Leptin-induced mitochondrial fusion mediates hepatic lipid accumulation

W. H. Hsu, B. H. Lee, T. M. Pan

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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.

Original languageEnglish
Pages (from-to)1750-1756
Number of pages7
JournalInternational Journal of Obesity
Volume39
Issue number12
DOIs
Publication statusPublished - 2015 Dec 1

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All Science Journal Classification (ASJC) codes

  • Medicine (miscellaneous)
  • Endocrinology, Diabetes and Metabolism
  • Nutrition and Dietetics

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