Central role for melanocortin-4 receptors in offspring hypertension arising from maternal obesity

Samuelsson, A; Mullier, Amandine; Maicas, Nuria; Oosterhuis, Nynke R.; Bae, Sung Eun; Novoselova, Tatiana V.; Chan, Li F.; Pombo, Joaquim; Taylor, Paul D.; Joles, Jaap A.; Coen, Clive W.; Balthasar, Nina; Poston, Lucilla

doi:10.1073/pnas.1607464113

Cited by 32 publications

(38 citation statements)

References 38 publications

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“…In the PVN of the hypothalamus, in addition to food intake, melanocortin receptors modulate sympathetic outflow, blood pressure and heart rate (Kuo et al 2003, Tallam et al 2005, Skibicka & Grill 2009. In the PVN, MC4R also appears essential for hypertension in the offspring of obese rats (Samuelsson et al 2016). MC4R agonists increase blood pressure by targeting cholinergic neurons, including the sympathetic preganglionic neurons of the IML (Sohn et al 2013).…”

Section: Mc4r Neuronsmentioning

confidence: 99%

The melanocortin pathway and control of appetite-progress and therapeutic implications

Baldini

Phelan

2019

Journal of Endocrinology

185

125

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The initial discovery thatob/obmice become obese because of a recessive mutation of the leptin gene has been crucial to discover the melanocortin pathway to control appetite. In the melanocortin pathway, the fed state is signaled by abundance of circulating hormones such as leptin and insulin, which bind to receptors expressed at the surface of pro-opiomelanocortin (POMC) neurons to promote processing of POMC to the mature hormone α-melanocyte-stimulating hormone (α-MSH). The α-MSH released by POMC neurons then signals to decrease energy intake by binding to melanocortin-4 receptor (MC4R) expressed by MC4R neurons to the paraventricular nucleus (PVN). Conversely, in the ‘starved state’ activity of agouti-related neuropeptide (AgRP) and of neuropeptide Y (NPY)-expressing neurons is increased by decreased levels of circulating leptin and insulin and by the orexigenic hormone ghrelin to promote food intake. This initial understanding of the melanocortin pathway has recently been implemented by the description of the complex neuronal circuit that controls the activity of POMC, AgRP/NPY and MC4R neurons and downstream signaling by these neurons. This review summarizes the progress done on the melanocortin pathway and describes how obesity alters this pathway to disrupt energy homeostasis. We also describe progress on how leptin and insulin receptors signal in POMC neurons, how MC4R signals and how altered expression and traffic of MC4R change the acute signaling and desensitization properties of the receptor. We also describe how the discovery of the melanocortin pathway has led to the use of melanocortin agonists to treat obesity derived from genetic disorders.

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Section: Mc4r Neuronsmentioning

confidence: 99%

The melanocortin pathway and control of appetite-progress and therapeutic implications

Baldini

Phelan

2019

Journal of Endocrinology

185

125

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“…Maternal obesity alters energy sensors (including mTOR and pAMPK) and epigenetic responses which modulate gene expression and neuronal differentiation and therefore can contribute to the obesity and related metabolic disorders, including hyperphagia, observed in offspring ( 29 ). Hyperleptinemia in the preweaning period arising from maternal obesity can induce lasting changes in the central melanocortin system ( 30 ) and melanocortin-4 receptor in the PVH appears to be a mechanism underpinning the programming of hypertension in later life ( 30 ).…”

Section: Experimental Models Of Maternal Obesitymentioning

confidence: 99%

Experimental Models of Maternal Obesity and Neuroendocrine Programming of Metabolic Disorders in Offspring

