Desnutrin/ATGL activates PPAR? to promote mitochondrial function for insulin secretion in islet ? cells.

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

SUBMITTER: Tang T 

PROVIDER: S-EPMC3871209 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature