The Brain Melanocortin System, Sympathetic Control, and Obesity Hypertension

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

doi:10.1152/physiol.00061.2013

Cited by 35 publications

(42 citation statements)

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“…However, it is possible that an adrenergic independent mechanism could explain the fall in BP during MC3/4R blockade in L-NAME hypertensive rats since acute ganglionic blockade lowered BP by a similar degree in L-NAME compared to Ang II hypertensive rats, suggesting an equal overall importance of SNA to the maintenance of BP in these models. Nevertheless, it is also important to recognize that acute ganglionic blockade may not recapitulate the effects of chronically blocking the SNS, especially if the chronic effects are mediated mainly by decreased renal SNA which, in turn, decreases renal tubular sodium reabsorption and leads to a slowly developing decreased in blood pressure over several days 31 . It is possible that renal SNA may be differentially affected by Ang II versus L-NAME hypertension.…”

Section: Discussionmentioning

confidence: 99%

Chronic Central Nervous System MC3/4R Blockade Attenuates Hypertension Induced by Nitric Oxide Synthase Inhibition but Not by Angiotensin II Infusion

et al. 2015

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We examined whether central melanocortin 3 and 4 receptor (MC3/4R) blockade attenuates the BP responses to chronic L-NAME or angiotensin II (Ang-II) infusion in Sprague Dawley rats implanted with telemetry transmitters, venous catheters and intracerebroventricular (ICV) cannula into the lateral ventricle. After 5 days of control measurements, L-NAME (10 μg/kg/day, i.v. – groups 1 and 2) or Ang II (10 ng/kg/min, i.v. – groups 3 and 4) were infused for 24 days and starting on day 7 of L-NAME or Ang II infusion the MC3/4R antagonist SHU-9119 (24 nmol/day, n=6/group – groups 1 and 3) or vehicle (saline 0.5 μl/hr, n=6/group – groups 2 and 4) was infused ICV for 10 days. A control normotensive group also received SHU-9119 for 10 days (n=5). L-NAME and Ang II increased BP by 40±3 and 56±5 mmHg, respectively; while heart rate (HR) was slightly reduced. MC3/4R blockade doubled food intake and reduced HR (~40 to ~50 bpm) in all groups. MC3/4R blockade caused only a small reduction in BP in normotensive group (4 mmHg) and no change in rats receiving Ang II, while markedly reducing BP by 21±4 mmHg in L-NAME treated rats. After SHU-9119 infusion was stopped, food intake, HR and BP gradually returned to values observed before SHU-9119 infusion was started. Ganglionic blockade performed at the end of L-NAME or Ang II infusion caused similar BP reduction in both groups. These results suggest that the brain MC3/4R contributes, at least in part, to the hypertension induced by chronic L-NAME infusion but not by Ang II.

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Section: Discussionmentioning

confidence: 99%

Chronic Central Nervous System MC3/4R Blockade Attenuates Hypertension Induced by Nitric Oxide Synthase Inhibition but Not by Angiotensin II Infusion

et al. 2015

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“…However, it is clear that this system plays an important role in the control of blood pressure (BP) (3,4). In humans with loss-of-function Mc4r mutation, there is severe obesity but no obesity-related hypertension (5).…”

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confidence: 99%

“…In humans with loss-of-function Mc4r mutation, there is severe obesity but no obesity-related hypertension (5). Mc4r-deficient (Mc4rKO) mice exhibit hyperphagia and marked obesity and, similarly, no obesity-related hypertension (3). Mc4r deletion also reduces the pressor response to salt loading, as well as preventing inflammatory and renal damage associated with obesity (6).…”

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confidence: 99%

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

Samuelsson

Mullier

Maicas

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Melanocortin-4 receptor (Mc4r)-expressing neurons in the autonomic nervous system, particularly in the paraventricular nucleus of the hypothalamus (PVH), play an essential role in blood pressure (BP) control. mice are severely obese but lack obesity-related hypertension; they also show a reduced pressor response to salt loading. We have previously reported that lean juvenile offspring born to diet-induced obese rats (OffOb) exhibit sympathetic-mediated hypertension, and we proposed a role for postnatally raised leptin in its etiology. Here, we test the hypothesis that neonatal hyperleptinemia due to maternal obesity induces persistent changes in the central melanocortin system, thereby contributing to offspring hypertension. Working on the OffOb paradigm in both sexes and using transgenic technology to restore Mc4r in the PVH of Mc4rKO (Mc4rPVH) mice, we have now shown that these mice develop higher BP than Mc4rKO or WT mice. We have also found that experimental hyperleptinemia induced in the neonatal period in Mc4rPVH and WT mice, but not in the Mc4rKO mice, leads to heightened BP and severe renal dysfunction. Thus, Mc4r in the PVH appears to be required for earlylife programming of hypertension arising from either maternal obesity or neonatal hyperleptinemia. Early-life exposure of the PVH to maternal obesity through postnatal elevation of leptin may have long-term consequences for cardiovascular health.melanocortin-4 receptors | developmental programming | maternal obesity | hypertension | sympathetic nerve activity T he main focus of research into the central melanocortin system has been on melanocortin-4 receptor(s) (Mc4r) and their relation to energy homeostasis, with relatively few studies addressing the role of Mc4r in cardiovascular control (1, 2). However, it is clear that this system plays an important role in the control of blood pressure (BP) (3, 4). In humans with loss-of-function Mc4r mutation, there is severe obesity but no obesity-related hypertension (5). Mc4r-deficient (Mc4rKO) mice exhibit hyperphagia and marked obesity and, similarly, no obesity-related hypertension (3). Mc4r deletion also reduces the pressor response to salt loading, as well as preventing inflammatory and renal damage associated with obesity (6). Pharmacological inhibition of Mc4r in adult rats reduces the obesity-related hypertension and renal sympathetic nerve activity (RSNA) associated with hyperleptinemia (7,8). Moreover, the highest expression of hypothalamic Mc4r mRNA is found in the paraventricular nucleus of the hypothalamus (PVH), which integrates and responds to a variety of neural and humoral signals regulating RSNA (9-12). It has been shown that leptin stimulates the tonic firing rate of Mc4r PVH neurons in rats, resulting in heightened arterial pressure, a finding that is consistent with causal links between obesity and adult hypertension (13).The increased prevalence of hypertension among children and young adults has been attributed to sympathetic hyperactivity (14). Although genetic and lifestyle factors un...

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“…35 This process is thought to be the main pathway of the brain melanocortin system's regulation of body weight, SNA, and blood pressure. 36 The inhibitory effect on NPY neurons causes a reduction in γ-aminobutyric acid production, which further stimulates pro-opiomelanocortin neurons, leading to reduced NPY and increased α-MSH production, and enhances stimulation of MC3/4 receptors, respectively. 37 This interaction facilitates weight loss by reducing appetite and food intake and increasing energy expenditure (thermogenesis) of the brown adipose tissues through sympathetic activation.…”

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Origin of Aberrant Blood Pressure and Sympathetic Regulation in Diet-Induced Obesity

et al. 2016

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O besity, a state of excessive adipose tissue accumulation, has reached epidemic proportions worldwide, and this increasing global prevalence constitutes a major public health challenge. Obesity is one of the main causes of hypertension. Both human and animal studies present a strong link between bodyweight gain and greater blood pressure.1 Importantly, obesity-related hypertension is caused by an interaction of humoral and neural mechanisms, 2,3 and inappropriate increases in sympathetic tone are thought to be the major cause of the hypertension. [4][5][6] Indeed, clinical data show that when compared with normal subjects, noradrenaline spillover rates are greater among obese individuals. 7 Furthermore, in studies using dog and rat models of obesity, bilateral renal denervation attenuated the hypertension 8,9 and combined α-and β-adrenergic blockade has been shown to prevent high fat diet (HFD)-induced hypertension in conscious rabbits. 10 Although the close link between the obesity and the prevalence of hypertension has been well established, a key focus in the field remains the identification of mechanisms underlying sympathetic overdrive in obesity.The adipokine leptin is a 16-kDa peptide that is secreted primarily by white adipose tissue and found in serum in direct proportion to adiposity. In addition to the weight loss effect, leptin has also been shown to activate sympathetic nerve activity (SNA) in the kidneys, hindlimbs, and adrenal glands, which suggested its potential role in the increased SNA in obesityrelated hypertension. 4 Plasma leptin levels correlate strongly with blood pressure and renal SNA (RSNA) while central administration of leptin increases mean arterial pressure (MAP) in both rats and rabbits via stimulation of the sympathetic nervous system. 3,11 Hence, the effect of increased circulating leptin because of high adiposity is considered a primary link between obesity and increased SNA. 3,12 The central effects of leptin are thought to be mediated primarily through the arcuate nucleus of the hypothalamus from which peripheral signals are relayed downstream to other hypothalamic nuclei via a network of second-order neurons.13 Pro-opiomelanocortin and neuropeptide Y (NPY) neurons in the arcuate nucleus form the main population of neurons expressing the leptin receptor, which propagate leptin signals throughout the hypothalamus Abstract-High fat diet (HFD)-induced hypertension in rabbits is neurogenic and caused by the central action of leptin, which is thought to be dependent on activation of α-melanocortin-stimulating hormone (α-MSH) and neuropeptide Y-positive neurons projecting to the dorsomedial hypothalamus (DMH) and ventromedial hypothalamus (VMH). However, leptin may act directly in these nuclei. Here, we assessed the contribution of leptin, α-MSH, and neuropeptide Y signaling in the DMH and VMH to diet-induced hypertension. Male New Zealand white rabbits were instrumented with a cannula for drug injections into the DMH or VMH and a renal sympathetic nerve activity (RSNA) electrode....

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The Brain Melanocortin System, Sympathetic Control, and Obesity Hypertension

Cited by 35 publications

References 55 publications

Chronic Central Nervous System MC3/4R Blockade Attenuates Hypertension Induced by Nitric Oxide Synthase Inhibition but Not by Angiotensin II Infusion

Chronic Central Nervous System MC3/4R Blockade Attenuates Hypertension Induced by Nitric Oxide Synthase Inhibition but Not by Angiotensin II Infusion

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

Origin of Aberrant Blood Pressure and Sympathetic Regulation in Diet-Induced Obesity

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