title: Leptin-induced mitochondrial fusion mediates hepatic lipid accumulation.
abstract: BACKGROUND
  Leptin alleviates metabolic conditions such as insulin resistance and obesity, although the precise mechanism of action is unclear. Mitochondrial fusion/fission states affect energy balance, but the association between mitochondrial fusion and lipid metabolism is also unknown. The aim of this study was to determine whether mitochondrial fusion/fission state regulates lipid accumulation and to understand the role of leptin in mitochondrial function and its mechanism of action in metabolic regulation.
  
  
  METHODS
  Primary mouse hepatocytes were isolated from C57BL/6J mice and treated with leptin (25 ng ml(-1)) for 3 days before determinations of mitochondrial morphology and fatty acid accumulation. Hyperglycemia in C57BL/6J mice was induced by providing a 30% fructose-rich diet (FRD) for 6 months, followed by intraperitoneal injections of leptin (1 mg kg(-1) per body weight) for 6 weeks (twice per week).
  
  
  RESULTS
  Leptin triggered mitochondrial fusion and alleviated high glucose-induced fatty acid accumulation in primary hepatocytes by promoting mitochondrial fusion-associated transcription factor peroxisome proliferative-activated receptor-α and co-activator peroxisome proliferative-activated receptor-γ co-activator (PGC)-1α. In turn, these activate the fusion protein mitofusin 1 (Mfn-1). RNA silencing of Mfn-1 or PGC-1 blocked the inhibitory effect of leptin. Leptin treatment also elevated liver Mfn-1 and PGC-1α and improved lipid profiles in FRD mice.
  
  
  CONCLUSIONS
  Mitochondrial fusion has a critical role in alleviating hepatic fatty acid accumulation. Leptin switches mitochondrial morphology via a PGC-1α-dependent pathway to improve hyperlipidemia.
authors.affiliation: Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei, Taiwan.|Department of Basic Medical Sciences, College of Veterinary Medicine, Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
authors.forename: W-H
authors.initials: WH
authors.lastname: Hsu
authors.affiliation: Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei, Taiwan.|Department of Basic Medical Sciences, College of Veterinary Medicine, Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
authors.forename: B-H
authors.initials: BH
authors.lastname: Lee
authors.affiliation: Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: T-M
authors.initials: TM
authors.lastname: Pan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000473:pathology*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D063154:Mitochondrial Dynamics
chemical_list: D020738:Leptin