Role of hormone-sensitive lipase in leptin-promoted fat loss and glucose lowering

Mikio Takanashi, Yoshino Taira, Sachiko Okazaki, Satoru Takase, Takeshi Kimura, Cheng Cheng Li, Peng Fei Xu, Akari Noda, Ichiro Sakata, Hidetoshi Kumagai, Yuichi Ikeda, Yoko Iizuka, Naoya Yahagi, Hitoshi Shimano, Jun Ichi Osuga, Shun Ishibashi, Takashi Kadowaki, Hiroaki Okazaki

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Aim: Myriad biological effects of leptin may lead to broad therapeutic applications for various metabolic diseases, including diabetes and its complications; however, in contrast to its anorexic effect, the molecular mechanisms underlying adipopenic and glucose-lowering effects of leptin have not been fully understood. Here we aim to clarify the role of hormone-sensitive lipase (HSL) in leptin’s action. Methods: Wild-type (WT) and HSL-deficient (HSLKO) mice were made hyperleptinemic by two commonly-used methods: adenovirus-mediated overexpression of leptin and continuous subcutaneous infusion of leptin by osmotic pumps. The amount of food intake, body weights, organ weights, and parameters of glucose and lipid metabolism were measured. Results: Hyperleptinemia equally suppressed the food intake in WT and HSLKO mice. On the other hand, leptin-mediated fat loss and glucose-lowering were significantly blunted in the absence of HSL when leptin was overexpressed by recombinant adenovirus carrying leptin. By osmotic pumps, the fat-losing and glucose-lowering effects of leptin were milder due to lower levels of hyperleptinemia; although the difference between WT and HSLKO mice did not reach statistical significance, HSLKO mice had a tendency to retain more fat than WT mice in the face of hyperleptinemia. Conclusions: We clarify for the first time the role of HSL in leptin’s effect using a genetic model: leptin-promoted fat loss and glucose-lowering are at least in part mediated via HSL-mediated lipolysis. Further studies to define the pathophysiological role of adipocyte lipases in leptin action may lead to a new therapeutic approach to circumvent leptin resistance.

Original languageEnglish (US)
Pages (from-to)1105-1116
Number of pages12
JournalJournal of Atherosclerosis and Thrombosis
Volume24
Issue number11
DOIs
StatePublished - 2017

Keywords

  • Hypoglycemia
  • Leptin
  • Leptin resistance
  • Lipase
  • Lipolysis

ASJC Scopus subject areas

  • Internal Medicine
  • Cardiology and Cardiovascular Medicine
  • Biochemistry, medical

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  • Cite this

    Takanashi, M., Taira, Y., Okazaki, S., Takase, S., Kimura, T., Li, C. C., Xu, P. F., Noda, A., Sakata, I., Kumagai, H., Ikeda, Y., Iizuka, Y., Yahagi, N., Shimano, H., Osuga, J. I., Ishibashi, S., Kadowaki, T., & Okazaki, H. (2017). Role of hormone-sensitive lipase in leptin-promoted fat loss and glucose lowering. Journal of Atherosclerosis and Thrombosis, 24(11), 1105-1116. https://doi.org/10.5551/jat.39552