Deficient ganglioside synthesis restores responsiveness to leptin and melanocortin signaling in obese KKAy mice

Kei ichiro Inamori, Hideki Ito, Yumi Tamura, Takahiro Nitta, Xiaohua Yang, Wataru Nihei, Fumi Shishido, Susumu Imazu, Sohei Tsukita, Tetsuya Yamada, Hideki Katagiri, Jin ichi Inokuchi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

GM3, a precursor for synthesis of a- and b-series gangliosides, is elevated in adipocytes of obese model animals and in sera of obese human patients with type 2 diabetes and/or dyslipidemia. GM3 synthase (GM3S)-KO C57BL/6 mice display enhanced insulin sensitivity and reduced development of high-fat diet-induced insulin resistance. However, the pathophysiological roles of GM3 and related gangliosides in the central control of feeding and metabolism remain unclear. We found that a mouse model (KKAy GM3S KO) generated by KO of the GM3S gene in the yellow obese strain, KKAy, displayed significant amelioration of obese phenotype. Whereas KKAy mice were hyperphagic and developed severe obesity, KKAy GM3S KO mice had significantly lower body weight and food intake, and greater glucose and insulin tolerance. The hypothalamic response to intraperitoneal administration of leptin was greatly reduced in KKAy mice, but was retained in KKAy GM3S KO mice. In studies of a cultured mouse hypothalamic neuronal cell line, enhanced leptin-dependent phosphorylation of ERK was observed in GM3S-deficient cells. Furthermore, KKAy GM3S KO mice did show altered coat color, suggesting that GM3S is also involved in melanocortin signaling. Our findings, taken together, indicate that GM3-related gangliosides play key roles in leptin and melanocortin signaling.—Inamori, K-i., H. Ito, Y. Tamura, T. Nitta, X. Yang, W. Nihei, F. Shishido, S. Imazu, S. Tsukita, T. Yamada, H. Katagiri, and J-i. Inokuchi. Deficient ganglioside synthesis restores responsiveness to leptin and melanocortin signaling in obese KKAy mice.

Original languageEnglish
Pages (from-to)1472-1481
Number of pages10
JournalJournal of lipid research
Volume59
Issue number8
DOIs
Publication statusPublished - 2018 Jan 1

Keywords

  • Animal models
  • Brain
  • Diabetes
  • GM3
  • GM3 synthase knockout
  • Hypothalamus
  • Leptin resistance
  • Receptors/hormone

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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  • Cite this

    Inamori, K. I., Ito, H., Tamura, Y., Nitta, T., Yang, X., Nihei, W., Shishido, F., Imazu, S., Tsukita, S., Yamada, T., Katagiri, H., & Inokuchi, J. I. (2018). Deficient ganglioside synthesis restores responsiveness to leptin and melanocortin signaling in obese KKAy mice. Journal of lipid research, 59(8), 1472-1481. https://doi.org/10.1194/jlr.M085753