotective Effects of Circadian-Timed Bromocriptine-QR Therapy in Type 2 Diabetes Subjects. Int J Mol Sci 2023; 24:13255. [PMID: 37686060 PMCID: PMC10487918 DOI: 10.3390/ijms241713255] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/19/2023] [Accepted: 07/27/2023] [Indexed: 09/10/2023] Open
Abstract
Despite enormous global efforts within clinical research and medical practice to reduce cardiovascular disease(s) (CVD), it still remains the leading cause of death worldwide. While genetic factors clearly contribute to CVD etiology, the preponderance of epidemiological data indicate that a major common denominator among diverse ethnic populations from around the world contributing to CVD is the composite of Western lifestyle cofactors, particularly Western diets (high saturated fat/simple sugar [particularly high fructose and sucrose and to a lesser extent glucose] diets), psychosocial stress, depression, and altered sleep/wake architecture. Such Western lifestyle cofactors are potent drivers for the increased risk of metabolic syndrome and its attendant downstream CVD. The central nervous system (CNS) evolved to respond to and anticipate changes in the external (and internal) environment to adapt survival mechanisms to perceived stresses (challenges to normal biological function), including the aforementioned Western lifestyle cofactors. Within the CNS of vertebrates in the wild, the biological clock circuitry surveils the environment and has evolved mechanisms for the induction of the obese, insulin-resistant state as a survival mechanism against an anticipated ensuing season of low/no food availability. The peripheral tissues utilize fat as an energy source under muscle insulin resistance, while increased hepatic insulin resistance more readily supplies glucose to the brain. This neural clock function also orchestrates the reversal of the obese, insulin-resistant condition when the low food availability season ends. The circadian neural network that produces these seasonal shifts in metabolism is also responsive to Western lifestyle stressors that drive the CNS clock into survival mode. A major component of this natural or Western lifestyle stressor-induced CNS clock neurophysiological shift potentiating the obese, insulin-resistant state is a diminution of the circadian peak of dopaminergic input activity to the pacemaker clock center, suprachiasmatic nucleus. Pharmacologically preventing this loss of circadian peak dopaminergic activity both prevents and reverses existing metabolic syndrome in a wide variety of animal models of the disorder, including high fat-fed animals. Clinically, across a variety of different study designs, circadian-timed bromocriptine-QR (quick release) (a unique formulation of micronized bromocriptine-a dopamine D2 receptor agonist) therapy of type 2 diabetes subjects improved hyperglycemia, hyperlipidemia, hypertension, immune sterile inflammation, and/or adverse cardiovascular event rate. The present review details the seminal circadian science investigations delineating important roles for CNS circadian peak dopaminergic activity in the regulation of peripheral fuel metabolism and cardiovascular biology and also summarizes the clinical study findings of bromocriptine-QR therapy on cardiometabolic outcomes in type 2 diabetes subjects.
Collapse
|
|
5
|
Sánchez-Lozada LG, Madero M, Mazzali M, Feig DI, Nakagawa T, Lanaspa MA, Kanbay M, Kuwabara M, Rodriguez-Iturbe B, Johnson RJ. Sugar, salt, immunity and the cause of primary hypertension. Clin Kidney J 2023; 16:1239-1248. [PMID: 37529651 PMCID: PMC10387395 DOI: 10.1093/ckj/sfad058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Indexed: 08/03/2023] Open
Abstract
Despite its discovery more than 150 years ago, the cause of primary hypertension remains unknown. Most studies suggest that hypertension involves genetic, congenital or acquired risk factors that result in a relative inability of the kidney to excrete salt (sodium chloride) in the kidneys. Here we review recent studies that suggest there may be two phases, with an initial phase driven by renal vasoconstriction that causes low-grade ischemia to the kidney, followed by the infiltration of immune cells that leads to a local autoimmune reaction that maintains the renal vasoconstriction. Evidence suggests that multiple mechanisms could trigger the initial renal vasoconstriction, but one way may involve fructose that is provided in the diet (such as from table sugar or high fructose corn syrup) or produced endogenously. The fructose metabolism increases intracellular uric acid, which recruits NADPH oxidase to the mitochondria while inhibiting AMP-activated protein kinase. A drop in intracellular ATP level occurs, triggering a survival response. Leptin levels rise, triggering activation of the sympathetic central nervous system, while vasopressin levels rise, causing vasoconstriction in its own right and stimulating aldosterone production via the vasopressin 1b receptor. Low-grade renal injury and autoimmune-mediated inflammation occur. High-salt diets can amplify this process by raising osmolality and triggering more fructose production. Thus, primary hypertension may result from the overactivation of a survival response triggered by fructose metabolism. Restricting salt and sugar and hydrating with ample water may be helpful in the prevention of primary hypertension.
Collapse
Affiliation(s)
- Laura G Sánchez-Lozada
- Department of Cardio-Renal Physiopathology, Instituto Nacional de Cardiología “Ignacio Chavez”, Mexico City, Mexico
| | - Magdalena Madero
- Division of Nephrology, Department of Medicine, Instituto Nacional de Cardiología “Ignacio Chavez”, Mexico City, Mexico
| | - Marilda Mazzali
- Division of Nephrology, University of Campinas, São Paulo, Brazil
| | - Daniel I Feig
- Division of Pediatric Nephrology, University of Alabama, Birmingham, AL, USA
| | | | - Miguel A Lanaspa
- Department of Medicine, University of Colorado Anschutz Medical Center, Aurora, CO, USA
| | - Mehmet Kanbay
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | | | - Bernardo Rodriguez-Iturbe
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”, Mexico City
| | - Richard J Johnson
- Department of Medicine, University of Colorado Anschutz Medical Center, Aurora, CO, USA
| |
Collapse
|
|
6
|
Zhao Y, Li H. Association of serum leptin and insulin levels among type 2 diabetes mellitus patients: A case-control study. Medicine (Baltimore) 2022; 101:e31006. [PMID: 36254065 PMCID: PMC9575727 DOI: 10.1097/md.0000000000031006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Secretion of insulin is compromised in type 2 diabetes (T2DM) individuals and inadequate to accommodate for insulin resistance (IR) in peripheral tissue. Hyperleptinemia reflects leptin resistance, which is a key factor in the production of IR in T2DM patients, making leptin a potential biomarker for evaluating IR levels. The objective of the study was to assess the association of serum leptin and insulin levels among T2DM patients. This case-control research was carried out on T2DM patients. A total of 73 patients diagnosed with T2DM (the case group) and 40 healthy participants (control; group 3) were enrolled according to the American Diabetes Association (ADA) criteria. In the case group, T2DM patients were enrolled with metabolic syndrome (group 1, n = 38) or without metabolic syndrome (group 2, n = 35) according to the WHO criteria. Metabolic profiles of T2DM patients with or without metabolic syndrome were evaluated, and compare these two groups with healthy controls. The subjects of all groups were age- and gender-matched. Body mass index (BMI, P < .01), fasting (P = .0133) and postprandial (P < .01) blood sugar levels, % glycated hemoglobin (HbA1c, P < .01), and lipid profile (P < .01) were found significantly different and higher in group 1 as compared to groups 2 and 3. Serum leptin and insulin levels were found higher and significant in patients with metabolic syndrome (P < .01 for both). The values of serum leptin levels were 10.01 ± 2.7 ng/mL, 6.9 ± 2.4 ng/mL, and 4.11 ± 1.8 ng/mL, and those of serum insulin 120 ± 40.7 µIU/mL, 20.43 ± 5.2 µIU/mL, and 11.4 ± 2.5 µIU/mL in groups 1, 2, and 3, respectively. There was a positive linear correlation between BMI, blood sugar, HbA1c, serum cholesterol (TC), and triglycerides (TG) with serum insulin and leptin levels in the case group. An extremely significant correlation (R = 0.74, P < .001) was found in BMI and serum leptin level in the case group. Serum leptin and insulin levels have a positive association, with serum leptin being a significant predictor of IR syndrome (Evidence Level: 5; Technical Efficacy: Stage 3).
Collapse
Affiliation(s)
- Yanfei Zhao
- VIP Ward, Tianjin TEDA Hospital, Tianjin, China
| | - Huihui Li
- Department of Endocrinology, Tianjin TEDA Hospital, Tianjin, China
- * Correspondence: Huihui Li, Department of Endocrinology, Tianjin TEDA Hospital, Tianjin 300456, China (e-mail: )
| |
Collapse
|
|
7
|
Yang T. Soluble (Pro)Renin Receptor in Hypertension. Nephron Clin Pract 2022; 147:234-243. [PMID: 35871512 PMCID: PMC9867785 DOI: 10.1159/000525635] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 05/27/2022] [Indexed: 01/26/2023] Open
Abstract
The (pro)renin receptor (PRR) was originally cloned as a specific single-transmembrane receptor for prorenin and renin and has now emerged as a multifunctional protein implicated in a wide variety of developmental and physiopathological processes. Activation of PRR in the kidney causes Na+ and water retention, contributing to elevation of blood pressure in response to various hypertensive stimuli. Part of the renal action of PRR depends on activation of intrarenal renin-angiotensin system. In recent years, accumulating evidence suggests that the prohypertensive action of renal PRR was largely mediated by production of the 28-kDa soluble (pro)renin receptor through protease-mediated cleavage of the extracellular domain of PRR. The generation of multiple isoforms of PRR due to the protease-mediated cleavage partially explains diversified actions of PRR. The current review will summarize recent advances in understanding the roles of sPPR in animal models of hypertension.
Collapse
Affiliation(s)
- Tianxin Yang
- Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah, USA
| |
Collapse
|
|
8
|
Singh U, Jiang J, Saito K, Toth BA, Dickey JE, Rodeghiero SR, Deng Y, Deng G, Xue B, Zhu Z, Zingman LV, Geerling JC, Cui H. Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations. Mol Metab 2022; 55:101401. [PMID: 34823066 PMCID: PMC8689242 DOI: 10.1016/j.molmet.2021.101401] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/04/2021] [Accepted: 11/17/2021] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVE The paraventricular nucleus of hypothalamus (PVN), an integrative center in the brain, orchestrates a wide range of physiological and behavioral responses. While the PVN melanocortin 4 receptor (MC4R) signaling (PVNMC4R+) is involved in feeding regulation, the neuroanatomical organization of PVNMC4R+ connectivity and its role in other physiological regulations are incompletely understood. Here we aimed to better characterize the input-output organization of PVNMC4R+ neurons and test their physiological functions beyond feeding. METHODS Using a combination of viral tools, we mapped PVNMC4R+ circuits and tested the effects of chemogenetic activation of PVNMC4R+ neurons on thermoregulation, cardiovascular control, and other behavioral responses beyond feeding. RESULTS We found that PVNMC4R+ neurons innervate many different brain regions that are known to be important not only for feeding but also for neuroendocrine and autonomic control of thermoregulation and cardiovascular function, including but not limited to the preoptic area, median eminence, parabrachial nucleus, pre-locus coeruleus, nucleus of solitary tract, ventrolateral medulla, and thoracic spinal cord. Contrary to these broad efferent projections, PVNMC4R+ neurons receive monosynaptic inputs mainly from other hypothalamic nuclei (preoptic area, arcuate and dorsomedial hypothalamic nuclei, supraoptic nucleus, and premammillary nucleus), the circumventricular organs (subfornical organ and vascular organ of lamina terminalis), the bed nucleus of stria terminalis, and the parabrachial nucleus. Consistent with their broad efferent projections, chemogenetic activation of PVNMC4R+ neurons not only suppressed feeding but also led to an apparent increase in heart rate, blood pressure, and brown adipose tissue temperature. These physiological changes accompanied acute transient hyperactivity followed by hypoactivity and resting-like behavior. CONCLUSIONS Our results elucidate the neuroanatomical organization of PVNMC4R+ circuits and shed new light on the roles of PVNMC4R+ pathways in autonomic control of thermoregulation, cardiovascular function, and biphasic behavioral activation.
