Melanocortin-4 Receptor–Deficient Mice Are Not Hypertensive or Salt-Sensitive Despite Obesity, Hyperinsulinemia, and Hyperleptinemia

Tallam, Lakshmi S.; Stec, David E.; Willis, Mary Alissa; Silva, Alexandre A. da; Hall, John E.

doi:10.1161/01.hyp.0000175474.99326.bf

Cited by 132 publications

(107 citation statements)

References 40 publications

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“…Chronic pharmacologic blockade of MC3R and MC4R causes weight gain and a reduction in heart rate but no increase in arterial pressure. Mc4r-null mice maintain normal blood pressure despite marked obesity and are unresponsive to the pressor effects of central α-MSH administration (64). We have shown that both increases and decreases in central melanocortin signaling influence blood pressure in humans and that the effects are not explained by changes in circulating insulin levels or insulin sensitivity (65).…”

Section: Mutations That Disrupt Melanocortin Signalingmentioning

confidence: 80%

Genetic approaches to understanding human obesity

Ramachandrappa¹,

Farooqi²

2011

J. Clin. Invest.

173

143

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Obesity and its associated comorbidities represent one of the biggest public health challenges facing the world today. The heritability of body weight is high, and genetic variation plays a major role in determining the interindividual differences in susceptibility or resistance to the obesogenic environment. Here we discuss how genetic studies in humans have contributed to our understanding of the central pathways that govern energy homeostasis. We discuss how the arrival of technological advances such as next-generation sequencing will result in a major acceleration in the pace of gene discovery. The study of patients harboring these genetic variants has informed our understanding of the molecular and physiological pathways involved in energy homeostasis. We anticipate that future studies will provide the framework for the development of a more rational targeted approach to the prevention and treatment of genetically susceptible individuals.

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Section: Mutations That Disrupt Melanocortin Signalingmentioning

confidence: 80%

Genetic approaches to understanding human obesity

Ramachandrappa¹,

Farooqi²

2011

J. Clin. Invest.

173

143

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“…Conversely, blockade of CNS MC3/4Rs in rodents causes voracious feeding and rapid weight gain and reduces rather than increases BP (31). Similarly, mice with MC4R deficiency are hyperphagic and obese and have many features of the metabolic syndrome but are not hypertensive on normal or high salt diets (32).…”

Section: Chronic Activation Of the Cns Pomc-mc3/4r Pathway Causes Snsmentioning

confidence: 99%

Obesity-induced Hypertension: Role of Sympathetic Nervous System, Leptin, and Melanocortins

Hall

Silva

Carmo

et al. 2010

Journal of Biological Chemistry

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437

400

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Excess weight gain contributes to increased blood pressure in most patients with essential hypertension. Although the mechanisms of obesity hypertension are not fully understood, increased renal sodium reabsorption and impaired pressure natriuresis play key roles. Several mechanisms contribute to altered kidney function and hypertension in obesity, including activation of the sympathetic nervous system, which appears to be mediated in part by increased levels of the adipocyte-derived hormone leptin, stimulation of pro-opiomelanocortin neurons, and subsequent activation of central nervous system melanocortin 4 receptors.The worldwide prevalence of obesity and associated cardiometabolic diseases have increased dramatically in the past 2-3 decades, rapidly becoming major challenges to the health care systems of most industrialized countries. Current estimates indicate that Ͼ1 billion people in the world are overweight or obese (1). In the United States, at least 65% of adults are overweight, and approximately one-third of adults are obese with a body mass index (defined as kilograms of weight/m 2 of height) of Ͼ30 (2). In children, the prevalence of obesity has also risen rapidly in parallel with increasing obesity in adults; a recent report indicates that 18.4% of 4-year-old children in the United States are obese, with significantly higher rates of obesity in Hispanic, black, and Native American children (3).Associated with obesity is a cascade of metabolic and cardiovascular disorders, including hypertension, a primary mediator of obesity-induced cardiovascular disease. Population studies show that excess weight gain predicts future development of hypertension, and the relationship between body mass index and blood pressure (BP) 2 appears to be nearly linear in diverse populations throughout the world (4). Some studies suggest that excess weight gain may account for 65-75% of human essential hypertension (5). Moreover, clinical studies indicate that weight loss is effective in primary prevention of hypertension and in reducing BP in most hypertensive subjects (6).Although the importance of obesity as a major cause of essential hypertension is well established, the physiological and molecular mechanisms that mediate the BP effects of excess weight gain are only beginning to be elucidated. Excess Weight Gain Increases Renal SodiumReabsorption and Impairs Pressure Natriuresis Table 1 summarizes some of the changes in cardiovascular, neurohormonal, and renal function that occur in obese humans and experimental animals (4,7,8). Notable changes, in addition to increased BP, include increases in cardiac output and heart rate as well as activation of the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS). Rapid weight gain also stimulates renal tubular sodium reabsorption, and obese subjects require higher than normal BP to maintain balance between intake and renal excretion of sodium, indicating impaired renal pressure natriuresis (4).Three factors are especially important in increasing re...

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“…The hyperinsulinemia in this model is partially independent of obesity, as young MC4-R-deficient animals have been shown to have elevated circulating insulin levels prior to the onset of obesity (Fan et al, 2000). Despite their profound obesity in adulthood, the MC4-R-deficient animals are not hypertensive, but tend to be hypotensive (Tallam et al, 2005). Finally, another notable feature of the MC4-R null mouse is a profound sensitivity to high-fat feeding, which exacerbates the hyperphagia, obesity and hyperinsulinemia (Sutton et al, 2006).…”

Section: Melanocortin 4 Receptor (Mc4-r) Null Mousementioning

confidence: 99%

Mouse models of the metabolic syndrome

Kennedy

Ellacott

King

et al. 2010

Disease Models &Amp; Mechanisms

233

224

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The metabolic syndrome (MetS) is characterized by obesity concomitant with other metabolic abnormalities such as hypertriglyceridemia, reduced high-density lipoprotein levels, elevated blood pressure and raised fasting glucose levels. The precise definition of MetS, the relationships of its metabolic features, and what initiates it, are debated. However, obesity is on the rise worldwide, and its association with these metabolic symptoms increases the risk for diabetes and cardiovascular disease (among many other diseases). Research needs to determine the mechanisms by which obesity and MetS increase the risk of disease. In light of this growing epidemic, it is imperative to develop animal models of MetS. These models will help determine the pathophysiological basis for MetS and how MetS increases the risk for other diseases. Among the various animal models available to study MetS, mice are the most commonly used for several reasons. First, there are several spontaneously occurring obese mouse strains that have been used for decades and that are very well characterized. Second, high-fat feeding studies require only months to induce MetS. Third, it is relatively easy to study the effects of single genes by developing transgenic or gene knockouts to determine the influence of a gene on MetS. For these reasons, this review will focus on the benefits and caveats of the most common mouse models of MetS. It is our hope that the reader will be able to use this review as a guide for the selection of mouse models for their own studies.

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Melanocortin-4 Receptor–Deficient Mice Are Not Hypertensive or Salt-Sensitive Despite Obesity, Hyperinsulinemia, and Hyperleptinemia

Cited by 132 publications

References 40 publications

Genetic approaches to understanding human obesity

Genetic approaches to understanding human obesity

Obesity-induced Hypertension: Role of Sympathetic Nervous System, Leptin, and Melanocortins

Mouse models of the metabolic syndrome

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