• Vol. 38 No. 1, 34–44
  • 15 January 2009

The Role of Leptin-Melanocortin System and Human Weight Regulation: Lessons from Experiments of Nature



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Introduction: Common obesity is a multi-factorial trait, contributed by the “obesogenic” environment of caloric abundance and increasing automation, sedentary lifestyle and an underlying genetic susceptibility. There have been major advances in the past decade in our understanding of the human weight regulation mechanism and pathogenesis of obesity, abetted by discoveries of genetic defects which lead to human obesity.

Materials and Methods: Reports of genetic mutations causing obesity in humans and murine models were reviewed

Results: Humans with genetic defects resulting in leptin deficiency, leptin receptor deficiency, pro-opiomelanocortin deficiency (POMC), and melanocortin 4 receptor (MC4R) deficiency developed severe obesity as the dominant phenotypic feature, though these are rare autosomal recessive conditions, except MC4R deficiency which is inherited in an autosomal co-dominant fashion. Common and rare variants of the POMC and melanocortin 3 receptor genes may be pre-disposing factors in the development of common obesity. Recent reports of human obesity associated with thyrosine kinase B (TrkB) defect and brain derived neurotrophic factor (BDNF) disruption, coupled with other murine studies, supported the role of BDNF/TrkB as effectors downstream of the melanocortin receptors.

Conclusions: Despite exciting discoveries of single gene mutations resulting in human obesity, most cases of obesity are likely the result of subtle interactions of several related genetic variants with environmental factors which favour the net deposition of calories as fat, culminating in the obese phenotype. The mechanisms of action of these genes in the development of obesity are now being examined, with the aim of eventually discovering a therapeutic intervention for obesity.

Obesity predisposes to significant morbidities and premature mortality, and the increasing obesity prevalence all over the world has been attributed to industrialisation and modernisation which encourages a sedentary lifestyle and increased calorie intake. This results in energy intake and expenditure imbalance and the net deposition of calories as fat. Although this trend of increasing body girth is very much driven by the “obesogenic” environment, it is facilitated by the individual’s genetic susceptibility to excessive weight gain.

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