Collapse
Affiliation(s)
- Uday Singh
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, United States
| | - Jingwei Jiang
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, United States
| | - Kenji Saito
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, United States
| | - Brandon A Toth
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, United States
| | - Jacob E Dickey
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, United States
| | - Samuel R Rodeghiero
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, United States
| | - Yue Deng
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, United States
| | - Guorui Deng
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, United States
| | - Baojian Xue
- Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA, United States
| | - Zhiyong Zhu
- Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United States
| | - Leonid V Zingman
- Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United States
| | - Joel C Geerling
- Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, United States; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA, United States
| | - Huxing Cui
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, United States; F.O.E. Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, United States; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA, United States; Obesity Research and Educational Initiative, University of Iowa Carver College of Medicine, Iowa City, IA, United States.
| |
Collapse
|
|
9
|
Copperi F, Kim JD, Diano S. Role of the Melanocortin System in the Central Regulation of Cardiovascular Functions. Front Physiol 2021; 12:725709. [PMID: 34512392 PMCID: PMC8424695 DOI: 10.3389/fphys.2021.725709] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 07/30/2021] [Indexed: 11/18/2022] Open
Abstract
Increasing evidence indicates that the melanocortin system is not only a central player in energy homeostasis, food intake and glucose level regulation, but also in the modulation of cardiovascular functions, such as blood pressure and heart rate. The melanocortins, and in particular α- and γ-MSH, have been shown to exert their cardiovascular activity both at the central nervous system level and in the periphery (e.g., in the adrenal gland), binding their receptors MC3R and MC4R and influencing the activity of the sympathetic nervous system. In addition, some studies have shown that the activation of MC3R and MC4R by their endogenous ligands is able to improve the outcome of cardiovascular diseases, such as myocardial and cerebral ischemia. In this brief review, we will discuss the current knowledge of how the melanocortin system influences essential cardiovascular functions, such as blood pressure and heart rate, and its protective role in ischemic events, with a particular focus on the central regulation of such mechanisms.
Collapse
Affiliation(s)
- Francesca Copperi
- Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY, United States
| | - Jung Dae Kim
- Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY, United States
| | - Sabrina Diano
- Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY, United States
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY, United States
- Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, United States
| |
Collapse
|
|
10
|
Obesity-associated cardiovascular risk in women: hypertension and heart failure. Clin Sci (Lond) 2021; 135:1523-1544. [PMID: 34160010 DOI: 10.1042/cs20210384] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/14/2021] [Accepted: 06/07/2021] [Indexed: 02/07/2023]
Abstract
The pathogenesis of obesity-associated cardiovascular diseases begins long prior to the presentation of a cardiovascular event. In both men and women, cardiovascular events, and their associated hospitalizations and mortality, are often clinically predisposed by the presentation of a chronic cardiovascular risk factor. Obesity increases the risk of cardiovascular diseases in both sexes, however, the clinical prevalence of obesity, as well as its contribution to crucial cardiovascular risk factors is dependent on sex. The mechanisms via which obesity leads to cardiovascular risk is also discrepant in women between their premenopausal, pregnancy and postmenopausal phases of life. Emerging data indicate that at all reproductive statuses and ages, the presentation of a cardiovascular event in obese women is strongly associated with hypertension and its subsequent chronic risk factor, heart failure with preserved ejection fraction (HFpEF). In addition, emerging evidence indicates that obesity increases the risk of both hypertension and heart failure in pregnancy. This review will summarize clinical and experimental data on the female-specific prevalence and mechanisms of hypertension and heart failure in women across reproductive stages and highlight the particular risks in pregnancy as well as emerging data in a high-risk ethnicity in women of African ancestry (AA).
Collapse
|
|
11
|
Palei AC, Martin HL, Wilson BA, Anderson CD, Granger JP, Spradley FT. Impact of hyperleptinemia during placental ischemia-induced hypertension in pregnant rats. Am J Physiol Heart Circ Physiol 2021; 320:H1949-H1958. [PMID: 33710923 DOI: 10.1152/ajpheart.00724.2019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The prevalence of preeclampsia and obesity have increased. Although obesity is a major risk factor for preeclampsia, the mechanisms linking these morbidities are poorly understood. Circulating leptin levels increase in proportion to fat mass. Infusion of this adipokine elicits hypertension in nonpregnant rats, but less is known about how hyperleptinemia impacts blood pressure during placental ischemia, an initiating event in the pathophysiology of hypertension in preeclampsia. We tested the hypothesis that hyperleptinemia during reduced uterine perfusion pressure (RUPP) exaggerates placental ischemia-induced hypertension. On gestational day (GD) 14, Sprague-Dawley rats were implanted with osmotic mini-pumps delivering recombinant rat leptin (1 µg/kg/min iv) or vehicle concurrently with the RUPP procedure to induce placental ischemia or Sham. On GD 19, plasma leptin was elevated in Sham + Leptin and RUPP + Leptin. Leptin infusion did not significantly impact mean arterial pressure (MAP) in Sham. MAP was increased in RUPP + Vehicle vs. Sham + Vehicle. In contrast to our hypothesis, placental ischemia-induced hypertension was attenuated by leptin infusion. To examine potential mechanisms for attenuation of RUPP-induced hypertension during hyperleptinemia, endothelial-dependent vasorelaxation to acetylcholine was similar between Sham and RUPP; however, endothelial-independent vasorelaxation to the nitric oxide (NO)-donor, sodium nitroprusside, was increased in Sham and RUPP. These findings suggest that NO/cyclic guanosine monophosphate (cGMP) signaling was increased in the presence of hyperleptinemia. Plasma cGMP was elevated in Sham and RUPP hyperleptinemic groups compared with vehicle groups but plasma and vascular NO metabolites were reduced. These data suggest that hyperleptinemia during placental ischemia attenuates hypertension by compensatory increases in NO/cGMP signaling.NEW & NOTEWORTHY Ours is the first study to examine the impact of hyperleptinemia on the development of placental ischemia-induced hypertension using an experimental animal model.
Collapse
Affiliation(s)
- Ana C Palei
- Department of Surgery, The University of Mississippi Medical Center, Jackson, Mississippi
| | - Hunter L Martin
- Department of Surgery, The University of Mississippi Medical Center, Jackson, Mississippi.,Department of Physiology and Biophysics, The University of Mississippi Medical Center, Jackson, Mississippi
| | - Barbara A Wilson
- Department of Surgery, The University of Mississippi Medical Center, Jackson, Mississippi
| | - Christopher D Anderson
- Department of Surgery, The University of Mississippi Medical Center, Jackson, Mississippi
| | - Joey P Granger
- Department of Physiology and Biophysics, The University of Mississippi Medical Center, Jackson, Mississippi
| | - Frank T Spradley
- Department of Surgery, The University of Mississippi Medical Center, Jackson, Mississippi.,Department of Physiology and Biophysics, The University of Mississippi Medical Center, Jackson, Mississippi
| |
Collapse
|
|
12
|
Ahmari N, Hayward LF, Zubcevic J. The importance of bone marrow and the immune system in driving increases in blood pressure and sympathetic nerve activity in hypertension. Exp Physiol 2020; 105:1815-1826. [PMID: 32964557 DOI: 10.1113/ep088247] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 09/01/2020] [Indexed: 12/27/2022]
Abstract
NEW FINDINGS What is the topic of this review? This manuscript provides a review of the current understanding of the role of the sympathetic nervous system in regulation of bone marrow-derived immune cells and the effect that the infiltrating bone marrow cells may have on perpetuation of the sympathetic over-activation in hypertension. What advances does it highlight? We highlight the recent advances in understanding of the neuroimmune interactions both peripherally and centrally as they relate to blood pressure control. ABSTRACT The sympathetic nervous system (SNS) plays a crucial role in maintaining physiological homeostasis, in part by regulating, integrating and orchestrating processes between many physiological systems, including the immune system. Sympathetic nerves innervate all primary and secondary immune organs, and all cells of the immune system express β-adrenoreceptors. In turn, immune cells can produce cytokines, chemokines and neurotransmitters capable of modulating neuronal activity and, ultimately, SNS activity. Thus, the essential role of the SNS in the regulation of innate and adaptive immune functions is mediated, in part, via β-adrenoreceptor-induced activation of bone marrow cells by noradrenaline. Interestingly, both central and systemic inflammation are well-established hallmarks of hypertension and its co-morbidities, including an inflammatory process involving the transmigration and infiltration of immune cells into tissues. We propose that physiological states that prolong β-adrenoreceptor activation in bone marrow can disrupt neuroimmune homeostasis and impair communication between the immune system and SNS, leading to immune dysregulation, which, in turn, is sustained via a central mechanism involving neuroinflammation.
Collapse
Affiliation(s)
- Niousha Ahmari
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Linda F Hayward
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, USA.,Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA
| | - Jasenka Zubcevic
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, USA.,Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA
| |
Collapse
|
|
13
|
Spradley FT. High-fat diet from parental generation exaggerates body and adipose tissue weights in pregnant offspring. PLoS One 2020; 15:e0237708. [PMID: 32817646 PMCID: PMC7446828 DOI: 10.1371/journal.pone.0237708] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 07/25/2020] [Indexed: 11/18/2022] Open
Abstract
Parental high-fat diet (HFD) programs for obesity and hypertension in female offspring in rats, but it is unknown how the pregnancies of these offspring are impacted. Therefore, the hypothesis was tested that parental HFD exaggerates obesity and hypertension during pregnancy of the offspring. Wistar Hannover rat dams (the parental, P generation) were maintained on normal-fat diet (NFD) or HFD from weaning and were kept on respective diets through pregnancy and lactation. Their offspring (the first filial, F1 generation) were weaned onto the same diet as the P generation, or they were changed to the other diet to determine if combined HFD in the P and F1 generations exaggerates body weight and blood pressure levels during pregnancy in these offspring. This diet paradigm resulted in the following groups of pregnant F1 offspring: P-NFD/F1-NFD, P-HFD/F1-NFD, P-NFD/F1-HFD, and P-HFD/F1-HFD. Maternal body and adipose tissue weights were greatest in the P-HFD/F1-HFD group compared to the other 3 groups by the end of pregnancy. Plasma leptin and conscious mean arterial blood pressure were not significantly different between any group, although there was a main effect for increased blood pressure in the F1-HFD groups. Circulating levels of the antihypertensive pregnancy factor, placental growth factor (PlGF), were assessed. Although average PlGF levels were similar among all groups, correlative studies revealed that lower levels of PlGF were associated with higher blood pressure only in the P-HFD/F1-HFD group. In summary, HFD feeding from the P generation exaggerated HFD-induced body and adipose tissue weights in the pregnant offspring.
