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

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 RELM␤ were elevated in insulin-resistant rodent models, in this study we investigated the effect of RELM␤ on insulin signaling and metabolism using transgenic mice and primary cultured hepatocytes. First, transgenic mice with hepatic RELM␤ 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 RELM␤ transgenic mice. Similar down-regulations of IRS-1 and IRS-2 proteins were observed in primary cultured hepatocytes chronically treated (for 24 h) with RELM␤, suggesting the insulin resistance-inducing effect of RELM␤ to be direct. Furthermore, it was shown that RELM␤ 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 RELM␤ transgenic mice. In conclusion, RELM␤, a gut-derived hormone, impairs insulin signaling probably via the activations of classic MAPKs, and increased expression of RELM␤ may be involved in the pathogenesis of glucose intolerance and hyperlipidemia in some insulin-resistant models. Thus, RELM␤ is a potentially useful marker for assessing insulin resistance and may also be a target for future novel anti-diabetic agents.

Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease

“…55,56 The real role of p38MAPK upregulation in the NAFLD pathogenesis is still unclear even though it was previously demonstrated that this kinase together with ERK is remarkably activated in rodent models of NAFLD. 57 Our data, agree with other studies which found that hepatic expression of FLT1 mRNA was decreased in obese mice compared with lean mice and suggest a potential involvement of vascular endothelial growth factor and its receptor in the pathogenesis of NAFLD. 58 In a general view, it is recognized that protein expression is directly correlated to the expression of its cognate mRNA, which in turn generally is inversely correlated to the expression of its regulatory miRNA(s).…”

Role of resistin in cardiac contractility and hypertrophy

“…Several previous studies have established that the activation of the MAPKs leads to down-regulation of IRSs and to the suppression of insulin-induced PI3-Kinase activation through the phosphorylation of the serine residue in IRS-1. Recently, RELMβ (resistin-like molecule beta) was reported to increase the activity of ERK, p38 and, slightly, JNK in primary cultured hepatocytes [37] while resistin was reported to phosphorylate and activate ERK and p38 in smooth muscle cells [38].…”

Absence of bacterially induced RELMβ reduces injury in the dextran sodium sulfate model of colitis

“…Although the physiologic function of RELMβ has yet to be determined, like resistin (32), RELMβ seems to induce insulin resistance in vivo when either administered systemically or ectopically expressed (33,34). There is growing evidence that insulin resistance, the hallmark of type 2 diabetes mellitus, is due in part to a state of chronic inflammation perpetuated by circulating inflammatory mediators such as TNF-α (35).…”