Resistin-like molecule β activates MAPKs, suppresses insulin signaling in hepatocytes, and induces diabetes, hyperlipidemia, and fatty liver in transgenic mice on a high fat diet

Akifumi Kushiyama, Nobuhiro Shojima, Takehide Ogihara, Kouichi Inukai, Hideyuki Sakoda, Midori Fujishiro, Yasushi Fukushima, Motonobu Anai, Hiraku Ono, Nanao Horike, Amelia Y.I. Viana, Yasunobu Uchijima, Koichi Nishiyama, Tatsuo Shimosawa, Toshiro Fujita, Hideki Katagiri, Yoshitomo Oka, Hiroki Kurihara, Tomoichiro Asano

研究成果: Article査読

58 被引用数 (Scopus)

抄録

Resistin and resistin-like molecules (RELMs) are a family of proteins reportedly related to insulin resistance and inflammation. Because the serum concentration and intestinal expression level of RELMβ were elevated in insulin-resistant rodent models, in this study we investigated the effect of RELMβ on insulin signaling and metabolism using transgenic mice and primary cultured hepatocytes. First, transgenic mice with hepatic RELMβ overexpression were shown to exhibit significant hyperglycemia, hyperlipidemia, fatty liver, and pancreatic islet enlargement when fed a high fat diet. Hyperinsulinemic glucose clamp showed a decreased glucose infusion rate due to increased hepatic glucose production. In addition, the expression levels of IRS-1 and IRS-2 proteins as well as the degrees of insulin-induced phosphatidylinositol 3-kinase and Akt activations were attenuated in RELMβ transgenic mice. Similar down-regulations of IRS-1 and IRS-2 proteins were observed in primary cultured hepatocytes chronically treated (for 24 h) with RELMβ, suggesting the insulin resistance-inducing effect of RELMβ to be direct. Furthermore, it was shown that RELMβ acutely and markedly activates ERK and p38, while weakly activating JNK, in primary cultured hepatocytes. This increased basal p38 phosphorylation level was also observed in the livers of RELMβ transgenic mice. In conclusion, RELMβ, a gut-derived hormone, impairs insulin signaling probably via the activations of classic MAPKs, and increased expression of RELMβ maybe involved in the pathogenesis of glucose intolerance and hyperlipidemia in some insulin-resistant models. Thus, RELMβ is a potentially useful marker for assessing insulin resistance and may also be a target for future novel anti-diabetic agents.

本文言語English
ページ(範囲)42016-42025
ページ数10
ジャーナルJournal of Biological Chemistry
280
51
DOI
出版ステータスPublished - 2005 12 23
外部発表はい

ASJC Scopus subject areas

  • 生化学
  • 分子生物学
  • 細胞生物学

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