Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells.
Sir2 and insulin/IGF-1 are the major pathways that impinge upon aging in lower organisms. In Caenorhabditis elegans a possible genetic link between Sir2 and the insulin/IGF-1 pathway has been reported. Here we investigate such a link in mammals. We show that Sirt1 positively regulates insulin secretion in pancreatic beta cells. Sirt1 represses the uncoupling protein (UCP) gene UCP2 by binding directly to the UCP2 promoter. In beta cell lines in which Sirt1 is reduced by SiRNA, UCP2 levels are elevated and insulin secretion is blunted. The up-regulation of UCP2 is associated with a failure of cells to increase ATP levels after glucose stimulation. Knockdown of UCP2 restores the ability to secrete insulin in cells with reduced Sirt1, showing that UCP2 causes the defect in glucose-stimulated insulin secretion. Food deprivation induces UCP2 in mouse pancreas, which may occur via a reduction in NAD (a derivative of niacin) levels in the pancreas and down-regulation of Sirt1. Sirt1 knockout mice display constitutively high UCP2 expression. Our findings show that Sirt1 regulates UCP2 in beta cells to affect insulin secretion.
Bordone
Laura
L
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. laura.bordone@novartis.com
Motta
Maria Carla
MC
Picard
Frederic
F
Robinson
Ashley
A
Jhala
Ulupi S
US
Apfeld
Javier
J
McDonagh
Thomas
T
Lemieux
Madeleine
M
McBurney
Michael
M
Szilvasi
Akos
A
Easlon
Erin J
EJ
Lin
Su-Ju
SJ
Guarente
Leonard
L
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D005215:Fasting; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D056564:Sirtuin 1; D037761:Sirtuins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071246:Uncoupling Protein 2
D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; C470545:Sirt1 protein, mouse; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D037761:Sirtuins; D005947:Glucose