Desnutrin/ATGL Activates PPARδ to Promote Mitochondrial Function for Insulin Secretion in Islet β Cells

Excessive caloric intake leading to obesity is associated with insulin resistance and dysfunction of islet beta cells. High-fat feeding decreases desnutrin (also called ATGL/PNPLA2) levels in islets. Here we show that desnutrin ablation via RIP-Cre (beta KO) or RIP-CreER results in hyperglycemia with impaired glucose-stimulated insulin secretion (GSIS). Due to decreased lipolysis, islets have higher TAG content but lower free FA levels. beta KO islets exhibit impaired mitochondrial respiration and lower production of ATP required for GSIS, along with decreased expression of PPAR delta target genes involved in mitochondrial oxidation. Furthermore, synthetic PPAR delta, but not PPAR alpha, agonist restores GSIS and expression of mitochondrial oxidative genes in beta KO mice, revealing that desnutrin-catalyzed lipolysis generates PPAR delta ligands. Finally, adenoviral expression of desnutrin in beta KO islets restores all defects of beta KO islet phenotype and function, including GSIS and mitochondrial defects, demonstrating the critical role of the desnutrin-PPAR delta-mitochondrial oxidation axis in regulating islet beta cell GSIS.