Evidence that multiple genetic variants of MC4R play a functional role in the regulation of energy expenditure and appetite in Hispanic children

Cole, Shelley A.; Butte, Nancy F.; Voruganti, V. Saroja; Cai, Guowen; Haack, Karin; Kent, Jack W.; Blangero, John; Comuzzie, Anthony G.; Mcpherson, John Douglas; Gibbs, Richard A.

doi:10.3945/ajcn.2009.28514

Cited by 64 publications

(56 citation statements)

References 54 publications

(61 reference statements)

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“…In children from the UK ALSPAC cohort, the rs17782313 C allele was additively associated with an increase in BMI from the age of 7-11 years, of a magnitude greater than that seen in adults, linked both to variation in weight and also increased body fatness . A functional role for common variants near MC4R in body weight regulation in children has been confi rmed in other studies (Cole et al, 2010;Stutzmann et al, 2009). Thus, the example of MC4R illustrates the considerable and complex overlap in the genetic susceptibility for monogenic and polygenic obesity.…”

Section: Melanocortin 4 Receptor Gene and A Role In Polygenic Obesitymentioning

confidence: 74%

“…In studies assessing patterns of eating through self-report and dietary recall, the rs17782313 C allele has been associated with increased snacking and food intake in obese and non-obese European children and adolescents (Cole et al, 2010;Stutzmann et al, 2009). Similarly, rs17782313 has been linked to eating behaviours related to obesity such as low satiety responsiveness and increased enjoyment of food in obese children assessed by a psychometric tool to characterize children ' s eating behaviour (Valladares et al, 2010).…”

Section: Melanocortin 4 Receptor and Eating Behaviourmentioning

confidence: 99%

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Obesity and eating behaviour in children and adolescents: Contribution of common gene polymorphisms

Cecil

Dalton

Finlayson

et al. 2012

International Review of Psychiatry

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The prevalence of childhood obesity is increasing in many countries and confers risks for early type 2 diabetes, cardiovascular disease and metabolic syndrome. In the presence of potent ' obesogenic ' environments not all children become obese, indicating the presence of susceptibility and resistance. Taking an energy balance approach, susceptibility could be mediated through a failure of appetite regulation leading to increased energy intake or via diminished energy expenditure. Evidence shows that heritability estimates for BMI and body fat are paralleled by similar coeffi cients for energy intake and preferences for dietary fat. Twin studies implicate weak satiety and enhanced food responsiveness as factors determining an increase in BMI. Single gene mutations, for example in the leptin receptor gene, that lead to extreme obesity appear to operate through appetite regulating mechanisms and the phenotypic response involves overconsumption and a failure to inhibit eating. Investigations of robustly characterized common gene variants of fat mass and obesity associated ( FTO ), peroxisome proliferator-activated receptor ( PPARG ) and melanocortin 4 receptor ( MC4R ) which contribute to variance in BMI also infl uence the variance in appetite factors such as measured energy intake, satiety responsiveness and the intake of palatable energy-dense food. A review of the evidence suggests that susceptibility to childhood obesity involving specifi c allelic variants of certain genes is mediated primarily through food consumption (appetite regulation) rather than through a decrease in activity-related energy expenditure. This conclusion has implications for early detection of susceptibility, and for prevention and management of childhood obesity.

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Section: Melanocortin 4 Receptor Gene and A Role In Polygenic Obesitymentioning

confidence: 74%

Section: Melanocortin 4 Receptor and Eating Behaviourmentioning

confidence: 99%

Obesity and eating behaviour in children and adolescents: Contribution of common gene polymorphisms

Cecil

Dalton

Finlayson

et al. 2012

International Review of Psychiatry

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“…Additionally, chronic icv SHU9119 treatment in rats increases the RER ( 8 ), indicative of reduced lipid utilization. Interestingly, variants near and in the MC4R gene in humans are associated not only with an increased RER ( 8 ), but also with reduced total energy expenditure (EE) ( 11,12 ), underscoring the importance of the melanocortin system in the regulation of EE.…”

Section: Vldl Productionmentioning

confidence: 99%

Inhibition of the central melanocortin system decreases brown adipose tissue activity

