α/β-Hydrolase Domain Containing 5 Supports Glucose-Stimulated Lipolysis and Insulin Secretion in Pancreatic β-Cells

Adipose triglyceride (TG) lipase (ATGL) is the rate-limiting enzyme of TG catabolism at the surface of lipid droplets (LDs). In pancreatic β-cells, lipolysis by ATGL increases with glucose and produces metabolites that support glucose-stimulated insulin secretion (GSIS). Upregulation of lipolysis by glucose is blunted in human islets affected by type 2 diabetes. However, how glucose regulates lipolysis in β-cells is unknown. We found that glucose recruits ATGL coactivator α/β-hydrolase domain containing 5 (ABHD5) to LDs in INS-1 cells and human β-cells. ABHD5 recruitment to LDs was reduced by inhibitors of cAMP-dependent protein kinase (PKA) or the expression of PKA-resistant mutant ABHD5, indicating that PKA phosphorylation contributes to ABHD5 recruitment to LDs. Importantly, ABHD5 was indispensable for glucose-stimulated lipolysis in INS-1 cells and human β-cells. ABHD5 knockdown increased LDs and TG content in INS-1 cells and human islets, indicating that ABHD5 is a critical regulator of ATGL activity in β-cells. Additionally, GSIS was impaired in ABHD5-downregulated INS-1 cells and human pseudoislets, which agrees with a role of ATGL in supporting GSIS in β-cells. Thus, ABHD5 plays an important role in conferring glucose responsiveness in lipolysis and supporting insulin secretion in β-cells.

Lipolysis is stimulated by glucose and supports glucose-stimulated insulin secretion in pancreatic β-cells. However, the mechanism by which glucose increases lipolysis in β-cells is unknown. We aimed to identify a glucose-responsive regulator of lipolysis in β-cells. Glucose promotes α/β-hydrolase domain containing 5 (ABHD5) recruitment to lipid droplets where lipolysis occurs, which is at least partially mediated by cAMP-dependent kinase A. ABHD5 is required for glucose-stimulated lipolysis and insulin secretion. ABHD5 is a potential target to restore glucose-stimulated lipolysis in β-cells affected by type 2 diabetes.