Editors' ChoiceMetabolic Disease

Weighty Considerations

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Science Translational Medicine  14 Nov 2012:
Vol. 4, Issue 160, pp. 160ec209
DOI: 10.1126/scitranslmed.3005305

Obesity, which has been estimated to affect more than one-third of the adult population in the United States, increases the likelihood of various diseases, including heart disease and type 2 diabetes. However, the exact mechanisms by which obesity increases the risk of these diseases remain to be elucidated. One way to get at these mechanisms is human genome-wide association studies (GWASs), which connect particular genes to disease phenotypes. However, these studies frequently result in large lists of genes that may or may not have a pathophysiological role in the disease examined. More than 50 genes have been associated with type 2 diabetes (T2D) in GWASs. One of these is TCF7L2, a transcription factor that controls the Wnt signaling pathway, which is involved in metabolic regulation and adipogenesis. Specifically, two single-nucleotide polymorphisms (SNPs) within intronic regions of the TCF7L2 gene are robustly associated with increased risk for T2D. Intronic SNPs could affect mRNA splicing; therefore, these TCF7L2 polymorphisms may potentially impair TCF7L2 function and increase diabetes risk by changing mRNA variant distribution. Now, Kaminska et al. report that TCF7L2 splicing variants in human adipose tissue correlate with weight loss, glucose metabolism, and free fatty acid levels.

To analyze TCF7L2 splicing variants, the authors took advantage of liver, subcutaneous, and visceral adipose tissue biopsies collected from 95 morbidly obese individuals participating in the Kuopio Obesity Surgery Study (KOBS), in which all subjects received the Roux-en-Y gastric bypass surgery. Through this surgery, the subjects lost ~24% of their initial weight and achieved improved glucose and fatty acid metabolism at the end of 12 months. Although no change in total TCF7L2 was observed in those tissues before and after the surgery, the relative proportion of a short mRNA variant, lacking exons 12, 13, and 13a, was significantly reduced by 3% in subcutaneous fat and 7% in liver with reduction of body weight.

Conversely, the expression level of the short mRNA in subcutaneous adipose tissue was higher in type 2 diabetic patients than in nondiabetic subjects in a pooled analysis of KOBS, METSIM (the population-based Metabolic Syndrome in Men), and EUGENE2 (the European Network on Functional Genomics of Type 2 Diabetes) data. Importantly, the expression of the short TCF7L2 mRNA in adipose tissue was positively correlated with high BMI (body mass index) and glucose levels but not with insulin levels, sex, and age in the study groups. As the TCF7L2 small splicing variant was associated with high levels of serum-free fatty acids during hyperinsulinemia, the TCF7L2 variants in adipose tissue may reflect the status of fatty acid metabolism and insulin action in adipose tissue.

Future studies examining the exact pathways responsible for the alterations in TCF7L2 splicing are of great interest and may reveal a new aspect of RNA biology in the context of metabolism, obesity, and type 2 diabetes.

D. Kaminska et al., Adipose tissue TCF7L2 splicing is regulated by weight loss and associates with glucose and fatty acid metabolism. Diabetes, published online 11 November 2012 (10.2337/db12-0239). [PubMed]

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