Collapse
Affiliation(s)
- Frank T. Spradley
- Department of Surgery, University of Mississippi Medical Center, Jackson, MS, United States of America
- * E-mail:
| |
Collapse
|
|
14
|
do Carmo JM, da Silva AA, Moak SP, da Silva FS, Spradley FT, Hall JE. Role of melanocortin 4 receptor in hypertension induced by chronic intermittent hypoxia. Acta Physiol (Oxf) 2019; 225:e13222. [PMID: 30466186 DOI: 10.1111/apha.13222] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 11/13/2018] [Accepted: 11/15/2018] [Indexed: 12/23/2022]
Abstract
AIM We previously demonstrated that central nervous system (CNS) melanocortin 4 receptors (MC4R) play a key role in regulating blood pressure (BP) in some conditions associated with increased SNS activity, including obesity. In this study, we examined whether activation of CNS MC4R contributes to chronic intermittent hypoxia (CIH)-induced hypertension and ventilatory responses to hypercapnia. METHODS Rats were instrumented with an intracerebroventricular (ICV) cannula in the lateral cerebral ventricle for continuous infusion of MC4R antagonist (SHU-9119) and telemetry probes for measuring mean arterial pressure (MAP) and heart rate (HR). Untreated and SHU-9119-treated rats as well as obese and lean MC4R-deficient rats were exposed to CIH for 7-18 consecutive days. RESULTS Chronic intermittent hypoxia reduced cumulative food intake by 18 ± 5 g while MAP and HR increased by 10 ± 3 mm Hg and 9 ± 5 bpm in untreated rats. SHU-9119 increased food intake (from 15 ± 1 to 46 ± 3 g) and prevented CIH-induced reduction in food intake. CIH-induced hypertension was not attenuated by MC4R antagonism (average increase of 10 ± 1 vs 9 ± 1 mm Hg for untreated and SHU-9119 treated rats). In obese MC4R-deficient rats, CIH for 7 days raised BP by 11 ± 4 mm Hg. However, when MC4R-deficient rats were food restricted to prevent obesity, CIH-induced hypertension was attenuated by 32%. We also found that MC4R deficiency was associated with impaired ventilatory responses to hypercapnia independently of obesity. CONCLUSION These results show that obesity and the CNS melanocortin system interact in complex ways to elevate BP during CIH and that MC4R may be important in the ventilatory responses to hypercapnia.
Collapse
Affiliation(s)
- Jussara M. do Carmo
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular‐Renal Research Center University of Mississippi Medical Center Jackson Mississippi
| | - Alexandre A. da Silva
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular‐Renal Research Center University of Mississippi Medical Center Jackson Mississippi
- Barão de Mauá University Center Ribeirão Preto Brazil
- Universidade Estadual de Minas Gerais Passos Brazil
| | - Sydney P. Moak
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular‐Renal Research Center University of Mississippi Medical Center Jackson Mississippi
| | - Fernanda S. da Silva
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular‐Renal Research Center University of Mississippi Medical Center Jackson Mississippi
- Barão de Mauá University Center Ribeirão Preto Brazil
| | - Frank T. Spradley
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular‐Renal Research Center University of Mississippi Medical Center Jackson Mississippi
- Department of Surgery University of Mississippi Medical Center Jackson Mississippi
| | - John E. Hall
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular‐Renal Research Center University of Mississippi Medical Center Jackson Mississippi
| |
Collapse
|
|
15
|
Ray A. Cancer and comorbidity: The role of leptin in breast cancer and associated pathologies. World J Clin Cases 2018; 6:483-492. [PMID: 30397604 PMCID: PMC6212611 DOI: 10.12998/wjcc.v6.i12.483] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 08/23/2018] [Accepted: 08/30/2018] [Indexed: 02/05/2023] Open
Abstract
Obesity is an important risk factor for postmenopausal breast cancer and also a poor prognostic factor among cancer patients. Moreover, obesity is associated with a number of health disorders such as insulin resistance/type-2 diabetes mellitus, hypertension, and other cardiovascular diseases. Frequently, these health disorders exhibit as components/complications of the metabolic syndrome. Nevertheless, obesity-related diseases may coexist with postmenopausal breast cancer; and these comorbid conditions could be substantial. Therefore, it may be assumed that different diseases including breast cancer could originate from a common pathological background in excessive adipose tissue. Adipocyte-released hormone-like cytokine (or adipokine) leptin behaves differently in a normal healthy state and obesity. A growing body of evidence suggests an important role of leptin in our major obesity-related health issues such as insulin resistance, hypertension, and neoplasia. In this context, this review describes the relationships of the abovementioned pathologies with leptin.
Collapse
Affiliation(s)
- Amitabha Ray
- Lake Erie College of Osteopathic Medicine, Seton Hill University, Greensburg, PA 15601, United State
| |
Collapse
|
|
16
|
Idelevich A, Baron R. Brain to bone: What is the contribution of the brain to skeletal homeostasis? Bone 2018; 115:31-42. [PMID: 29777919 PMCID: PMC6110971 DOI: 10.1016/j.bone.2018.05.018] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 05/15/2018] [Accepted: 05/15/2018] [Indexed: 12/13/2022]
Abstract
The brain, which governs most, if not all, physiological functions in the body, from the complexities of cognition, learning and memory, to the regulation of basal body temperature, heart rate and breathing, has long been known to affect skeletal health. In particular, the hypothalamus - located at the base of the brain in close proximity to the medial eminence, where the blood-brain-barrier is not as tight as in other regions of the brain but rather "leaky", due to fenestrated capillaries - is exposed to a variety of circulating body cues, such as nutrients (glucose, fatty acids, amino acids), and hormones (insulin, glucagon, leptin, adiponectin) [1-3].Information collected from the body via these peripheral cues is integrated by hypothalamic sensing neurons and glial cells [4-7], which express receptors for these nutrients and hormones, transforming these cues into physiological outputs. Interestingly, many of the same molecules, including leptin, adiponectin and insulin, regulate both energy and skeletal homeostasis. Moreover, they act on a common set of hypothalamic nuclei and their residing neurons, activating endocrine and neuronal systems, which ultimately fine-tune the body to new physiological states. This review will focus exclusively on the brain-to-bone pathway, highlighting the most important anatomical sites within the brain, which are known to affect bone, but not covering the input pathways and molecules informing the brain of the energy and bone metabolic status, covered elsewhere [8-10]. The discussion in each section will present side by side the metabolic and bone-related functions of hypothalamic nuclei, in an attempt to answer some of the long-standing questions of whether energy is affected by bone remodeling and homeostasis and vice versa.
Collapse
Affiliation(s)
- Anna Idelevich
- Department of Medicine, Harvard Medical School and Endocrine Unit MGH, Division of Bone and Mineral Metabolism, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA
| | - Roland Baron
- Department of Medicine, Harvard Medical School and Endocrine Unit MGH, Division of Bone and Mineral Metabolism, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA.
| |
Collapse
|
|
17
|
Jiang P, Ma D, Wang X, Wang Y, Bi Y, Yang J, Wang X, Li X. Astragaloside IV Prevents Obesity-Associated Hypertension by Improving Pro-Inflammatory Reaction and Leptin Resistance. Mol Cells 2018; 41:244-255. [PMID: 29562733 PMCID: PMC5881098 DOI: 10.14348/molcells.2018.2156] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 12/05/2017] [Accepted: 12/18/2017] [Indexed: 12/13/2022] Open
Abstract
Low-grade pro-inflammatory state and leptin resistance are important underlying mechanisms that contribute to obesity-associated hypertension. We tested the hypothesis that Astragaloside IV (As IV), known to counteract obesity and hypertension, could prevent obesity-associated hypertension by inhibiting pro-inflammatory reaction and leptin resistance. High-fat diet (HFD) induced obese rats were randomly assigned to three groups: the HFD control group (HF con group), As IV group, and the As IV + α-bungaratoxin (α-BGT) group (As IV+α-BGT group). As IV (20 mg·Kg-1·d-1) was administrated to rats for 6 weeks via daily oral gavage. Body weight and blood pressure were continuously measured, and NE levels in the plasma and renal cortex was evaluated to reflect the sympathetic activity. The expressions of leptin receptor (LepRb) mRNA, phosphorylated signal transducer and activator of transcription-3 (p-STAT3), phosphorylated phosphatidylinositol 3-kinase (p-PI3K), suppressor of cytokine signaling 3 (SOCS3) mRNA, and protein-tyrosine phosphatase 1B (PTP1B) mRNA, pro-opiomelanocortin (POMC) mRNA and neuropeptide Y (NPY) mRNA were measured by Western blot or qRT-PCR to evaluate the hypothalamic leptin sensitivity. Additionally, we measured the protein or mRNA levels of α7nAChR, inhibitor of nuclear factor κB kinase subunit β/ nuclear factor κB (IKKβ/NF-KB) and pro-inflammatory cytokines (IL-1β and TNF-α) in hypothalamus and adipose tissue to reflect the anti-inflammatory effects of As IV through upregulating expression of α7nAChR. We found that As IV prevented body weight gain and adipose accumulation, and also improved metabolic disorders in HFD rats. Furthermore, As IV decreased BP and HR, as well as NE levels in blood and renal tissue. In the hypothalamus, As IV alleviated leptin resistance as evidenced by the increased p-STAT3, LepRb mRNA and POMC mRNA, and decreased p-PI3K, SOCS3 mRNA, and PTP1B mRNA. The effects of As IV on leptin sensitivity were related in part to the up-regulated α7nAchR and suppressed IKKβ/NF-KB signaling and pro-inflammatory cytokines in the hypothalamus and adipose tissue, since co-administration of α7nAChR selective antagonist α-BGT could weaken the improved effect of As IV on central leptin resistance. Our study suggested that As IV could efficiently prevent obesity-associated hypertension through inhibiting inflammatory reaction and improving leptin resistance; furthermore, these effects of As IV was partly related to the increased α7nAchR expression.
Collapse
Affiliation(s)
- Ping Jiang
- Shandong University of Traditional Chinese Medicine, Jinan, Shandong,
R.P, China
| | - Dufang Ma
- Shandong University of Traditional Chinese Medicine, Jinan, Shandong,
R.P, China
| | - Xue Wang
- China Academy of Chinese Medica Sciences, Beijing,
R.P, China
| | - Yongcheng Wang
- Shandong University of Traditional Chinese Medicine, Jinan, Shandong,
R.P, China
| | - Yuxin Bi
- Shandong University of Traditional Chinese Medicine, Jinan, Shandong,
R.P, China
| | - Jinlong Yang
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong,
P.R, China
| | - Xuebing Wang
- Shandong University of Traditional Chinese Medicine, Jinan, Shandong,
R.P, China
| | - Xiao Li
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong,
P.R, China
| |
Collapse
|
|
18
|
Effects of Intrauterine Growth Restriction and Female Sex on Future Blood Pressure and Cardiovascular Disease. Curr Hypertens Rep 2017; 19:13. [PMID: 28233240 DOI: 10.1007/s11906-017-0712-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
PURPOSE OF THE REVIEW It is well-established that the age-related increase in blood pressure is augmented after menopause. Yet, the prevalence of hypertension is enhanced in low birth weight women relative to normal birth weight counterparts by 60 years of age suggesting that adverse influences during fetal life heighten cardiovascular risk in later life. RECENT FINDINGS A changing hormonal milieu may contribute to increased cardiovascular risk that occurs after the menopausal transition. Low birth weight is associated with early age at menopause. A recent study indicates that a shift towards testosterone excess following early reproductive senescence may contribute to the etiology of age-dependent increases in blood pressure in a rodent model of low birth weight. This review will highlight current findings related to postmenopausal hypertension and discuss potential mechanisms that may contribute to the enhanced cardiovascular risk that develops with age in low birth weight women.
