Identification of a novel player in insulin-mediated lipolysis inhibition

Zadoorian A, James DE and Stoeckli J

Charles Perkins Centre, University of Sydney.

Responsible for releasing free fatty acids (FFA) from triglycerides (TG), lipolysis is a catabolic process essential for maintaining whole-body energy homeostasis. It is activated by β-adrenergic stimulation during starvation or prolonged exercise, and is inhibited by insulin following nutrient intake. Dysregulated lipolysis, as is the case in insulin resistance, can lead to increased circulating FFA and ectopic TG accumulation, which exacerbates insulin resistance, leading to type 2 diabetes and non-alcoholic fatty liver disease. Despite its importance in such metabolic disorders, the mechanism governing insulin’s inhibition of lipolysis remains controversial. Currently, the prevailing model hinges on the enzymatic function of the Akt substrate, phosphodiesterase 3B (PDE3B) in explaining insulin’s antilipolytic action. However, several studies have challenged this and suggested that whilst PDE3B is essential, its function alone cannot explain this regulation. Instead, we implicate another Akt substrate, α/β-hydrolase domain-containing protein 15 (ABHD15), as a novel player in insulin’s inhibition of lipolysis. Through stable knockdown or knockout of ABHD15 in 3T3-L1 or brown adipocytes, we show an impairment in insulin-mediated inhibition of lipolysis that is rescued upon ABHD15 re-expression. Moreover, through the generation of ABHD15 and PDE3B mutants lacking novel insulin-regulated phosphorylation sites previously identified by our lab, we have explored a putative mechanism by which these proteins facilitate insulin’s inhibition of lipolysis. In summary, we have identified a novel regulator of lipolysis that will likely shed light on the mechanism of this important process.