Melanocortin-4 Receptors and Sympathetic Nervous System Activation in Hypertension

Silva, Alexandre A. da; Carmo, Jussara M. do; Wang, Zhen; Hall, John E.

doi:10.1007/s11906-019-0951-x

Cited by 28 publications

(10 citation statements)

References 44 publications

(43 reference statements)

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“…In addition to metabolic homeostasis, it has been well established that brain MC4R signaling pathways affect sympathetic control of cardiovascular function, which has been an obstacle for developing a safe anti-obesity medication by targeting MC4Rs[6]. MC4Rs are broadly expressed in different brain regions involving in autonomic control of cardiovascular function[20], and our results now support an idea that PVN could be one of the important brain regions where MC4R signaling affects cardiovascular physiology.…”

Section: Discussionsupporting

confidence: 77%

Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations

Cui

Singh

Saito

et al. 2021

Preprint

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Objective: The paraventricular nucleus of hypothalamus (PVN) is an integrative center in the brain orchestrating a wide range of physiological and behavioral responses. While the PVN melanocortin 4 receptor (MC4R) signaling (PVNMC4R+) is undoubtedly involved in feeding regulation, the neuroanatomical organization of PVNMC4R+ pathway and its role in diverse physiological and behavioral regulations have not been fully understood. Here we aimed to better characterize the input-output organization of PVNMC4R+ neurons and further test their potential functional roles beyond feeding. Methods: Using a combination of viral tools, we performed a comprehensive mapping of PVNMC4R+ circuits and tested the effects of chemogenetic activation of PVNMC4R+ neurons on thermogenesis, cardiovascular control and other behavioral regulations beyond feeding. Results: We found that PVNMC4R+ neurons broadly innervate many different brain regions known to be important not only for feeding but also for neuroendocrine and autonomic control of thermogenesis and cardiovascular function, including but not limited to preoptic area, median eminence, parabrachial nucleus, locus coeruleus, nucleus of solitary tract, ventrolateral medulla and thoracic spinal cord. Contrary to broad efferent projections, PVNMC4R+ neurons receive monosynaptic inputs from limited brain regions, including medial preoptic nucleus, arcuate and dorsomedial hypothalamic nuclei, and supraoptic nucleus. Consistent with 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 thermogenesis. Strikingly, these physiological changes accompanied an unexpected repetitive bedding-removing behavior followed by hypoactivity and resting-like behavior. Conclusions: Our results clarify the neuroanatomical organization of PVNMC4R+ circuits and shed new light on the roles of PVNMC4R+ pathways in autonomic control of thermogenesis, cardiovascular function and other behavioral regulations.

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Section: Discussionsupporting

confidence: 77%

Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations

Cui

Singh

Saito

et al. 2021

Preprint

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“…Sympathetic overactivity has been established in obese individuals and is considered one of the major contributors to the development of obesity-associated hypertension [ 2 , 3 ]. Mounting evidence indicates that the central melanocortin signaling pathway, mainly via melanocortin 4 receptor (MC4R), plays a key role in obesity [ [4] , [5] , [6] , [7] ]. Besides having a prominent role in energy homeostasis [ 8 , 9 ], MC4R signaling pathways are known to affect the sympathetic activity and cardiovascular physiology.…”

Section: Introductionmentioning

confidence: 99%

Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations

Singh

Jiang

Saito

et al. 2022

Molecular Metabolism

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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 (PVN MC4R+ ) is involved in feeding regulation, the neuroanatomical organization of PVN MC4R+ connectivity and its role in other physiological regulations are incompletely understood. Here we aimed to better characterize the input–output organization of PVN MC4R+ neurons and test their physiological functions beyond feeding. Methods Using a combination of viral tools, we mapped PVN MC4R+ circuits and tested the effects of chemogenetic activation of PVN MC4R+ neurons on thermoregulation, cardiovascular control, and other behavioral responses beyond feeding. Results We found that PVN MC4R+ 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, PVN MC4R+ 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 PVN MC4R+ 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 PVN MC4R+ circuits and shed new light on the roles of PVN MC4R+ pathways in autonomic control of thermoregulation, cardiovascular function, and biphasic behavioral activation.

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“…143 Sympathetic nervous system and BP are regulated through the activation of melanocortin-4 receptors (MC4Rs) in brain stem nuclei, hence the renal SNS is altered. 144 The lysis of POMC protein induces the synthesis of α-melanocyte-stimulating hormone (α-MSH), which in turn activates MC4Rs. 144 The sensitization of hypothalamus MC4Rs induces an increase in renal system activity, including elevated sodium retention and secretion of renin, further leading to an increase in BP.…”

Section: Dovepressmentioning

confidence: 99%

“…144 The lysis of POMC protein induces the synthesis of α-melanocyte-stimulating hormone (α-MSH), which in turn activates MC4Rs. 144 The sensitization of hypothalamus MC4Rs induces an increase in renal system activity, including elevated sodium retention and secretion of renin, further leading to an increase in BP. 144 In addition to this, receptors of leptin are mainly expressed in the hypothalamus and are responsible for elevated secretion of aldosterone, which also depends on the level of Ca2+.…”

Section: Dovepressmentioning

confidence: 99%

“…144 The sensitization of hypothalamus MC4Rs induces an increase in renal system activity, including elevated sodium retention and secretion of renin, further leading to an increase in BP. 144 In addition to this, receptors of leptin are mainly expressed in the hypothalamus and are responsible for elevated secretion of aldosterone, which also depends on the level of Ca2+. 145 Xie and Bollag et al 146 in their focused review elaborate that leptin stimulates overproduction of aldosterone.…”

Section: Dovepressmentioning

confidence: 99%

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Effect of Leptin on Chronic Inflammatory Disorders: Insights to Therapeutic Target to Prevent Further Cardiovascular Complication

Dessie¹,

Ayelign²,

Akalu³

et al. 2021

DMSO

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In response to obesity-associated chronic inflammatory disorders, adipose tissue releases a biologically active peptide known as leptin. Leptin activates the secretion of chemical mediators, which contribute to the pathogenesis of chronic inflammatory disorders, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and psoriasis. Conversely, adiposity and obesity are the major aggravating risk factors in the pathogenesis of metabolic syndrome (MetS), including type II diabetes mellitus and obesity-associated hypertension. Elevated level of leptin in obesity-associated hypertension causes an increase in the production of aldosterone, which also results in elevation of arterial blood pressure. Hyperleptinemia is associated with the progress of the atherosclerosis through secretion of pro-inflammatory cytokines, like interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), IL-17, and other cytokines to promote inflammation. The release of those cytokines leads to chronic inflammatory disorders and obesity-associated MetS. Thus, the aberrant leptin level in both MetS and chronic inflammatory disorders also leads to the complication of cardiovascular diseases (CVD). Therapeutic target of leptin regarding its pro-inflammatory effect and dysregulated sympathetic nervous system activity may prevent further cardiovascular complication. This review mainly assesses the mechanism of leptin on the pathogenesis and further cardiovascular risk complication of chronic inflammatory disorders.

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Melanocortin-4 Receptors and Sympathetic Nervous System Activation in Hypertension

Cited by 28 publications

References 44 publications

Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations

Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations

Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations

Effect of Leptin on Chronic Inflammatory Disorders: Insights to Therapeutic Target to Prevent Further Cardiovascular Complication

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