Hormone-Sensitive Lipase Has a Role in Lipid Signaling for Insulin Secretion but Is Nonessential for the Incretin Action of Glucagon-Like Peptide 1

Hormone-Sensitive Lipase Has a Role in Lipid Signaling for Insulin Secretion but Is Nonessential for the Incretin Action of Glucagon-Like Peptide 1 Marie-Line Peyot 1 , Christopher J. Nolan 1 , Krishnakant Soni 2 , Erik Joly 1 , Roxane Lussier 1 , Barbara E. Corkey 3 , Shu Pei Wang 2 , Grant A. Mitchell 2 and Marc Prentki 1 1 Molecular Nutrition Unit, Department of Nutrition, University of Montréal and the Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada 2 Department of Pediatrics, Research Center, Saint-Justine Hospital, Montréal, Quebec, Canada 3 Boston University School of Medicine, Obesity Research Center, Boston, Massachusetts Address correspondence and reprint requests to Dr. Marc Prentki, CR-CHUM, Pavillon de Sève 4 e , 1560 Sherbrooke Est, Montréal, QC, H2L 4M1, Canada. E-mail: marc.prentki{at}umontreal.ca Abstract We previously reported decreased glucose-stimulated insulin secretion (GSIS) in hormone-sensitive lipase-null mice (HSL −/− ), both in vivo and in vitro. The focus of the current study was to gain further insight into the signaling role and regulation of lipolysis in islet tissue. The effect of glucagon-like peptide 1 (GLP-1) on GSIS was also studied, as GLP-1 could augment GSIS via protein kinase A activation of HSL and lipolysis. Freshly isolated islets from fasted and fed male HSL −/− and wild-type (HSL +/+ ) mice were studied at ages 4 and 7 months. Neutral cholesteryl ester hydrolase activity was markedly reduced in islets from both 4- and 7-month-old male HSL −/− mice, whereas a marked deficiency in triglyceride lipase activity became evident only in the older mice. The deficiencies in lipase activities were associated with higher islet triglyceride content and reduced lipolysis at basal glucose levels. Lipolysis was stimulated by high glucose in islets of both wild-type and HSL-null mice. Severe deficiencies in GSIS were found, but only in islets from 7-month-old, fasted, male HSL −/− mice. GSIS was less affected in 4-month-old fasted male HSL −/− mice and not reduced in female mice. Exogenous delivery of free fatty acids (FFAs) rescued GSIS, supporting the view that the lack of endogenous FFA supply for lipid-signaling processes in HSL −/− mice was responsible for the loss of GSIS. GLP-1 also rescued GSIS in HSL −/− mice, indicating that signaling via HSL is not a major pathway for its incretin effect. Thus, the secretory phenotype of HSL-null mice is gender dependent, increases with age, and is influenced