Leptin-mediated changes in hepatic mitochondrial metabolism, structure, and protein levels.
Leptin reduces body weight in ob/ob mice by decreasing food intake and increasing energy expenditure; however, the mechanisms by which it does the latter are not known. Here we report that 30% of the weight loss induced by leptin treatment of ob/ob mice is due to changes in energy expenditure. In assessing leptin's effects on specific tissues, we found that hepatic basal metabolic rate was paradoxically decreased 1.7-fold with leptin treatment, which was the result of a 1.6-fold reduction in mitochondrial volume density and altered substrate oxidation kinetics. The altered kinetics were associated with a decrease in protein levels of 2 mitochondrial respiratory chain components--cytochrome c oxidase subunit VIa and cytochrome c oxidase subunit IV. In addition to reduced hepatic metabolism, there was reduced long chain fatty acid production and a 2.5-fold increase in hepatic lipid export, both of which explain the reduced steatosis in leptin-treated animals. These data help clarify the role of the liver in leptin-mediated weight loss and define the mechanisms by which leptin alters hepatic metabolism and corrects steatosis.
Singh
Amandeep
A
Laboratory of Molecular Genetics, The Rockefeller University, New York, NY 10065, USA.
Wirtz
Martin
M
Parker
Nadeene
N
Hogan
Matthew
M
Strahler
John
J
Michailidis
George
G
Schmidt
Sarah
S
Vidal-Puig
Antonio
A
Diano
Sabrina
S
Andrews
Philip
P
Brand
Martin D
MD
Friedman
Jeffrey
J
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000032:analysis*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D010766:Phosphorylation; D040901:Proteomics
D005227:Fatty Acids; D020738:Leptin; D024101:Mitochondrial Proteins