Collapse
|
|
19
|
Yu B, Cai D. Neural Programmatic Role of Leptin, TNFα, Melanocortin, and Glutamate in Blood Pressure Regulation vs Obesity-Related Hypertension in Male C57BL/6 Mice. Endocrinology 2017; 158:1766-1775. [PMID: 28419227 PMCID: PMC5460935 DOI: 10.1210/en.2016-1872] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 04/10/2017] [Indexed: 02/07/2023]
Abstract
Continuous nutritional surplus sets the stage for hypertension development. Whereas moderate dietary obesity in mice is normotensive, the homeostatic balance is disrupted concurrent with an increased risk of hypertension. However, it remains unclear how the obesity-associated prehypertensive state is converted into overt hypertension. Here, using mice with high-fat-diet (HFD)-induced moderate obesity vs control diet (CD)-fed lean mice, we comparatively studied the effects of central leptin and tumor necrosis factor-α (TNFα) as well as the involvement of the neuropeptide melanocortin pathway vs the neurotransmitter glutamate pathway. Compared with CD-fed lean mice, the pressor effect of central excess leptin and TNFα, but not melanocortin, was sensitized in HFD-fed mice. The pressor effect of central leptin in HFD-fed mice was strongly suppressed by glutamatergic inhibition but not by melanocortinergic inhibition. The pressor effect of central TNFα was substantially reversed by melanocortinergic inhibition in HFD-fed mice but barely in CD-fed mice. Regardless of diet, the hypertensive effects of central TNFα and melanocortin were both partially reversed by glutamatergic suppression. Hence, neural control of blood pressure is mediated by a signaling network between leptin, TNFα, melanocortin, and glutamate and changes in dynamics due to central excess leptin and TNFα mediate the switch from normal physiology to obesity-related hypertension.
Collapse
Affiliation(s)
- Bin Yu
- Department of Molecular Pharmacology, Diabetes Research Center, Institute of Aging, Albert Einstein College of Medicine, Bronx, New York 10461
| | - Dongsheng Cai
- Department of Molecular Pharmacology, Diabetes Research Center, Institute of Aging, Albert Einstein College of Medicine, Bronx, New York 10461
| |
Collapse
|
|
20
|
Chen H, Luo M, Huang J, Xu H, Xie N, Zheng H. Leptin is associated with heart rate recovery in Chinese hypertensive patients. Clin Exp Hypertens 2017; 39:241-245. [PMID: 28448190 DOI: 10.1080/10641963.2016.1246560] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Elevated serum leptin concentrations are closely related to sympathetic nervous system activation in essential hypertension (EH); however, it is not clear whether or not they are associated with parasympathetic nervous system impairment in EH. Heart rate recovery (HRR) is a reproducible method used to assess parasympathetic activity. This study aimed to investigate the relationship between serum leptin and HRR in Chinese untreated EH patients. This was a cross-sectional study enrolling 471 Chinese EH patients (205 men, 266 women; mean age 63.1 years). HRR was calculated during an incremental cardiopulmonary exercise test. Simple and multiple regression analyses were used to assess the correlation between serum leptin level and HRR value. Serum leptin levels elevated with increasing BP values. Moreover, univariate analysis revealed that the HRR value was negatively correlated with serum leptin (r = -0.037, P < 0.01). In multiple regression analysis, the age-adjusted serum leptin level was negatively correlated with HRR (β = -0.268, P < 0.01). Serum leptin remained negatively associated with HRR (β = -0.017, P < 0.01) after further adjustments for factors including age, systolic blood pressure, total cholesterol, and several factors that correlated with HRR. Our findings demonstrated that a raised serum leptin concentration is related to HRR blunt, which suggests that the role of leptin in the development of EH might be associated with impairment of the parasympathetic nervous system as well.
Collapse
Affiliation(s)
- Haibin Chen
- a Cardiology Department , Tongji Hospital Affiliated to Tongji University , Shanghai , P.R. China
| | - Ming Luo
- b Geriatrics Department , Tongji Hospital Affiliated to Tongji University , Shanghai , P.R. China
| | - Junling Huang
- b Geriatrics Department , Tongji Hospital Affiliated to Tongji University , Shanghai , P.R. China
| | - Huifeng Xu
- a Cardiology Department , Tongji Hospital Affiliated to Tongji University , Shanghai , P.R. China
| | - Nanzi Xie
- b Geriatrics Department , Tongji Hospital Affiliated to Tongji University , Shanghai , P.R. China
| | - Huan Zheng
- b Geriatrics Department , Tongji Hospital Affiliated to Tongji University , Shanghai , P.R. China
| |
Collapse
|
|
21
|
Samson R, Qi A, Jaiswal A, Le Jemtel TH, Oparil S. Obesity-Associated Hypertension: the Upcoming Phenotype in African-American Women. Curr Hypertens Rep 2017; 19:41. [DOI: 10.1007/s11906-017-0738-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
|
|
22
|
Senba E, Kami K. A new aspect of chronic pain as a lifestyle-related disease. NEUROBIOLOGY OF PAIN 2017; 1:6-15. [PMID: 31194049 PMCID: PMC6550110 DOI: 10.1016/j.ynpai.2017.04.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 04/14/2017] [Indexed: 12/22/2022]
Abstract
Activation of mesolimbic dopamine system underlies exercise-induced hypoalgesia. Interaction between mesolimbic system and hypothalamus determines physical activity. Changing the lifestyle inactive to active may attenuate and prevent chronic pain. Physical exercise has been established as a low-cost, safe, and effective way to manage chronic intractable pain. We investigated the underlying mechanisms of exercise-induced hypoalgesia (EIH) using a mouse model of neuropathic pain (NPP). Epigenetic changes in activated microglia and maintained GABA synthesis in the spinal dorsal horn may contribute to EIH. Voluntary exercise (VE), a strong reward for animals, also induced EIH, which may be due in part to the activation of dopamine (DA) neurons in the ventral tegmental area (VTA). VE increases the expression of pCREB in dopaminergic neurons in the VTA, which would enhance dopamine production, and thereby contributes to the activation of the mesolimbic reward system in NPP model mice. We demonstrated that neurons in the laterodorsal tegmental and pedunculopontine tegmental nuclei, a major input source of rewarding stimuli to the VTA, were activated by exercise. Chronic pain is at least partly attributed to sedentary and inactive lifestyle as indicated by the Fear-avoidance model. Therefore, chronic pain could be recognized as a lifestyle-related disease. Physical activity/inactivity may be determined by genetic/epigenetic and neural factors encoded in our brain. The hypothalamus and reward system is closely related in the axis of food intake, energy metabolism and physical activity. Understanding the interactions between the mesolimbic DA system and the hypothalamus that sense and regulate energy balance is thus of significant importance. For example, proopiomelanocortin neurons and melanocortin 4 receptors may play a role in connecting these two systems. Therefore, in a certain sense, chronic pain and obesity may share common behavioral and neural pathology, i.e. physical inactivity, as a result of inactivation of the mesolimbic DA system. Exercise and increasing physical activity in daily life may be important in treating and preventing chronic pain, a life-style related disease.
Collapse
Key Words
- CBP, chronic low back pain
- Chronic pain
- DA, dopamine
- Dopamine
- Exercise-induced hypoalgesia
- FM, fibromyalgia
- GABA, gamma-aminobutyric acid
- HDAC, histone deacetylase
- LDT, laterodorsal tegmental nucleus
- LH, lateral hypothalamus
- LHb, lateral habenula
- Laterodorsal tegmental nucleus
- NAc, nucleus accumbens
- NPP, neuropathic pain
- PPTg, pedunculopontine tegmental nucleus
- PSL, partial sciatic nerve ligation
- Physical activity/inactivity
- RMTg, rostromedial tegmental nucleus
- TH, tyrosine hydroxylase
- TMD, temporomandibular disorder
- VTA, ventral tegmental area
- VWR, voluntary wheel running
- Ventral tegmental area
- delta FosB, delta FBJ murine osteosarcoma viral
- mPFC, medial prefrontal cortex
- pCREB, phosphorylated cyclic AMP response element-binding protein
Collapse
Affiliation(s)
- Emiko Senba
- Department of Physical Therapy, Osaka Yukioka College of Health Science, 1-1-41 Sojiji, Ibaraki-City, Osaka 567-0801, Japan.,Department of Rehabilitation Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama 641-8509, Japan
| | - Katsuya Kami
- Department of Rehabilitation Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama 641-8509, Japan
| |
Collapse
|
|
23
|
Lopez-Candales A, Hernández Burgos PM, Hernandez-Suarez DF, Harris D. Linking Chronic Inflammation with Cardiovascular Disease: From Normal Aging to the Metabolic Syndrome. JOURNAL OF NATURE AND SCIENCE 2017; 3:e341. [PMID: 28670620 PMCID: PMC5488800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
The metabolic syndrome (MetS) is a cluster of clinical disorders including an unhealthy body habitus with a large waistline, dyslipidemia, glucose intolerance and hypertension. It is known that these disorders not only increase the chances of developing type 2 diabetes mellitus (T2DM), but also cardiovascular disease (CVD). Furthermore, the co-occurrence of all these risk factors known as the MetS is linked to pathways sharing common underlying mediators and mechanisms. Though insulin resistance has been considered as the root of the problem to explain the conglomerate of metabolic abnormalities within this syndrome; new evidence points to several pro-inflammatory cytokines, reactive oxygen species and free fatty acid intermediates might play an even greater role in regulating a series of intracellular signaling pathways sustain as well as perpetuate the development of the MetS and its CVD complications. Since having a diagnosis of MetS confers not only a 5-fold increase in the risk of T2DM, but also a 2-fold risk of developing CVD over a period of 5 to 10 years; it is vital to better recognize the mechanisms by which the MetS is associated with such adverse outcomes. Therefore, it is the purpose of this review to address (1) how inflammation modifies insulin sensitivity, (2) known factors believed to contribute to this process, and (3) new concepts of inflammatory markers in regulating the development of MetS and its individual components.
Collapse
Affiliation(s)
- Angel Lopez-Candales
- Cardiovascular Medicine Division, University of Puerto Rico School of Medicine, San Juan, Puerto Rico
| | | | | | - David Harris
- Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, OH, USA
| |
Collapse
|
|
24
|
do Carmo JM, da Silva AA, Wang Z, Fang T, Aberdein N, Perez de Lara CE, Hall JE. Role of the brain melanocortins in blood pressure regulation. Biochim Biophys Acta Mol Basis Dis 2017; 1863:2508-2514. [PMID: 28274841 DOI: 10.1016/j.bbadis.2017.03.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Revised: 02/27/2017] [Accepted: 03/02/2017] [Indexed: 10/20/2022]
Abstract
Melanocortins play an important role in regulating blood pressure (BP) and sympathetic nervous system (SNS) activity as well as energy balance, glucose and other metabolic functions in humans and experimental animals. In experimental models of hypertension with high SNS activity, blockade of the melanocortin-4 receptor (MC4R) reduces BP despite causing marked hyperphagia and obesity. Activation of the central nervous system (CNS) pro-opiomelanocortin (POMC)-MC4R pathway appears to be an important link between obesity, SNS activation and hypertension. Despite having severe obesity, subjects with MC4R deficiency exhibit reductions in BP, heart rate, and urinary catecholamine excretion, as well as attenuated SNS responses to cold stimuli compared to obese subjects with normal MC4R function. In this review we discuss the importance of the brain POMC-MC4R system in regulating SNS activity and BP in obesity and other forms of hypertension. We also highlight potential mechanisms and brain circuitry by which the melanocortin system regulates cardiovascular function.
