Obese Insulin Resistant Humans with Compensatory Hyperinsulinemia Dissociate Lipolysis from Glycemia as Possible Adaptive Response to Fatness

High blood levels of free fatty acids link obesity with type-2 diabetes, but this connection remains poorly understood. We have investigated lipolysis and glucose homeostasis in recently diagnosed obese type-2 diabetics; in obese insulin resistant non-diabetic subjects (obese-IR) matched for age, sex, body composition and fasting insulin levels; and in healthy lean individuals. Our results show that obese-IR dissociate lipolysis from glycemic control, revealing that the action of compensatory hyperinsulinemia on blood glucose is not mediated by reduced lipolysis. In the obese adipose tissue free fatty acids and glycerol levels were elevated in spite of high local levels of insulin or lactate; correlated with adipocyte size and metabolic inflammation, with reduced adipose tissue mRNA levels of genes implicated in beta-adrenergic signaling, de-novo lipogenesis, and increased expression of genes implicated in adipose tissue hyperplasia. These results shed light on the nature of the interaction between lipolysis and glucose homeostasis and indicate an possible adaptive response to fatness. To undersrand the mechanisms driving elevated levels of FFA and glycerol in the obese groups we have performed genome-wide RNASeq analysis of RNA preparations from abdominal subcutaneous adipose tissues of Lean, Obese-IR, and Obese-T2D subjects