Editors' ChoiceMetabolism

Obesity: It’s (Kind of) Genetic

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Science Translational Medicine  18 Apr 2012:
Vol. 4, Issue 130, pp. 130ec67
DOI: 10.1126/scitranslmed.3004136

Appetite and satiety are ruled by the central nervous system, whereas nutrient metabolism and energy utilization are regulated by local mechanisms. Any imbalance in these systems unsettles the equilibrium between caloric intake and energy expenditure, leading to obesity in the long run. For some individuals, weight control is still difficult despite a balanced lifestyle. Now, Ichimura and colleagues make the case that the dysfunction of a particular fatty acid–sensing receptor, the G protein–coupled receptor 120 (GPR120), might be linked to obesity, fat production (adipogenesis), and appetite. If true, some people may be able to finally blame their genes on not fitting in their jeans.

When put on a high-fat diet, young mice deficient in GPR120 expression revealed a disproportionate weight gain compared with normal (wild-type) mice, with white adipose tissue (WAT) and liver being substantially heavier than those of controls. Functionally, these differences were associated with an increase in insulin resistance and glucose intolerance. Ichimura et al. profiled gene expression pathways in liver and WAT and identified groups of up-regulated genes associated with inflammation. Conversely, genes associated with insulin signaling (Insr, Irs1, and Irs2), adipocyte differentiation (Fabp4), and lipogenesis (Scd1) were down-regulated in WAT and the liver by the lack of GPR120. Expression changes in Scd1 were reflected in the tissue lipid composition. The reduction of one lipid in particular, the mono-unsaturated fatty acid palmitoleate, was proposed to cause the metabolic changes observed in obese GPR120-deficient mice.

The authors further observed that GPR120 expression is increased in adipose tissue in obese humans. Cohorts of obese children and adults had the amino acid substitution R270H in the coding region of GPR120, whereas lean adults and children did not. The next step will be to define more closely the molecular mechanism of GPR120 function in humans, with the hopes of using this receptor as a candidate drug target to control appetite and, in turn, obesity.

A. Ichimura et al., Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 483, 350–354 (2012). [Abstract]

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