Increased subcutaneous adipose tissue expression of genes involved in glycerolipid-fatty acid cycling in obese insulin-resistant versus -sensitive individuals.

Abstract

A subpopulation of obese individuals remains insulin sensitive (ISO). They represent a unique human model to investigate factors underlying insulin resistance (IR) without the confounding effect of major differences in weight/adiposity. Altered fatty-acid (FA) metabolism in sc adipose tissue (SAT) contributes to obesity-associated IR. To test the hypothesis that ISO and body mass index-matched insulin-resistant obese (IRO) patients demonstrate differential SAT expression profiles of genes involved in glycerolipid-FA metabolism and that weight loss-induced improvement of IR ameliorates these changes. A cross-sectional and longitudinal study. Thirty-eight nondiabetic obese women were stratified into ISO (n = 25) or IRO (n = 13) groups based on hyperinsulinemic-euglycemic clamp results. Subjects were studied before and after a 6-month hypocaloric diet intervention. mRNA (quantitative RT-PCR) and protein (mass spectrometry and immunoblots) levels were measured in SAT biopsies. Despite having age, body mass index, and fat mass similar to ISO individuals, IRO patients had lower insulin sensitivity and glucose tolerance (P < .05). Baseline SAT mRNA and protein levels of genes involved in both the synthesis and lipolysis of glycerolipid-FAs were higher in IRO individuals (P < .05), even when groups were matched for visceral adipose tissue content. The dietary intervention resulted in approximately 6% weight loss in both the IRO and ISO groups (P < .05) but only ameliorated insulin sensitivity in IRO individuals (P < .05). Likewise, the intervention reduced the expression of most glycerolipid-FA metabolism genes (P < .05), with expression levels in IRO individuals being restored to ISO levels. Increased SAT expression of genes involved in both the synthesis and hydrolysis of glycerolipid-FAs is closely associated with IR in obese women. The results suggest that enhanced glycerolipid-FA cycling in SAT contributes to obesity-associated IR.