Collapse
Affiliation(s)
- Jussara M do Carmo
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS, USA.
| | - Alexandre A da Silva
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS, USA; Barão de Mauá University Center, Ribeirão Preto, São Paulo, Brazil; Universidade Estadual de Minas Gerais, Passos, Minas Gerais, Brazil
| | - Zhen Wang
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS, USA
| | - Taolin Fang
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS, USA
| | - Nicola Aberdein
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS, USA
| | - Cecilia E Perez de Lara
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS, USA
| | - John E Hall
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS, USA
| |
Collapse
|
|
25
|
Martins FF, Bargut TCL, Aguila MB, Mandarim-de-Lacerda CA. Thermogenesis, fatty acid synthesis with oxidation, and inflammation in the brown adipose tissue of ob/ob (−/−) mice. Ann Anat 2017; 210:44-51. [DOI: 10.1016/j.aanat.2016.11.013] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 11/10/2016] [Accepted: 11/22/2016] [Indexed: 01/17/2023]
|
|
26
|
Le Jemtel TH, Richardson W, Samson R, Jaiswal A, Oparil S. Pathophysiology and Potential Non-Pharmacologic Treatments of Obesity or Kidney Disease Associated Refractory Hypertension. Curr Hypertens Rep 2017; 19:18. [PMID: 28243928 DOI: 10.1007/s11906-017-0713-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW The review assesses the role of non-pharmacologic therapy for obesity and chronic kidney disease (CKD) associated refractory hypertension (rf HTN). RECENT FINDINGS Hypertensive patients with markedly heightened sympathetic nervous system (SNS) activity are prone to develop refractory hypertension (rfHTN). Patients with obesity and chronic kidney disease (CKD)-associated HTN have particularly heightened SNS activity and are at high risk of rfHTN. The role of bariatric surgery is increasingly recognized in treatment of obesity. Current evidence advocates for a greater role of bariatric surgery in the management of obesity-associated HTN. In contrast, renal denervation does not appear have a role in the management of obesity or CKD-associated HTN. The role of baroreflex activation as adjunctive anti-hypertensive therapy remains to be defined.
Collapse
Affiliation(s)
- Thierry H Le Jemtel
- Division of Cardiology, Tulane University Medical Center, New Orleans, Louisiana, USA.
- Division of Cardiology, Tulane University School of Medicine, 1430 Tulane Ave SL-42, New Orleans, LA, 70112, USA.
| | - William Richardson
- Department of Surgery, Ochsner Health System, New Orleans, Louisiana, USA
| | - Rohan Samson
- Division of Cardiology, Tulane University Medical Center, New Orleans, Louisiana, USA
| | - Abhishek Jaiswal
- Division of Cardiology, Tulane University Medical Center, New Orleans, Louisiana, USA
| | - Suzanne Oparil
- Division of Cardiovascular Disease, University of Alabama, Birmingham, AL, USA
| |
Collapse
|
|
27
|
Mende CW, Giles TD, Bharucha DB, Ferguson WG, Mallick M, Patel MD. Efficacy of nebivolol-valsartan single-pill combination in obese and nonobese patients with hypertension. J Clin Hypertens (Greenwich) 2017; 19:632-639. [PMID: 28075064 PMCID: PMC5484387 DOI: 10.1111/jch.12965] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 11/16/2016] [Accepted: 11/19/2016] [Indexed: 11/29/2022]
Abstract
Antihypertensive efficacy of single-pill combinations (SPCs) consisting of a β1 -selective adrenergic blocker with vasodilatory properties via β3 -agonism (nebivolol) and an angiotensin II receptor blocker (valsartan) was demonstrated in an 8-week phase 3 trial (NCT01508026). In this post hoc analysis, seated blood pressure, heart rate, 24-hour ambulatory blood pressure monitoring, plasma aldosterone, estimated glomerular filtration rate, and safety measures were assessed in obese (body mass index >32 kg/m2 ; n=1823) and nonobese (body mass index <27 kg/m2 ; n=847) adults with hypertension (stage I or II) treated with nebivolol-valsartan SPCs, nebivolol or valsartan monotherapy, or placebo. At week 8, reductions from baseline in blood pressure and ambulatory blood pressure monitoring were greater with SPCs and most nebivolol and valsartan monotherapy doses vs placebo regardless of obesity status. Aldosterone declined with all active treatments and estimated glomerular filtration rate remained steady. The nebivolol-valsartan 5/80 mg/d SPC was efficacious regardless of degree of obesity.
Collapse
|
|
28
|
Dore R, Levata L, Lehnert H, Schulz C. Nesfatin-1: functions and physiology of a novel regulatory peptide. J Endocrinol 2017; 232:R45-R65. [PMID: 27754932 DOI: 10.1530/joe-16-0361] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 10/17/2016] [Indexed: 12/12/2022]
Abstract
Nesfatin-1 was identified in 2006 as a potent anorexigenic peptide involved in the regulation of homeostatic feeding. It is processed from the precursor-peptide NEFA/nucleobindin 2 (NUCB2), which is expressed both in the central nervous system as well as in the periphery, from where it can access the brain via non-saturable transmembrane diffusion. In hypothalamus and brainstem, nesfatin-1 recruits the oxytocin, the melancortin and other systems to relay its anorexigenic properties. NUCB2/nesfatin-1 peptide expression in reward-related areas suggests that nesfatin-1 might also be involved in hedonic feeding. Besides its initially discovered anorexigenic properties, over the last years, other important functions of nesfatin-1 have been discovered, many of them related to energy homeostasis, e.g. energy expenditure and glucose homeostasis. Nesfatin-1 is not only affecting these physiological processes but also the alterations of the metabolic state (e.g. fat mass, glycemic state) have an impact on the synthesis and release of NUCB2 and/or nesfatin-1. Furthermore, nesfatin-1 exerts pleiotropic actions at the level of cardiovascular and digestive systems, as well as plays a role in stress response, behavior, sleep and reproduction. Despite the recent advances in nesfatin-1 research, a putative receptor has not been identified and furthermore potentially distinct functions of nesfatin-1 and its precursor NUCB2 have not been dissected yet. To tackle these open questions will be the major objectives of future research to broaden our knowledge on NUCB2/nesfatin-1.
Collapse
Affiliation(s)
- Riccardo Dore
- Department of Internal Medicine ICenter of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
| | - Luka Levata
- Department of Internal Medicine ICenter of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
| | - Hendrik Lehnert
- Department of Internal Medicine ICenter of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
| | - Carla Schulz
- Department of Internal Medicine ICenter of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
| |
Collapse
|
|
29
|
Harrell CS, Gillespie CF, Neigh GN. Energetic stress: The reciprocal relationship between energy availability and the stress response. Physiol Behav 2016; 166:43-55. [PMID: 26454211 PMCID: PMC4826641 DOI: 10.1016/j.physbeh.2015.10.009] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 09/17/2015] [Accepted: 10/06/2015] [Indexed: 12/14/2022]
Abstract
The worldwide epidemic of metabolic syndromes and the recognized burden of mental health disorders have driven increased research into the relationship between the two. A maladaptive stress response is implicated in both mental health disorders and metabolic disorders, implicating the hypothalamic-pituitary-adrenal (HPA) axis as a key mediator of this relationship. This review explores how an altered energetic state, such as hyper- or hypoglycemia, as may be manifested in obesity or diabetes, affects the stress response and the HPA axis in particular. We propose that changes in energetic state or energetic demands can result in "energetic stress" that can, if prolonged, lead to a dysfunctional stress response. In this review, we summarize the role of the hypothalamus in modulating energy homeostasis and then briefly discuss the relationship between metabolism and stress-induced activation of the HPA axis. Next, we examine seven mechanisms whereby energetic stress interacts with neuroendocrine stress response systems, including by glucocorticoid signaling both within and beyond the HPA axis; by nutrient-induced changes in glucocorticoid signaling; by impacting the sympathetic nervous system; through changes in other neuroendocrine factors; by inducing inflammatory changes; and by altering the gut-brain axis. Recognizing these effects of energetic stress can drive novel therapies and prevention strategies for mental health disorders, including dietary intervention, probiotics, and even fecal transplant.
Collapse
Affiliation(s)
- C S Harrell
- Department of Physiology, Emory University, Atlanta, GA 30322, USA
| | - C F Gillespie
- Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA 30322, USA
| | - G N Neigh
- Department of Physiology, Emory University, Atlanta, GA 30322, USA;; Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA 30322, USA.
| |
Collapse
|
|
30
|
Martin R, Shapiro JI. Role of adipocytes in hypertension. World J Hypertens 2016; 6:66-75. [DOI: 10.5494/wjh.v6.i2.66] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 06/02/2016] [Indexed: 02/06/2023] Open
Abstract
Although it has known for some time that obesity is associated with salt sensitivity and hypertension, recent data suggests that the adipocyte may actually be the proximate cause of this physiological changes. In the following review, the data demonstrating this association as well as the potentially operative pathophysiological mechanisms are reviewed and discussed.
Collapse
|
|
31
|
Han C, Wu W, Ale A, Kim MS, Cai D. Central Leptin and Tumor Necrosis Factor-α (TNFα) in Diurnal Control of Blood Pressure and Hypertension. J Biol Chem 2016; 291:15131-42. [PMID: 27226618 DOI: 10.1074/jbc.m116.730408] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Indexed: 12/21/2022] Open
Abstract
Leptin and TNFα can individually work in the brain to affect blood pressure; however, it remains unknown whether these two cytokines might have an interactive role in this process and, if so, how. In this work, we found that leptin stimulation led to TNFα production under both in vitro and in vivo conditions, and diurnal fluctuation of leptin concentrations in the cerebrospinal fluid predicted the circadian changes of TNFα gene expression in the hypothalamus. Signaling analysis showed that leptin stimulation led to a rapid and strong STAT3 activation followed by a second-phase moderate STAT3 activation, which was selectively abolished by anti-inflammatory chemical PS1145 or TNFα antagonist WP9QY. Physiological study in normal mice revealed that diurnal rise of blood pressure was abrogated following central administration of PS1145 or a leptin receptor antagonist. Central TNFα pretreatment was found to potentiate the effect of leptin in elevating blood pressure in normal mice. In pathophysiology, dietary obesity mimicked TNFα pretreatment in promoting leptin-induced blood pressure rise, and this effect was blocked by central treatment with either PS1145 or WP9QY. Hence, central leptin employs TNFα to mediate the diurnal blood pressure elevation in physiology while enhancement of this mechanism can contribute to hypertension development.
