Kim_2025_bioRxiv__

PNPLA2 (aka adipose triglyceride lipase) is the rate limiting enzyme of triglyceride (TG) catabolism at the surface of lipid droplets (LDs). Lipolysis by PNPLA2 increases with glucose in pancreatic beta cells 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. Here, we aim to determine how glucose regulates lipolysis in beta cells. We found that glucose recruits alpha/beta hydrolase domain containing 5 (ABHD5), a co-activator of PNPLA2 to LDs where lipolysis occurs. ABHD5 recruitment to LDs was reduced by the addition of H-89 and the expression of a mutant ABHD5 that is resistant to phosphorylation by a cAMP dependent kinase (PKA) indicating partial dependence of recruitment on PKA. Importantly, ABHD5 was indispensable for glucose responsiveness of lipolysis in INS-1 832/13 (INS-1) cells. Downregulation of ABHD5 increased LDs and TG content in INS-1 cells and human islets indicating that ABHD5 is highly active in beta cells. Additionally, glucose-stimulated insulin secretion was impaired in ABHD5 downregulated INS-1 and human pseudoislets, which agrees with impaired GSIS in ATGL downregulated beta cells. Thus, ABHD5 plays an important role in conferring glucose responsiveness of lipolysis and supporting insulin secretion in beta cells.