Mutations in ligands and receptors of the leptin–melanocortin pathway that lead to obesity

@article{Farooqi2008MutationsIL,
  title={Mutations in ligands and receptors of the leptin–melanocortin pathway that lead to obesity},
  author={I Sadaf Farooqi and Stephen O’Rahilly},
  journal={Nature Clinical Practice Endocrinology \&Metabolism},
  year={2008},
  volume={4},
  pages={569-577}
}
Obesity is associated with increased morbidity and mortality from cardiovascular disease, diabetes mellitus and certain cancers. The prevalence of obesity is increasing rapidly throughout the world and is now recognized as a major global public-health concern. Although the increased prevalence of obesity is undoubtedly driven by environmental factors, the evidence that inherited factors profoundly influence human fat mass is equally compelling. Twin and adoption studies indicate that up to 70… 
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Research on the central melanocortin system in rodents suggests that this system might be a fundamental component of the adipostat, the mechanism by which energy stores are held relatively constant, and this hypothesis will be the focus of this review.
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BACKGROUND Melanocortin 4 receptor (MC4R) deficiency is the commonest monogenic form of obesity. However, the clinical spectrum and mode of inheritance have not been defined, pathophysiological
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To assess the role of the MC3-R in energy homeostasis, the majority of themc3r coding sequence was deleted from the mouse genome and found that homozygous null mc3r mice exhibit an exclusively metabolic syndrome.
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Leptin replacement therapy in leptin-deficient adults with established morbid obesity results in profound weight loss, increased physical activity, changes in endocrine function and metabolism, including resolution of type 2 diabetes mellitus and hypogonadism, and beneficial effects on ingestive and noningestive behavior.
A Unique Metalolic Sysdrone Causes Obesity in the Melanocortin-3 Receptor-Deficient Mouse.
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To assess the role of the MC3-R in energy homeostasis, the majority of themc3r coding sequence was deleted from the mouse genome and found that homozygous null mc3r mice exhibit an exclusively metabolic syndrome.
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The wide range of phenotypic abnormalities seen in the leptin-deficient ob/ob mouse and their reversibility by leptin administration provide compelling evidence for the existence of multiple
Prevalence of Melanocortin-4 Receptor Deficiency in Europeans and Their Age-Dependent Penetrance in Multigenerational Pedigrees
TLDR
A robust estimate of age-related penetrance for MC4R deficiency is established and a generational effect on penetrance is demonstrated, which may relate to the development of an “obesogenic” environment.
Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms.
TLDR
It is established that defective expression on the cell surface is a common mechanism impairing receptor function and a potentially novel molecular mechanism of receptor dysfunction whereby a mutation alters the relative affinities of a receptor for its natural agonist versus antagonist is identified.
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