2017

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Evidence from epidemiological, clinical, and experimental studies have clearly shown that disease risk in later life is increased following a poor early life environment, a process preferentially termed developmental programming. In particular, this work clearly highlights the importance of the nutritional environment during early development with alterations in maternal nutrition, including both under- and overnutrition, increasing the risk for a range of cardiometabolic and neurobehavioral disorders in adult offspring characterized by both adipokine resistance and obesity. Although the mechanistic basis for such developmental programming is not yet fully defined, a common feature derived from experimental animal models is that of alterations in the wiring of the neuroendocrine pathways that control energy balance and appetite regulation during early stages of developmental plasticity. The adipokine leptin has also received significant attention with clear experimental evidence that normal regulation of leptin levels during the early life period is critical for the normal development of tissues and related signaling pathways that are involved in metabolic and cardiovascular homeostasis. There is also increasing evidence that alterations in the epigenome and other underlying mechanisms including an altered gut–brain axis may contribute to lasting cardiometabolic dysfunction in offspring. Ongoing studies that further define the mechanisms between these associations will allow for identification of early risk markers and implementation of strategies around interventions that will have obvious beneficial implications in breaking a programmed transgenerational cycle of metabolic disorders.

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“…Moreover, MC4R mediates a leptin-induced increase in renal sympathetic nerve activity (RSNA) in mice [39] . MC4R is also involved in early life programming of hypertension resulting either from maternal obesity or exposure to hyperleptinemia [41] . In addition to MC4R, POMC neurons are implicated in mediating leptin-induced hypertension [42] , and administration of POMC peptides such as α-MSH and ACTH increases blood pressure [43] .…”

Section: Introductionmentioning

confidence: 99%

Reduced renal sympathetic nerve activity contributes to elevated glycosuria and improved glucose tolerance in hypothalamus-specific Pomc knockout mice

Chhabra

Morgan

Tooke

et al. 2017

Molecular Metabolism

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ObjectiveHypothalamic arcuate nucleus-specific pro-opiomelanocortin deficient (ArcPomc−/−) mice exhibit improved glucose tolerance despite massive obesity and insulin resistance. We demonstrated previously that their improved glucose tolerance is due to elevated glycosuria. However, the underlying mechanisms that link glucose reabsorption in the kidney with ArcPomc remain unclear. Given the function of the hypothalamic melanocortin system in controlling sympathetic outflow, we hypothesized that reduced renal sympathetic nerve activity (RSNA) in ArcPomc−/− mice could explain their elevated glycosuria and consequent enhanced glucose tolerance.MethodsWe measured RSNA by multifiber recording directly from the nerves innervating the kidneys in ArcPomc−/− mice. To further validate the function of RSNA in glucose reabsorption, we denervated the kidneys of WT and diabetic db/db mice before measuring their glucose tolerance and urine glucose levels. Moreover, we performed western blot and immunohistochemistry to determine kidney GLUT2 and SGLT2 levels in either ArcPomc−/− mice or the renal-denervated mice.ResultsConsistent with our hypothesis, we found that basal RSNA was decreased in ArcPomc−/− mice relative to their wild type (WT) littermates. Remarkably, both WT and db/db mice exhibited elevated glycosuria and improved glucose tolerance after renal denervation. The elevated glycosuria in obese ArcPomc−/−, WT and db/db mice was due to reduced renal GLUT2 levels in the proximal tubules. Overall, we show that renal-denervated WT and diabetic mice recapitulate the phenotype of improved glucose tolerance and elevated glycosuria associated with reduced renal GLUT2 levels observed in obese ArcPomc−/− mice.ConclusionHence, we conclude that ArcPomc is essential in maintaining basal RSNA and that elevated glycosuria is a possible mechanism to explain improved glucose tolerance after renal denervation in drug resistant hypertensive patients.

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Central role for melanocortin-4 receptors in offspring hypertension arising from maternal obesity

Cited by 32 publications

References 38 publications

The melanocortin pathway and control of appetite-progress and therapeutic implications

The melanocortin pathway and control of appetite-progress and therapeutic implications

Experimental Models of Maternal Obesity and Neuroendocrine Programming of Metabolic Disorders in Offspring

Reduced renal sympathetic nerve activity contributes to elevated glycosuria and improved glucose tolerance in hypothalamus-specific Pomc knockout mice

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