title: Resistin-like molecule beta activates MAPKs, suppresses insulin signaling in hepatocytes, and induces diabetes, hyperlipidemia, and fatty liver in transgenic mice on a high fat diet.
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 RELMbeta were elevated in insulin-resistant rodent models, in this study we investigated the effect of RELMbeta on insulin signaling and metabolism using transgenic mice and primary cultured hepatocytes. First, transgenic mice with hepatic RELMbeta 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 RELMbeta transgenic mice. Similar down-regulations of IRS-1 and IRS-2 proteins were observed in primary cultured hepatocytes chronically treated (for 24 h) with RELMbeta, suggesting the insulin resistance-inducing effect of RELMbeta to be direct. Furthermore, it was shown that RELMbeta 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 RELMbeta transgenic mice. In conclusion, RELMbeta, a gut-derived hormone, impairs insulin signaling probably via the activations of classic MAPKs, and increased expression of RELMbeta may be involved in the pathogenesis of glucose intolerance and hyperlipidemia in some insulin-resistant models. Thus, RELMbeta is a potentially useful marker for assessing insulin resistance and may also be a target for future novel anti-diabetic agents.
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Kushiyama
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Shojima
authors.forename: Takehide
authors.initials: T
authors.lastname: Ogihara
authors.forename: Kouichi
authors.initials: K
authors.lastname: Inukai
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sakoda
authors.forename: Midori
authors.initials: M
authors.lastname: Fujishiro
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fukushima
authors.forename: Motonobu
authors.initials: M
authors.lastname: Anai
authors.forename: Hiraku
authors.initials: H
authors.lastname: Ono
authors.forename: Nanao
authors.initials: N
authors.lastname: Horike
authors.forename: Amelia Y I
authors.initials: AY
authors.lastname: Viana
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Uchijima
authors.forename: Koichi
authors.initials: K
authors.lastname: Nishiyama
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shimosawa
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Oka
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurihara
authors.forename: Tomoichiro
authors.initials: T
authors.lastname: Asano
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000209:etiology*; D004041:Dietary Fats / Q000008:administration & dosage*; D004789:Enzyme Activation / Q000502:physiology*; D005234:Fatty Liver / Q000209:etiology*; D006949:Hyperlipidemias / Q000209:etiology*; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D052243:Resistin / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D004041:Dietary Fats; D007328:Insulin; D052243:Resistin; D020928:Mitogen-Activated Protein Kinases