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Animal Models

Leptin-induced mitochondrial fusion mediates hepatic lipid accumulation

International Journal of Obesity volume 39, pages 1750–1756 (2015)Cite this article

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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.

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Author notes

  1. W-H Hsu and B-H Lee: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei, Taiwan

    W-H Hsu, B-H Lee & T-M Pan

  2. Department of Basic Medical Sciences, College of Veterinary Medicine, Center for Cancer Research, Purdue University, West Lafayette, IN, USA

    W-H Hsu & B-H Lee

Authors
  1. W-H Hsu
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  2. B-H Lee
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Correspondence to T-M Pan.

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The authors declare no conflict of interest.

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Supplementary Information accompanies this paper on International Journal of Obesity website

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Hsu, WH., Lee, BH. & Pan, TM. Leptin-induced mitochondrial fusion mediates hepatic lipid accumulation. Int J Obes 39, 1750–1756 (2015). https://doi.org/10.1038/ijo.2015.120

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