Collapse
Affiliation(s)
- Cheng Han
- From the Department of Molecular Pharmacology, Diabetes Research Center, Institute of Aging, Albert Einstein College of Medicine, Bronx, New York 10461 and
| | - Wenhe Wu
- From the Department of Molecular Pharmacology, Diabetes Research Center, Institute of Aging, Albert Einstein College of Medicine, Bronx, New York 10461 and Key Laboratory of Laboratory Medicine, Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Albert Ale
- From the Department of Molecular Pharmacology, Diabetes Research Center, Institute of Aging, Albert Einstein College of Medicine, Bronx, New York 10461 and
| | - Min Soo Kim
- From the Department of Molecular Pharmacology, Diabetes Research Center, Institute of Aging, Albert Einstein College of Medicine, Bronx, New York 10461 and
| | - Dongsheng Cai
- From the Department of Molecular Pharmacology, Diabetes Research Center, Institute of Aging, Albert Einstein College of Medicine, Bronx, New York 10461 and
| |
Collapse
|
|
32
|
Comorbidity Factors and Brain Mechanisms Linking Chronic Stress and Systemic Illness. Neural Plast 2016; 2016:5460732. [PMID: 26977323 PMCID: PMC4761674 DOI: 10.1155/2016/5460732] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 10/11/2015] [Accepted: 10/25/2015] [Indexed: 12/16/2022] Open
Abstract
Neuropsychiatric symptoms and mental illness are commonly present in patients with chronic systemic diseases. Mood disorders, such as depression, are present in up to 50% of these patients, resulting in impaired physical recovery and more intricate treatment regimen. Stress associated with both physical and emotional aspects of systemic illness is thought to elicit detrimental effects to initiate comorbid mental disorders. However, clinical reports also indicate that the relationship between systemic and psychiatric illnesses is bidirectional, further increasing the complexity of the underlying pathophysiological processes. In this review, we discuss the recent evidence linking chronic stress and systemic illness, such as activation of the immune response system and release of common proinflammatory mediators. Altogether, discovery of new targets is needed for development of better treatments for stress-related psychiatric illnesses as well as improvement of mental health aspects of different systemic diseases.
Collapse
|
|
33
|
Claflin KE, Grobe JL. Control of energy balance by the brain renin-angiotensin system. Curr Hypertens Rep 2016; 17:38. [PMID: 25833461 DOI: 10.1007/s11906-015-0549-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The renin-angiotensin system (RAS) exists as a circulating hormone system but it is also used by various tissues of the body, including the brain, as a paracrine signaling mechanism. The local brain version of the RAS is mechanistically involved in fluid balance and blood pressure control, and there is growing appreciation for a role of the brain RAS in the control of energy balance. Here, we review major evidence for the control of energy balance by the brain RAS; outline the current understanding of the RAS components, targets, and mechanisms involved; and highlight some major questions that currently face the field.
Collapse
Affiliation(s)
- Kristin E Claflin
- Department of Pharmacology, Center for Hypertension Research, Obesity Research & Education Initiative, François M. Abboud Cardiovascular Research Center, and Fraternal Order of Eagles' Diabetes Research Center, University of Iowa, 51 Newton Rd., 2-307 BSB, Iowa City, IA, 52242, USA
| | | |
Collapse
|
|
34
|
The impacts of obesity on the cardiovascular and renal systems: cascade of events and therapeutic approaches. Curr Hypertens Rep 2016; 17:7. [PMID: 25620635 DOI: 10.1007/s11906-014-0520-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
There is a neglected epidemic of both obesity and metabolic syndrome in industrialized and unindustrialized countries all over the globe. Both conditions are associated with a high incidence of other serious pathologies, such as cardiovascular and renal diseases. In this article, we review the potential underlying mechanisms by which obesity and metabolic syndrome promote hypertension, including changes in cardiovascular-renal physiology induced by leptin, the sympathetic nervous system, the renin-angiotensin-aldosterone system, insulin resistance, free fatty acids, natriuretic peptides, and proinflammatory cytokines. We also discuss the potential underlying mechanisms by which obesity promotes other cardiovascular and renal conditions, as well as available nonpharmacologic and pharmacologic approaches for treating obesity-induced hypertension. The findings presented herein suggest that adipocytes may be a key regulator of cardiovascular and renal function.
Collapse
|
|
35
|
Regensteiner JG, Golden S, Huebschmann AG, Barrett-Connor E, Chang AY, Chyun D, Fox CS, Kim C, Mehta N, Reckelhoff JF, Reusch JEB, Rexrode KM, Sumner AE, Welty FK, Wenger NK, Anton B. Sex Differences in the Cardiovascular Consequences of Diabetes Mellitus: A Scientific Statement From the American Heart Association. Circulation 2015; 132:2424-47. [PMID: 26644329 DOI: 10.1161/cir.0000000000000343] [Citation(s) in RCA: 234] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
|
|
36
|
Kokubo Y, Watanabe M, Higashiyama A, Nakao YM, Kobayashi T, Watanabe T, Okamura T, Okayama A, Miyamoto Y. Interaction of Blood Pressure and Body Mass Index With Risk of Incident Atrial Fibrillation in a Japanese Urban Cohort: The Suita Study. Am J Hypertens 2015; 28:1355-61. [PMID: 25845964 DOI: 10.1093/ajh/hpv038] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Accepted: 02/20/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND PURPOSE To prevent stroke, strategies for atrial fibrillation (AF) prevention and an early detection of AF by electrocardiogram are essential. However, only a limited prospective studies have examined the risk factors for AF, even in blood pressure (BP) and body mass index (BMI), which are not clear among general populations. We investigated the impacts of BP and BMI on the risk of incident AF in a general population. METHODS A total of 6,906 participants (30-84 years) in the Suita Study were prospectively followed up for incident AF. Participants were diagnosed with AF if AF or atrial flutter was present on an electrocardiogram from a routine health examination (every 2 years) or if AF was indicated as a present illness from health examinations and/or medical records during follow-up. Adjusted Cox proportional hazard ratios (HRs) were calculated. RESULTS During the 12.8-year follow-up, 253 incident AF events occurred. Compared with the systolic BP (SBP) < 120 mm Hg and normal-weight, the adjusted HRs (95% confidence intervals; CIs) of incident AF in the systolic hypertension and the overweight (BMI ≥ 25kg/m(2)) groups were 1.74 (1.22-2.49) and 1.35 (1.01-1.80), respectively. Compared with SBP < 120 mm Hg and normal weight, the adjusted HRs (95% CIs) of incident AF in the SBP = 120-139 mm Hg with overweight and the systolic hypertension with normal or overweight were 1.72 (1.01-2.91), 1.66 (1.10-2.50), and 2.31 (1.47-3.65), respectively (P for interaction = 0.04). CONCLUSIONS Systolic prehypertension and overweight are associated with incident AF in Japanese population. The association between SBP and AF may be evident by overweight.
Collapse
Affiliation(s)
- Yoshihiro Kokubo
- Department of Preventive Cardiology, National Cardiovascular Center, Suita, Japan;
| | - Makoto Watanabe
- Department of Preventive Cardiology, National Cardiovascular Center, Suita, Japan
| | - Aya Higashiyama
- Department of Preventive Medicine and Epidemiologic Informatics, National Cardiovascular Center, Suita, Japan
| | - Yoko M Nakao
- Department of Preventive Cardiology, National Cardiovascular Center, Suita, Japan; Department of Preventive Medicine and Epidemiologic Informatics, National Cardiovascular Center, Suita, Japan
| | - Takashi Kobayashi
- Department of Preventive Cardiology, National Cardiovascular Center, Suita, Japan
| | - Takuya Watanabe
- Department of Preventive Cardiology, National Cardiovascular Center, Suita, Japan
| | - Tomonori Okamura
- Department of Preventive Cardiology, National Cardiovascular Center, Suita, Japan; Department of Preventive Medicine and Public Health, Keio University, Tokyo, Japan
| | - Akira Okayama
- Department of Preventive Cardiology, National Cardiovascular Center, Suita, Japan; The First Institute for Health Promotion and Health Care, Anti-tuberculosis Association, Tokyo, Japan
| | - Yoshihiro Miyamoto
- Department of Preventive Cardiology, National Cardiovascular Center, Suita, Japan; Department of Preventive Medicine and Epidemiologic Informatics, National Cardiovascular Center, Suita, Japan
| |
Collapse
|
|
37
|
Affiliation(s)
- Christine M Kusminski
- From the Department of Internal Medicine (C.M.K., P.E.S.), and Department of Cell Biology (P.E.S.), Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas
| | - Philipp E Scherer
- From the Department of Internal Medicine (C.M.K., P.E.S.), and Department of Cell Biology (P.E.S.), Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas.
| |
Collapse
|
|
38
|
Hall JE, do Carmo JM, da Silva AA, Wang Z, Hall ME. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ Res 2015; 116:991-1006. [PMID: 25767285 DOI: 10.1161/circresaha.116.305697] [Citation(s) in RCA: 799] [Impact Index Per Article: 79.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Excess weight gain, especially when associated with increased visceral adiposity, is a major cause of hypertension, accounting for 65% to 75% of the risk for human primary (essential) hypertension. Increased renal tubular sodium reabsorption impairs pressure natriuresis and plays an important role in initiating obesity hypertension. The mediators of abnormal kidney function and increased blood pressure during development of obesity hypertension include (1) physical compression of the kidneys by fat in and around the kidneys, (2) activation of the renin-angiotensin-aldosterone system, and (3) increased sympathetic nervous system activity. Activation of the renin-angiotensin-aldosterone system is likely due, in part, to renal compression, as well as sympathetic nervous system activation. However, obesity also causes mineralocorticoid receptor activation independent of aldosterone or angiotensin II. The mechanisms for sympathetic nervous system activation in obesity have not been fully elucidated but may require leptin and activation of the brain melanocortin system. With prolonged obesity and development of target organ injury, especially renal injury, obesity-associated hypertension becomes more difficult to control, often requiring multiple antihypertensive drugs and treatment of other risk factors, including dyslipidemia, insulin resistance and diabetes mellitus, and inflammation. Unless effective antiobesity drugs are developed, the effect of obesity on hypertension and related cardiovascular, renal and metabolic disorders is likely to become even more important in the future as the prevalence of obesity continues to increase.
Collapse
Affiliation(s)
- John E Hall
- From the Departments of Physiology and Biophysics (J.E.H., J.M.d.C., A.A.d.S., Z.W., M.E.H.), Medicine (M.E.H.), Mississippi Center for Obesity Research (J.E.H., J.M.d.C., A.A.d.S., Z.W., M.E.H.), and Cardiovascular-Renal Research Center (J.E.H., J.M.d.C., A.A.d.S., Z.W., M.E.H.), University of Mississippi Medical Center, Jackson.
