Human White Adipose Tissue Displays Selective Insulin Resistance in the Obese State

Selective hepatic insulin resistance is a feature of obesity and type 2 diabetes. Whether similar mechanisms operate in white adipose tissue (WAT) of obese subjects and to what extent these are normalized by weight loss is unknown. We determined insulin sensitivity by hyperinsulinemic euglycemic clamp and the insulin response in subcutaneous WAT by RNA-sequencing in 23 women with obesity before and two years after bariatric surgery. To control for effects of surgery, women post-surgery were matched to never-obese subjects. Multidimensional analyses of 138 samples allowed us to classify the effects of insulin into three distinct expression responses: a common set was present in all three groups and included genes encoding several lipid/cholesterol biosynthesis enzymes; a set of obesity-attenuated genes linked to tissue remodelling and protein translation was selectively regulated in the two non-obese states and several post obesity-enriched genes encoding proteins involved in e.g. one carbon metabolism were only responsive to insulin in the women who had lost weight. Altogether, human WAT displays a selective insulin response in the obese state where most genes are normalized by weight loss. This comprehensive atlas provides insights into the transcriptional effects of insulin in WAT and may identify targets to improve insulin action.