Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity

Vaisse, Christian; Clément, Karine; Durand, Emmanuelle; Herçberg, Serge; Guy‐Grand, Bernard; Froguel, Philippe

doi:10.1172/jci9238

Cited by 801 publications

(653 citation statements)

References 36 publications

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“…35,79,80 The MC4-R is an established regulator of food intake and body weight, and blockade of this receptor causes obesity. 77,78 An overeating/obesity syndrome is produced, for example, by targeted deletion of the MC4-R 81 and by mutations in the human MC4-R. [82][83][84][85][86][87][88] The importance of MC4-Rs in humans is highlighted by an estimate that 3-5% of the population suffering from morbid obesity may result from MC4-R mutations. 89 Another important piece of data supporting this model is that POMC-deficient mice and humans display similar obesity phenotypes.…”

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confidence: 99%

Body weight is regulated by the brain: a link between feeding and emotion

2005

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Regulated energy homeostasis is fundamental for maintaining life. Unfortunately, this critical process is affected in a high number of mentally ill patients. Eating disorders such as anorexia nervosa are prevalent in modern societies. Impaired appetite and weight loss are common in patients with depression. In addition, the use of neuroleptics frequently produces obesity and diabetes mellitus. However, the neural mechanisms underlying the pathophysiology of these behavioral and metabolic conditions are largely unknown. In this review, we first concentrate on the established brain machinery of food intake and body weight, especially on the melanocortin and neuropeptide Y (NPY) systems as illustration. These systems play a critical role in receiving and processing critical peripheral metabolic cues such as leptin and ghrelin. It is also notable that both systems modulate emotion and motivated behavior as well. Secondly, we discuss the significance and potential promise of multidisciplinary molecular and neuroanatomic techniques that will likely increase the understanding of brain circuitries coordinating energy homeostasis and emotion. Finally, we introduce several lines of evidence suggesting a link between the melanocortin/NPY systems and several neurotransmitter systems on which many of the psychotropic agents exert their influence. Maintaining energy homeostasis is fundamental for survival. However, obesity due to over-nutrition is an increasing worldwide public health problem. 1 In psychiatric practice, on the other hand, impaired appetite is one of the crucial issues. Anorexia and weight loss are common, for example, in patients suffering from depression. Eating disorders are medically intractable and life threatening. In addition, the so-called 'atypical' antipsychotic agents, currently and widely used to treat psychoses, often induce hyperphagia, obesity, and diabetes mellitus. [2][3][4] In the past decade, fortunately, there has been remarkable progress in understanding the molecular mechanisms of food intake and body weight. This is due in large part to increased research activity towards combating the rising incidences of obesity and associated metabolic disorders. As a result, it is now established that the central nervous system (CNS) senses and processes peripheral metabolic cues including leptin 5 and ghrelin, 6,7 resulting in coordinated energy homeostasis. However, the pathophysiology of the disequilibrium between energy intake and expenditure in psychiatric disorders remains largely unknown. Nevertheless, evidence suggests that several CNS systems regulating energy balance may be dysregulated in patients with mental illnesses, for example, eating disorders, and drug addiction. [8][9][10][11][12][13][14] In the current review, we will illustrate the neuroanatomic and molecular genetic aspects of the melanocortin and neuropeptide Y (NPY) systems residing in the CNS downstream of leptin and ghrelin, to discuss the neural bases of feeding, metabolism, and emotion. Additionally, we point the reader to...

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confidence: 99%

Body weight is regulated by the brain: a link between feeding and emotion

2005

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“…35 However, functional analysis of all three polymorphisms did not indicate a difference to wild type MC4R. 14,15,18,34 …”

Section: Discussionmentioning

confidence: 92%

“…A number of groups detected mutations at high frequency among obese patients. [12][13][14][15][19][20][21][22][23][24] As shown in Table 3, the frequency of pathogenic MC4R mutations in these populations ranged from 2.5% 21 to as high as 6.3%. 12 These studies clearly focused on children with severe obesity and adults with reported early onset of obesity.…”

Section: Discussionmentioning

confidence: 94%

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Screening for melanocortin-4 receptor mutations in a cohort of Belgian morbidly obese adults and children

et al. 2005

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Objective: To investigate whether pathogenic melanocortin-4 receptor (MC4R) mutations are a common cause of obesity in Belgium. Design: Cross-sectional mutation analysis. Subjects: In total, 95 morbidly obese adults (mean age 44.02711.35 years; mean BMI 47.8774.17 kg/m 2 ) and 123 obese children and adolescents were screened for mutations in MC4R (mean age 16.5672.58 years; BMI495th percentile for age and sex; mean % overweight 170.86723.63). Measurements: A series of anthropometric (e.g. weight, height, waist, hip), biochemical and clinical measurements were performed on all subjects. The entire coding region of MC4R was screened using DHPLC, a highly sensitive and specific method for mutation analysis. Direct sequencing was performed when the chromatogram deviated from the WT pattern. Results: Mutation screening of a cohort of Belgian obese adults and children did not detect any pathogenic mutations as only the previously described polymorphisms Val103Ile, Thr112Met and Ile251Leu were detected. Conclusion: Pathogenic mutations in MC4R are not a common cause of obesity in a Belgian population of obese adults, children and adolescents.

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“…Now that the role of the MC system in obesity is widely accepted [7,26,31,45], it was hypothesized that inadequate suppression of the MC system may contribute to development or maintenance of anorexia. Given that stimulation of MC activity decreases food intake, increases energy expenditure and stimulates the HPA axis (phenomena which also occur in ABA), a hyperactive MC system possibly underlies ABA.…”

Section: Introductionmentioning

confidence: 99%

a-MSH enhances activity-based anorexia

2005

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Activity-based anorexia (ABA) is considered an animal model of anorexia nervosa (AN). In ABA, scheduled feeding in combination with voluntary access to running wheels, results in hyperactivity, hypophagia, body weight loss and activation of the HPA axis. Since stimulation of the melanocortin (MC) system has similar effects, this system is a candidate system involved in ABA. Here it is shown that chronic a-MSH treatment enhances ABA by increasing running wheel activity (RWA), decreasing food intake and increasing HPA axis activation.

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Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity

Cited by 801 publications

References 36 publications

Body weight is regulated by the brain: a link between feeding and emotion

Body weight is regulated by the brain: a link between feeding and emotion

Screening for melanocortin-4 receptor mutations in a cohort of Belgian morbidly obese adults and children

a-MSH enhances activity-based anorexia

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