| | - Jussara M do Carmo
- From the Departments of Physiology and Biophysics (J.E.H., J.M.d.C., A.A.d.S., Z.W., M.E.H.), Medicine (M.E.H.), Mississippi Center for Obesity Research (J.E.H., J.M.d.C., A.A.d.S., Z.W., M.E.H.), and Cardiovascular-Renal Research Center (J.E.H., J.M.d.C., A.A.d.S., Z.W., M.E.H.), University of Mississippi Medical Center, Jackson
| | - Alexandre A da Silva
- From the Departments of Physiology and Biophysics (J.E.H., J.M.d.C., A.A.d.S., Z.W., M.E.H.), Medicine (M.E.H.), Mississippi Center for Obesity Research (J.E.H., J.M.d.C., A.A.d.S., Z.W., M.E.H.), and Cardiovascular-Renal Research Center (J.E.H., J.M.d.C., A.A.d.S., Z.W., M.E.H.), University of Mississippi Medical Center, Jackson
| | - Zhen Wang
- From the Departments of Physiology and Biophysics (J.E.H., J.M.d.C., A.A.d.S., Z.W., M.E.H.), Medicine (M.E.H.), Mississippi Center for Obesity Research (J.E.H., J.M.d.C., A.A.d.S., Z.W., M.E.H.), and Cardiovascular-Renal Research Center (J.E.H., J.M.d.C., A.A.d.S., Z.W., M.E.H.), University of Mississippi Medical Center, Jackson
| | - Michael E Hall
- From the Departments of Physiology and Biophysics (J.E.H., J.M.d.C., A.A.d.S., Z.W., M.E.H.), Medicine (M.E.H.), Mississippi Center for Obesity Research (J.E.H., J.M.d.C., A.A.d.S., Z.W., M.E.H.), and Cardiovascular-Renal Research Center (J.E.H., J.M.d.C., A.A.d.S., Z.W., M.E.H.), University of Mississippi Medical Center, Jackson
| |
Collapse
|
|
39
|
Palei AC, Spradley FT, Granger JP. Chronic hyperleptinemia results in the development of hypertension in pregnant rats. Am J Physiol Regul Integr Comp Physiol 2015; 308:R855-61. [PMID: 25761697 DOI: 10.1152/ajpregu.00286.2014] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Accepted: 03/06/2015] [Indexed: 01/13/2023]
Abstract
Despite the fact that obesity is a major risk factor for preeclampsia (PE), the pathophysiological mechanisms whereby obesity and metabolic factors such as leptin increase this risk are unclear. While human data have shown that hyperleptinemia is associated with PE, the long-term effect of hyperleptinemia on blood pressure during pregnancy is unknown. Thus we tested the hypothesis whether chronic circulating leptin elevations in pregnant rats increase blood pressure and placental factors known to play a role in PE. On gestational day (GD)14, rats were assigned to the normal pregnant group with food intake ad libitum (control), leptin-treated (0.5 μg·kg(-1)·min(-1) ip) pregnant group with food intake ad libitum (pregnant+LEP), and normal pregnant group with food intake adjusted to the food intake of pregnant+LEP rats (pregnant-FR). On GD19, mean arterial pressure (MAP) was assessed and tissues were collected. Serum leptin concentration was elevated in pregnant+LEP compared with control and pregnant-FR (18.0 ± 2.8 vs. 0.8 ± 0.1 vs. 0.3 ± 0.1 ng/ml; P < 0.05), which was associated with increased MAP (121.3 ± 8.1 vs. 102.4 ± 2.4 vs. 101.3 ± 1.8 mmHg; P < 0.05). Food intake and body weight were reduced in pregnant+LEP and pregnant-FR by the end of gestation. Additionally, placentas and fetuses of these groups were lighter than those of control. However, placental expression of tumor necrosis factor-α was significantly greater in pregnant+LEP compared with controls (1.6 ± 0.1 vs. 1.1 ± 0.1 pg/mg; P < 0.05). In conclusion, leptin increases blood pressure and placental tumor necrosis factor-α during pregnancy despite its effect of reducing food intake and body weight, and represents a mechanism whereby obesity can promote the development of hypertension in PE.
Collapse
Affiliation(s)
- Ana C Palei
- Department of Physiology and Biophysics and Cardiovascular Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi
| | - Frank T Spradley
- Department of Physiology and Biophysics and Cardiovascular Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi
| | - Joey P Granger
- Department of Physiology and Biophysics and Cardiovascular Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi
| |
Collapse
|
|
40
|
Thorp AA, Schlaich MP. Relevance of Sympathetic Nervous System Activation in Obesity and Metabolic Syndrome. J Diabetes Res 2015; 2015:341583. [PMID: 26064978 PMCID: PMC4430650 DOI: 10.1155/2015/341583] [Citation(s) in RCA: 263] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 03/30/2015] [Indexed: 01/29/2023] Open
Abstract
Sympathetic tone is well recognised as being implicit in cardiovascular control. It is less readily acknowledged that activation of the sympathetic nervous system is integral in energy homeostasis and can exert profound metabolic effects. Accumulating data from animal and human studies suggest that central sympathetic overactivity plays a pivotal role in the aetiology and complications of several metabolic conditions that can cluster to form the Metabolic Syndrome (MetS). Given the known augmented risk for type 2 diabetes, cardiovascular disease, and premature mortality associated with the MetS understanding the complex pathways underlying the metabolic derangements involved has become a priority. Many factors have been proposed to contribute to increased sympathetic nerve activity in metabolic abnormalities including obesity, impaired baroreflex sensitivity, hyperinsulinemia, and elevated adipokine levels. Furthermore there is mounting evidence to suggest that chronic sympathetic overactivity can potentiate two of the key metabolic alterations of the MetS, central obesity and insulin resistance. This review will discuss the regulatory role of the sympathetic nervous system in metabolic control and the proposed pathophysiology linking sympathetic overactivity to metabolic abnormalities. Pharmacological and device-based approaches that target central sympathetic drive will also be discussed as possible therapeutic options to improve metabolic control in at-risk patient cohorts.
Collapse
Affiliation(s)
- Alicia A. Thorp
- Neurovascular Hypertension and Kidney Disease Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia
| | - Markus P. Schlaich
- Neurovascular Hypertension and Kidney Disease Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
- Department of Cardiovascular Medicine, Alfred Hospital, Melbourne, VIC 3004, Australia
- Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC 3800, Australia
- School of Medicine and Pharmacology, Royal Perth Hospital Unit, Faculty of Medicine, Dentistry & Health Sciences, The University of Western Australia, Level 3, MRF Building, Rear 50 Murray Street, Perth, WA 6000, Australia
- *Markus P. Schlaich:
| |
Collapse
|
|
41
|
Farr OM, Tsoukas MA, Mantzoros CS. Leptin and the brain: influences on brain development, cognitive functioning and psychiatric disorders. Metabolism 2015; 64:114-30. [PMID: 25092133 DOI: 10.1016/j.metabol.2014.07.004] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Revised: 06/16/2014] [Accepted: 07/05/2014] [Indexed: 12/20/2022]
Abstract
Receptors of leptin, the prototypical adipokine, are expressed throughout the cortex and several other areas of the brain. Although typically studied for its role in energy intake and expenditure, leptin plays a critical role in many other neurocognitive processes and interacts with various other hormones and neurotransmitters to perform these functions. Here, we review the literature on how leptin influences brain development, neural degradation, Alzheimer's disease, psychiatric disorders, and more complicated cognitive functioning and feeding behaviors. We also discuss modulators of leptin and the leptin receptor as they relate to normal cognitive functioning and may mediate some of the actions of leptin in the brain. Although we are beginning to better understand the critical role leptin plays in normal cognitive functioning, there is much to be discovered.
Collapse
Affiliation(s)
- Olivia M Farr
- Division of Endocrinology, Boston VA Healthcare System/Harvard Medical School, Boston, MA 02215.
| | - Michael A Tsoukas
- Division of Endocrinology, Boston VA Healthcare System/Harvard Medical School, Boston, MA 02215
| | - Christos S Mantzoros
- Division of Endocrinology, Boston VA Healthcare System/Harvard Medical School, Boston, MA 02215
| |
Collapse
|
|
42
|
Johnson RJ, Lanaspa MA, Gabriela Sánchez-Lozada L, Rodriguez-Iturbe B. The discovery of hypertension: evolving views on the role of the kidneys, and current hot topics. Am J Physiol Renal Physiol 2014; 308:F167-78. [PMID: 25377913 DOI: 10.1152/ajprenal.00503.2014] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Primary hypertension is increasingly common and is associated with significant morbidity. Here, we review the history of its discovery and rise during the last century with an emphasis on studies trying to identify its cause. Early studies identified a defect in sodium excretion by the kidney as being central to the pathogenesis. Recent studies have focused on a variety of genetic, congenital (fetal programming), and acquired mechanisms for causing the defect in natriuresis. Certain risk factors are apparent, including genetic polymorphisms that regulate sodium excretion, a congenital reduction in nephron number, obesity and hyperleptinemia, an elevated sympathetic nervous system, diet (salt and fructose), and metabolic (hyperuricemia) mechanisms. The kidney shows evidence for renal arteriolar vasoconstriction, an intrarenal inflammatory response, local oxidative stress, and intrarenal activation of the renin-angiotensin system. Recent studies suggest that intrarenal T cells have an important role in causing hypertension to be persistent, likely due to the induction of a local autoimmune response to neoantigens such as heat shock protein 70 and protein aggregates formed by isoketals resulting from lipid peroxidation. Salt retention due to impairment in pressure-diuresis leads to the release of cardiotonic steroids and central nervous system effects that cause systemic vasoconstriction and a rise in blood pressure. Some recent studies suggest that salt may increase blood pressure not simply by effects on extracellular volume but rather as a consequence of hyperosmolarity. These new insights could lead to new approaches for the prevention and treatment of this important disease.
Collapse
Affiliation(s)
- Richard J Johnson
- Division of Renal Diseases and Hypertension, University of Colorado, Denver, Colorado;
| | - Miguel A Lanaspa
- Division of Renal Diseases and Hypertension, University of Colorado, Denver, Colorado
| | - L Gabriela Sánchez-Lozada
- Laboratory of Renal Physiopathology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico; and
| | - Bernardo Rodriguez-Iturbe
- Hospital Universitario y Universidad del Zulia; and Instituto Venezolano de Investigaciones Científicas (IVIC)-Zulia, Maracaibo, Venezuela
| |
Collapse
|
|
43
|
Moraes DJA, Machado BH, Paton JFR. Specific Respiratory Neuron Types Have Increased Excitability That Drive Presympathetic Neurones in Neurogenic Hypertension. Hypertension 2014; 63:1309-18. [DOI: 10.1161/hypertensionaha.113.02283] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Davi J. A. Moraes
- From the School of Physiology and Pharmacology, Bristol Heart Institute, Medical Sciences Building, University of Bristol, Bristol, BS8 1TD, England (D.J.A.M., J.F.R.P.); and Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, 14049–900, SP, Brazil (D.J.A.M., B.H.M.)
| | - Benedito H. Machado
- From the School of Physiology and Pharmacology, Bristol Heart Institute, Medical Sciences Building, University of Bristol, Bristol, BS8 1TD, England (D.J.A.M., J.F.R.P.); and Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, 14049–900, SP, Brazil (D.J.A.M., B.H.M.)
| | - Julian F. R. Paton
- From the School of Physiology and Pharmacology, Bristol Heart Institute, Medical Sciences Building, University of Bristol, Bristol, BS8 1TD, England (D.J.A.M., J.F.R.P.); and Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, 14049–900, SP, Brazil (D.J.A.M., B.H.M.)
| |
Collapse
|
|
44
|
Yosten GLC, Samson WK. Neural circuitry underlying the central hypertensive action of nesfatin-1: melanocortins, corticotropin-releasing hormone, and oxytocin. Am J Physiol Regul Integr Comp Physiol 2014; 306:R722-7. [PMID: 24598461 DOI: 10.1152/ajpregu.00396.2013] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Nesfatin-1 is produced in the periphery and in the brain where it has been demonstrated to regulate appetite, stress hormone secretion, and cardiovascular function. The anorexigenic action of central nesfatin-1 requires recruitment of neurons producing the melanocortins and centrally projecting oxytocin (OT) and corticotropin-releasing hormone (CRH) neurons. We previously have shown that two components of this pathway, the central melanocortin and oxytocin systems, contribute to the hypertensive action of nesfatin-1 as well. We hypothesized that the cardiovascular effect of nesfatin-1 also was dependent on activation of neurons expressing CRH receptors, and that the order of activation of the melanocortin-CRH-oxytocin circuit was preserved for both the anorexigenic and hypertensive actions of the peptide. Pretreatment of male rats with the CRH-2 receptor antagonist astressin2B abrogated nesfatin-1-induced increases in mean arterial pressure (MAP). Furthermore, the hypertensive action of CRH was blocked by pretreatment with an oxytocin receptor antagonist ornithine vasotocin (OVT), indicating that the hypertensive effect of nesfatin-1 may require activation of oxytocinergic (OTergic) neurons in addition to recruitment of CRH neurons. Interestingly, we found that the hypertensive effect of α-melanocyte stimulating hormone (α-MSH) itself was not blocked by either astressin2B or OVT. These data suggest that while α-MSH-producing neurons are part of a core melanocortin-CRH-oxytocin circuit regulating food intake, and a subpopulation of melanocortin neurons activated by nesfatin-1 do mediate the hypertensive action of the peptide, α-MSH can signal independently from this circuit to increase MAP.
