Fatty acid cycling and type 2 diabetes : adipocyte glyceroneogenesis and phosphoenolpyruvate carboxykinase as selective targets

Abstract

Elevated plasma fatty acids (FA) is an early event in insulin-resistance and type 2 diabetes (T2DM). During fasting, a significant part of lipolytic FA (30–70%) is re-esterified in adipose tissue, so that a recycling occurs. Re-esterification requires glycerol-3-P (G3P) synthesis arising mainly from activated glyceroneogenesis, a pathway defined by Hanson and colleagues several decades ago as the de novo synthesis of G3P from pyruvate or lactate. The key enzyme in glyceroneogenesis is the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C). We demonstrated that the antidiabetic thiazolidinediones (TZD) and the omega-3 FA docosahexaenoic acid (DHA) are potent and selective inducers of glyceroneogenesis and PEPCK-C in human and rodent adipose tissue. We showed that the PEPCK-C gene was a primary transcriptional target for the prototype TZD rosiglitazone and for DHA but the mechanisms appear to be different. Among the two previously discovered PPARgamma/RXR binding sites in the PEPCK-C gene promoter, PCK2 and PCK1, PCK2 is the single TZD response element. PCK2 is highly conserved between rodents and humans. Two SNPs near this element were found in a sample of 403 subjects. One of the alleles exerts a co-dominant effect with fasting glucose and hemoglobin-A1c levels in T2DM patients. Besides, glucocorticoids repress all hormonal and nutritional inductions of glyceroneogenesis and PEPCK-C gene transcription, while stimulating the liver PEPCK-C. We showed that inhibition of TZD induction requires PCK1. All these arguments point to the involvement of glyceroneogenesis and PEPCK-C in the maintenance of FA homeostasis and ascribe the occurrence of T2DM to their disregulation.