The Metabolic connection. the triglyceride/fatty acid cycle Richard W. Hanson, Ph.D. (Case Western Reserve) Glyceroneogenesis is the synthesis of 3-glycerol phosphate by an abbreviated version of gluconeogenesis. This pathway occurs during fasting in white and brown adipose tissue and in the liver, as part of the triglyceride/fatty acid cycle. Glyceroneogenesis is critical for the extensive recycling of free fatty acids (FFA) back to triglyceride after lipolysis, when up to 65% of the fatty acids are re-esterified. The rate-limiting enzyme in this pathway is the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (4.1.1.32) (PEPCK-C). Transcription of this gene is induced in adipose tissue and liver during fasting. Ablation of expression of the gene for PEPCK-C in white adipose tissue of mice results in lipodsytrophy, while over-expression of the gene for this enzyme in adipose tissue causes obesity. The critical role of glyceroneogenesis in diabetes was suggested by experiments in which the gene for PEPCK-C is induced in white adipose tissue by rosiglitazone, a drug used to control diabetes in humans. This was accompanied by a marked decrease in FFA release from adipose tissue, due to an induction in glyceroneogenesis. Since the chronic release of FFA by adipose tissue is a critical factor in the development Type 2 diabetes, it is likely that rosiglitazone acts in part by stimulating transcription of the gene for PEPCK-C, thereby increasing rate of glyceroneogenesis and lowering the rate of FFA release from adipose tissue.