Collapse
Affiliation(s)
- Gina L C Yosten
- Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, Saint Louis, Missouri
| | - Willis K Samson
- Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, Saint Louis, Missouri
| |
Collapse
|
|
45
|
Ojeda NB, Intapad S, Alexander BT. Sex differences in the developmental programming of hypertension. Acta Physiol (Oxf) 2014; 210:307-16. [PMID: 24268043 DOI: 10.1111/apha.12206] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Revised: 07/29/2013] [Accepted: 11/19/2013] [Indexed: 02/06/2023]
Abstract
Experimental models of developmental programming provide proof of concept and support Barker's original findings that link birthweight and blood pressure. Many experimental models of developmental insult demonstrate a sex difference with male offspring exhibiting a higher blood pressure in young adulthood relative to their age-matched female counterparts. It is well recognized that men exhibit a higher blood pressure relative to age-matched women prior to menopause. Yet, whether this sex difference is noted in individuals born with low birthweight is not clear. Sex differences in the developmental programming of blood pressure may originate from innate sex-specific differences in expression of the renin angiotensin system that occur in response to adverse influences during early life. Sex differences in the developmental programming of blood pressure may also involve the influence of the hormonal milieu on regulatory systems key to the long-term control of blood pressure such as the renin angiotensin system in adulthood. In addition, the sex difference in blood pressure in offspring exposed to a developmental insult may involve innate sex differences in oxidative status or the endothelin system or may be influenced by age-dependent changes in the developmental programming of cardiovascular risk factors such as adiposity. Therefore, this review will highlight findings from different experimental models to provide the current state of knowledge related to the mechanisms that contribute to the aetiology of sex differences in the developmental programming of blood pressure and hypertension.
Collapse
Affiliation(s)
- N. B. Ojeda
- Department of Pediatrics; University of Mississippi Medical Center; Jackson MS USA
- Women's Health Research Center; University of Mississippi Medical Center; Jackson MS USA
| | - S. Intapad
- Department of Physiology and Biophysics; University of Mississippi Medical Center; Jackson MS USA
| | - B. T. Alexander
- Women's Health Research Center; University of Mississippi Medical Center; Jackson MS USA
- Department of Physiology and Biophysics; University of Mississippi Medical Center; Jackson MS USA
| |
Collapse
|
|
46
|
Abstract
Although obesity is a well-known risk factor for hypertension, the mechanisms by which hypertension develops in obese patients are not entirely clear. Animal models of obesity and their different susceptibilities to develop hypertension have revealed some of the mechanisms linking obesity and hypertension. Adipose tissue is an endocrine organ secreting hormones that impact blood pressure, such as elements of the renin-angiotensin system whose role in hypertension have been established. In addition, the appetite-suppressing adipokine leptin activates the sympathetic nervous system via the melanocortin system, and this activation, especially in the kidney, increases blood pressure. Leptin secretion from adipocytes is increased in most models of obesity due to leptin resistance, although the resistance is often selective to the anorexigenic effect, while the susceptibility to the hypertensive effect remains intact. Understanding the pathways by which obesity contributes to increased blood pressure will hopefully pave the way to and better define the appropriate treatment for obesity-induced hypertension.
Collapse
|
|
47
|
do Carmo JM, da Silva AA, Sessums PO, Ebaady SH, Pace BR, Rushing JS, Davis MT, Hall JE. Role of Shp2 in forebrain neurons in regulating metabolic and cardiovascular functions and responses to leptin. Int J Obes (Lond) 2013; 38:775-83. [PMID: 24030516 PMCID: PMC3954949 DOI: 10.1038/ijo.2013.177] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2013] [Revised: 08/29/2013] [Accepted: 09/05/2013] [Indexed: 02/04/2023]
Abstract
Objective We examined whether deficiency of Shp2 signaling in forebrain neurons alters metabolic and cardiovascular regulation under various conditions and if it attenuates the anorexic and cardiovascular effects of leptin. We also tested whether forebrain Shp2 deficiency alters blood pressure (BP) and heart rate (HR) responses to acute stress. Design Forebrain Shp2-/- mice were generated by crossing Shp2flox/flox mice with CamKIIα-cre mice. At 22 to 24 weeks of age, mice were instrumented for telemetry for measurement of BP, HR and body temperature (BT). Oxygen consumption (VO2), energy expenditure and motor activity were monitored by indirect calorimetry. Results Shp2/CamKIIα-cre mice were heavier (46±3 vs 32±1 g), hyperglycemic, hyperleptinemic, hyperinsulinemic, and hyperphagic compared to Shp2flox/flox control mice. Shp2/CamKIIα-cre mice exhibited reduced food intake responses to fasting/refeeding and impaired regulation of BT when exposed to 15°C and 30°C ambient temperatures. Despite being obese and having many features of metabolic syndrome, Shp2/CamKIIα-cre mice had similar daily average BP and HR compared to Shp2flox/flox mice (112±2 vs 113±1 mmHg and 595±34 vs 650±40 bpm), but exhibited increased BP and HR responses to cold exposure and acute air-jet stress test. Leptin's ability to reduce food intake and to raise BP were markedly attenuated in Shp2/CamKIIα-cre mice. Conclusion These results suggest that forebrain Shp2 signaling regulates food intake, appetite responses to caloric deprivation, and thermogenic control of body temperature during variations in ambient temperature. Deficiency of Shp2 signaling in the forebrain is associated with augmented cardiovascular responses to cold and acute stress but attenuated BP responses to leptin.
Collapse
Affiliation(s)
- J M do Carmo
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA
| | - A A da Silva
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA
| | - P O Sessums
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA
| | - S H Ebaady
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA
| | - B R Pace
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA
| | - J S Rushing
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA
| | - M T Davis
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA
| | - J E Hall
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA
| |
Collapse
|
|
48
|
Abstract
In addition to effects on appetite and metabolism, leptin influences many neuroendocrine and physiological systems, including the sympathetic nervous system. Building on my Carl Ludwig Lecture of the American Physiological Society, I review the sympathetic and cardiovascular actions of leptin. The review focuses on a critical analysis of the concept of selective leptin resistance (SLR) and the role of leptin in the pathogenesis of obesity-induced hypertension in both experimental animals and humans. We introduced the concept of SLR in 2002 to explain how leptin might increase blood pressure (BP) in obese states, such as diet-induced obesity (DIO), that are accompanied by partial leptin resistance. This concept, analogous to selective insulin resistance in the metabolic syndrome, holds that in several genetic and acquired models of obesity, there is preservation of the renal sympathetic and pressor actions of leptin despite attenuation of the appetite and weight-reducing actions. Two potential overlapping mechanisms of SLR are reviewed: 1) differential leptin molecular signaling pathways that mediate selective as opposed to universal leptin action and 2) brain site-specific leptin action and resistance. Although the phenomenon of SLR in DIO has so far focused on preservation of sympathetic and BP actions of leptin, consideration should be given to the possibility that this concept may extend to preservation of other actions of leptin. Finally, I review perplexing data on the effects of leptin on sympathetic activity and BP in humans and its role in human obesity-induced hypertension.
Collapse
Affiliation(s)
- Allyn L Mark
- Department of Internal Medicine and the Obesity Research and Education Initiative, University of Iowa Carver College of Medicine, Iowa City, Iowa
| |
Collapse
|
|
49
|
Koch E, Hue-Beauvais C, Galio L, Solomon G, Gertler A, Révillon F, Lhotellier V, Aujean E, Devinoy E, Charlier M. Leptin gene in rabbit: cloning and expression in mammary epithelial cells during pregnancy and lactation. Physiol Genomics 2013; 45:645-52. [PMID: 23715260 DOI: 10.1152/physiolgenomics.00020.2013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Leptin is known as a cytokine mostly produced by fat cells and implicated in regulation of energy metabolism and food intake but has also been shown to be involved in many physiological mechanisms such as tissue metabolism and cell differentiation and proliferation. In particular, leptin influences the development of mammary gland. Although leptin expression in mammary gland has been studied in several species, no data are available in the rabbit. Leptin transcripts in this species have been described as being encoded by only two exons rather than three as in other species. Our focus was to clone and sequence the rabbit leptin cDNA and to prepare the recombinant biologically active protein for validation of the proper sequence and then to describe leptin expression in rabbit mammary gland during different stages of pregnancy and lactation. The leptin sequence obtained was compared with those of other species, and genome alignment demonstrated that the rabbit leptin gene is also encoded by three exons. Additionally, we analyzed the expression of leptin during pregnancy and lactation. Leptin mRNA was weakly expressed throughout pregnancy, whereas mRNA levels were higher during lactation, with a significant increase between days 3 and 16. Leptin transcripts and protein were localized in luminal epithelial cells, thus indicating that leptin synthesis occurs in this compartment. Therefore, mammary synthesized leptin may constitute a major regulator of mammary gland development by acting locally as an autocrine and/or paracrine factor. Furthermore, our results support the possible physiological role of leptin in newborns through consumption of milk.
Collapse
Affiliation(s)
- Emmanuelle Koch
- INRA, UR1196, Génomique et Physiologie de la Lactation, Jouy-en-Josas, France
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Canale MP, Manca di Villahermosa S, Martino G, Rovella V, Noce A, De Lorenzo A, Di Daniele N. Obesity-related metabolic syndrome: mechanisms of sympathetic overactivity. Int J Endocrinol 2013; 2013:865965. [PMID: 24288531 PMCID: PMC3833340 DOI: 10.1155/2013/865965] [Citation(s) in RCA: 142] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Accepted: 09/10/2013] [Indexed: 12/15/2022] Open
Abstract
The prevalence of the metabolic syndrome has increased worldwide over the past few years. Sympathetic nervous system overactivity is a key mechanism leading to hypertension in patients with the metabolic syndrome. Sympathetic activation can be triggered by reflex mechanisms as arterial baroreceptor impairment, by metabolic factors as insulin resistance, and by dysregulated adipokine production and secretion from visceral fat with a mainly permissive role of leptin and antagonist role of adiponectin. Chronic sympathetic nervous system overactivity contributes to a further decline of insulin sensitivity and creates a vicious circle that may contribute to the development of hypertension and of the metabolic syndrome and favor cardiovascular and kidney disease. Selective renal denervation is an emerging area of interest in the clinical management of obesity-related hypertension. This review focuses on current understanding of some mechanisms through which sympathetic overactivity may be interlaced to the metabolic syndrome, with particular regard to the role of insulin resistance and of some adipokines.
Collapse
Affiliation(s)
- Maria Paola Canale
- Division of Hypertension and Nephrology, Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Simone Manca di Villahermosa
- Division of Hypertension and Nephrology, Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Giuliana Martino
- Division of Hypertension and Nephrology, Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Valentina Rovella
- Division of Hypertension and Nephrology, Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Annalisa Noce
- Division of Hypertension and Nephrology, Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Antonino De Lorenzo
- Division of Clinical Nutrition and Nutrigenomic, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Nicola Di Daniele
- Division of Hypertension and Nephrology, Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
- *Nicola Di Daniele:
| |
Collapse
|