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

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)42016-42025
Number of pages10
JournalJournal of Biological Chemistry
Volume280
Issue number51
DOIs
Publication statusPublished - 2005 Dec 23
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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