Lipolysis, which occurs mainly in adipose tissue, is the breakdown of triacylglycerols (TAGs) into free fatty acids that are released into the circulation for use by energy costly organs like the heart. Lipolysis is triggered by counterregulatory hormones like adrenaline, which activate adenylate cyclase to produce intracellular cAMP. cAMP then activates PKA, which in turn phosphorylates a series of proteins on the lipid droplet surface thus providing access by lipases to hydrolyse TAGs.  This process is very well understood at a molecular level. The other major regulatory arm of the lipolytic cycle represents its repression by insulin. A major action of insulin is to block fatty acid release into the blood and this occurs in the postprandial state. This action is a major component of the metabolic switch from fat to carbohydrate utilisation following consumption of a carbohydrate meal.  Defects in this process are thought to lead to excessive lipolysis and ectopic lipid deposition in tissues like liver and pancreas. The molecular details by which insulin represses lipolysis are much less clear than those that activate the process.

The most notorious model for insulin mediated repression of lipolysis involves activation of a phosphodiesterase (an enzyme that hydrolyses and inactivates cAMP) called phosphodiesterase 3B (PDE3B). PDE3B is phosphorylated by Akt and this is thought to (but never proven) stimulate PDE3B activity. However, various cracks in this theory have appeared in recent years.

Our lab has shown that another protein called abhydrolase domain containing protein 15 (ABHD15), is also important in insulin-mediated lipolysis inhibition. ABHD15 forms a stable interaction with PDE3B and like PDE3B, ABHD15 phosphorylation is markedly enhanced by Akt.  We have found that when ABHD15 levels are reduced or ablated in fat cells, insulin can no longer inhibit lipolysis. We are actively

Through a comprehensive interdisciplinary study comprising cell biology, mass spectrometry and animal metabolism we hope to clarify controversies about the process and shed light on ABHD15’s role in insulin’s inhibition of lipolysis.