title: PGC-1 coactivators in β-cells regulate lipid metabolism and are essential for insulin secretion coupled to fatty acids.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptor γ coactivator 1 (PPARGCA1, PGC-1) transcriptional coactivators control gene programs important for nutrient metabolism. Islets of type 2 diabetic subjects have reduced PGC-1α expression and this is associated with decreased insulin secretion, yet little is known about why this occurs or what role it plays in the development of diabetes. Our goal was to delineate the role and importance of PGC-1 proteins to β-cell function and energy homeostasis.
  
  
  METHODS
  We investigated how nutrient signals regulate coactivator expression in islets and the metabolic consequences of reduced PGC-1α and PGC-1β in primary and cultured β-cells. Mice with inducible β-cell specific double knockout of Pgc-1α/Pgc-1β (βPgc-1 KO) were created to determine the physiological impact of reduced Pgc1 expression on glucose homeostasis.
  
  
  RESULTS
  Pgc-1α and Pgc-1β expression was increased in primary mouse and human islets by acute glucose and palmitate exposure. Surprisingly, PGC-1 proteins were dispensable for the maintenance of mitochondrial mass, gene expression, and oxygen consumption in response to glucose in adult β-cells. However, islets and mice with an inducible, β-cell-specific PGC-1 knockout had decreased insulin secretion due in large part to loss of the potentiating effect of fatty acids. Consistent with an essential role for PGC-1 in lipid metabolism, β-cells with reduced PGC-1s accumulated acyl-glycerols and PGC-1s controlled expression of key enzymes in lipolysis and the glycerolipid/free fatty acid cycle.
  
  
  CONCLUSIONS
  These data highlight the importance of PGC-1s in coupling β-cell lipid metabolism to promote efficient insulin secretion.
authors.affiliation: Laboratory of Molecular Mechanisms of Diabetes, Institut de Recherches Cliniques de Montreal (IRCM), 110 Ave des Pins Ouest, Montreal, Quebec, H2W 1R7, Canada ; Department of Anatomy and Cell Biology, McGill University, 845 Rue Sherbrooke Ouest, Montreal, Quebec, H3A 0G4, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Oropeza
authors.affiliation: Laboratory of Molecular Mechanisms of Diabetes, Institut de Recherches Cliniques de Montreal (IRCM), 110 Ave des Pins Ouest, Montreal, Quebec, H2W 1R7, Canada ; Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jouvet
authors.affiliation: Montreal Diabetes Research Center, CRCHUM, Department of Medicine, University of Montreal, 2900 Boulevard Edouard-Montpetit, Montreal, Quebec, H3T 1J4, Canada.
authors.forename: Khalil
authors.initials: K
authors.lastname: Bouyakdan
authors.affiliation: Department of Anatomy and Cell Biology, McGill University, 845 Rue Sherbrooke Ouest, Montreal, Quebec, H3A 0G4, Canada.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Perron
authors.affiliation: Department of Anatomy and Cell Biology, McGill University, 845 Rue Sherbrooke Ouest, Montreal, Quebec, H3A 0G4, Canada.
authors.forename: Lea-Jeanne
authors.initials: LJ
authors.lastname: Ringuette
authors.affiliation: Department of Medicine, University of Chicago, 5801 South Ellis Avenue, Chicago, IL, USA.
authors.forename: Louis H
authors.initials: LH
authors.lastname: Philipson
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kiss
authors.affiliation: Montreal Diabetes Research Center, CRCHUM, Department of Medicine, University of Montreal, 2900 Boulevard Edouard-Montpetit, Montreal, Quebec, H3T 1J4, Canada.
authors.forename: Vincent
authors.initials: V
authors.lastname: Poitout
authors.affiliation: Montreal Diabetes Research Center, CRCHUM, Department of Medicine, University of Montreal, 2900 Boulevard Edouard-Montpetit, Montreal, Quebec, H3T 1J4, Canada.
authors.forename: Thierry
authors.initials: T
authors.lastname: Alquier
authors.affiliation: Laboratory of Molecular Mechanisms of Diabetes, Institut de Recherches Cliniques de Montreal (IRCM), 110 Ave des Pins Ouest, Montreal, Quebec, H2W 1R7, Canada ; Department of Anatomy and Cell Biology, McGill University, 845 Rue Sherbrooke Ouest, Montreal, Quebec, H3A 0G4, Canada ; Montreal Diabetes Research Center, CRCHUM, Department of Medicine, University of Montreal, 2900 Boulevard Edouard-Montpetit, Montreal, Quebec, H3T 1J4, Canada.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Estall
keywords: Beta cell; Insulin secretion; Lipid metabolism; Lipolysis; Mitochondria; PGC-1