Identification of a novel player in insulin‐mediated lipolysis inhibition

Abstract

Lipolysis is a tightly regulated catabolic process essential for maintaining whole‐body energy homeostasis. It exists in a dynamic balance between activation by β‐adrenergic stimulation during starvation or prolonged exercise, and inhibition by insulin following nutrient intake. Dysregulation of lipolysis can lead to ectopic fat accumulation in the blood and insulin‐sensitive tissues, encouraging the development of metabolic disorders such as type 2 diabetes and non‐alcoholic fatty liver disease. Despite this, the mechanism by which insulin regulates lipolysis remains controversial and incomplete. 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 protein, α/β‐hydrolase domain‐containing protein 15 (ABHD15) as a novel player in insulin‐mediated lipolysis inhibition. Through stable knockdown or knockout of ABHD15 in 3T3‐L1, brown or fat explant adipocytes, we demonstrate a significant defect in insulin’s inhibition of lipolysis that is rescued upon ABHD15 re‐expression. Moreover, through the characterisation 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.Support or Funding InformationAustralian Government Research Training Program Scholarship, The Chen Family Research Scholarship.