Editors' ChoiceObesity

The Body Fat Paradox

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Science Translational Medicine  20 Jul 2011:
Vol. 3, Issue 92, pp. 92ec112
DOI: 10.1126/scitranslmed.3002891

More than 1 billion adults are projected to be obese by 2030. The rates of obesity-related diseases—such as diabetes, heart disease, and cancer—are equally staggering. Desperate measures are needed to stem the tide of this pandemic. Now, in a meta-analysis of over 15 genome-wide association studies (GWASs) of more than 70,000 individuals of European and Asian descent, Kilpeläinen et al. investigate genomic ties to body fat percentage in an attempt to shed light on the genetic underpinnings of obesity. Notably, one single-nucleotide polymorphism (SNP) in the fat mass and obesity-associated gene FTO (a previously validated obesity locus) and two new SNPs located near the insulin receptor substrate 1 (IRS1, rs2943650) and the sprouty homolog 2 gene (SPRY2, rs534870) were found to be significantly associated with body fat percentage at a genome-wide level (P < 5.0 × 10–8).

The IRS1 SNP correlated with a modest decrease (0.16%) in body fat percentage in men but not women. But the authors also found another, counterintuitive association with this SNP: In a subgroup of more than 20,000 men and women, the IRS1 SNP conferred a predisposition to a number of well-established cardiovascular risk factors, including a higher ratio of visceral to subcutaneous fat, higher plasma triglycerides, lower serum HDL and adiponectin concentrations, and insulin resistance

Further, gene expression profiles in 604 Icelandic individuals revealed that carriers of rs2943650 expressed less IRS1 in subcutaneous adipose tissue. Once again, this effect seemed to be greater in men than in women. To better understand this result, the investigators measured baseline IRS1 expression in visceral fat in 100 individuals and found it to be higher in women than men, independent of rs2943650 carrier status. The authors opined that this elevated baseline expression in women may be protective and therefore blunt the effects of the at-risk variant. In contrast, the second newly discovered locus near the SPRY2 gene was directly linked to body fat percentage and insulin resistance in European men and women. No association to other metabolic parameters was noted, and no effect of this SNP was observed in Indian Asians.

Together, these findings demonstrate that investigating intermediate phenotypes in various human populations can identify unexpected components of biologic pathways of disease that might otherwise remain unknown. This approach has also recently proven successful for blood glucose in diabetes and blood lipids in coronary artery disease. Going forward, we can rest assured that many more paradoxes will be uncovered as we start using whole-genome sequencing for the next wave of GWASs.

T. O. Kilpeläinen et al., Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. Nature 26 June 2011 (10.1038/ng.866). [Abstract]

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