Kooijman

Boon

Parlevliet

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org Supplementary key words energy expenditure • liver • triglycerides • very low density lipoprotein • white adipose tissueThe hypothalamus is important in the regulation of energy balance. Activation of pro-opiomelanocortin neurons (e.g., by insulin or leptin) induces secretion of ␣ -melanocytestimulating hormone, which in turn stimulates melanocortin 3/4 receptors (MC3/4Rs) within the paraventricular nucleus to cause a negative energy balance ( 1 ). Accordingly, activation of central melanocortin 4 receptor (MC4R) in rodent models results in anorexia and weight loss ( 2 ), whereas blockade or targeted gene disruption induces hyperphagia and obesity, even on regular chow diet ( 3, 4 ). Loss-of-function mutations in MC4R are the most common monogenic form of obesity in humans and are associated with severe obesity in childhood ( 5 ). In addition, recent meta-analyses of genome-wide association studies identifi ed common variants near MC4R to infl uence fat mass, obesity, and obesity risk ( 6, 7 ). These observations support an essential role for the melanocortin system in the regulation of energy homeostasis across mammalian species.In addition to the effects of the melanocortin system on food intake, this system also affects energy balance via other pathways. This notion is supported by the observation that pharmacological inhibition of central MC4R by Abstract The melanocortin system is an important regulator of energy balance, and melanocortin 4 receptor (MC4R) defi ciency is the most common monogenic cause of obesity. We investigated whether the relationship between melanocortin system activity and energy expenditure (EE) is mediated by brown adipose tissue (BAT) activity. Therefore, female APOE*3-Leiden.CETP transgenic mice were fed a Western-type diet for 4 weeks and infused intracerebroventricularly with the melanocortin 3/4 receptor (MC3/4R) antagonist SHU9119 or vehicle for 2 weeks. SHU9119 increased food intake (+30%) and body fat (+50%) and decreased EE by reduction in fat oxidation ( ؊ 42%). In addition, SHU9119 impaired the uptake of VLDL-TG by BAT. In line with this, SHU9119 decreased uncoupling protein-1 levels in BAT ( ؊ 60%) and induced large intracellular lipid droplets, indicative of severely disturbed BAT activity. Finally, SHU9119-treated mice pair-fed to the vehicletreated group still exhibited these effects, indicating that MC4R inhibition impairs BAT activity independent of food intake. These effects were not specifi c to the APOE*3-Leiden.CETP background as SHU9119 also inhibited BAT activity in wild-type mice. We conclude that inhibition of central MC3/4R signaling impairs BAT function, which is accompanied by reduced EE, thereby promoting adiposity. We anticipate that activation of MC4R is a promising strategy to combat obesity by increasing BAT activity. -Kooijman, S., M. R. Boon, E. T. Parlevliet, J. J. Geerling, V. van de Pol, J. A. Romijn, L. M. Havekes, I. Meurs, and P. C. N. Rensen. Inhibition of the central melanocortin system ...

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“…These results were confirmed in a GWAS performed to identify chromosomal regions contributing to increased consumption of dietary components among 1,030 Hispanic children. This study found that MC4R gene variants have a key role in regulating body weight through both increased energy consumption and decreased energy expenditure (Cai et al 2006;Cole et al 2010). A more recent study suggests that individuals possessing MC4R gene variants consume increased amounts of food enriched with total and saturated fatty acids (Bauer et al 2009).…”

Section: Obesity Susceptibility Genes That Interact With Dietary Fatsmentioning

confidence: 84%

The genetics of childhood obesity and interaction with dietary macronutrients

et al. 2013

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The genes contributing to childhood obesity are categorized into three different types based on distinct genetic and phenotypic characteristics. These types of childhood obesity are represented by rare monogenic forms of syndromic or non-syndromic childhood obesity, and common polygenic childhood obesity. In some cases, genetic susceptibility to these forms of childhood obesity may result from different variations of the same gene. Although the prevalence for rare monogenic forms of childhood obesity has not increased in recent times, the prevalence of common childhood obesity has increased in the United States and developing countries throughout the world during the past few decades. A number of recent genome-wide association studies and mouse model studies have established the identification of susceptibility genes contributing to common childhood obesity. Accumulating evidence suggests that this type of childhood obesity represents a complex metabolic disease resulting from an interaction with environmental factors, including dietary macronutrients. The objective of this article is to provide a review on the origins, mechanisms, and health consequences of obesity susceptibility genes and interaction with dietary macronutrients that predispose to childhood obesity. It is proposed that increased knowledge of these obesity susceptibility genes and interaction with dietary macronutrients will provide valuable insight for individual, family, and community preventative lifestyle intervention, and eventually targeted nutritional and medicinal therapies.

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Evidence that multiple genetic variants of MC4R play a functional role in the regulation of energy expenditure and appetite in Hispanic children

Abstract: This comprehensive investigation provides strong evidence that MC4R genetic variants are likely to play a functional role in the regulation of weight, not only through energy intake but through energy expenditure.

Cited by 64 publications

References 54 publications

Obesity and eating behaviour in children and adolescents: Contribution of common gene polymorphisms

Obesity and eating behaviour in children and adolescents: Contribution of common gene polymorphisms

Inhibition of the central melanocortin system decreases brown adipose tissue activity

The genetics of childhood obesity and interaction with dietary macronutrients

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