Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss.
Leptin elicits a metabolic response that cannot be explained by its anorectic effects alone. To examine the mechanism underlying leptin's metabolic actions, we used transcription profiling to identify leptin-regulated genes in ob/ob liver. Leptin was found to specifically repress RNA levels and enzymatic activity of hepatic stearoyl-CoA desaturase-1 (SCD-1), which catalyzes the biosynthesis of monounsaturated fatty acids. Mice lacking SCD-1 were lean and hypermetabolic. ob/ob mice with mutations in SCD-1 were significantly less obese than ob/ob controls and had markedly increased energy expenditure. ob/ob mice with mutations in SCD-1 had histologically normal livers with significantly reduced triglyceride storage and VLDL (very low density lipoprotein) production. These findings suggest that down-regulation of SCD-1 is an important component of leptin's metabolic actions.
Laboratory of Molecular Genetics, Center for Studies in Physics and Biology, Rogosin Institute, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Paul
P
Cohen
Makoto
M
Miyazaki
Nicholas D
ND
Socci
Aaron
A
Hagge-Greenberg
Wolfgang
W
Liedtke
Alexander A
AA
Soukas
Ratnendra
R
Sharma
Lisa C
LC
Hudgins
James M
JM
Ntambi
Jeffrey M
JM
Friedman
D000818:Animals; D001835:Body Weight; D003433:Crosses, Genetic; D015536:Down-Regulation; D004435:Eating; D004734:Energy Metabolism; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D020738:Leptin / Q000235:genetics / Q000502:physiology*; D050356:Lipid Metabolism; D008055:Lipids / Q000032:analysis; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008862:Microsomes, Liver / Q000201:enzymology; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010101:Oxygen Consumption; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism*; D014617:Vacuoles / Q000737:chemistry / Q000648:ultrastructure; D015431:Weight Loss
D020738:Leptin; D008055:Lipids; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; D013230:Stearoyl-CoA Desaturase