Serum concentrations of resistin-like molecules β and γ are elevated in high-fat-fed and obese db/db mice, with increased production in the intestinal tract and bone marrow

Shojima, Nobuhiro; Ogihara, Takehide; Inukai, Kouichi; Fujishiro, Midori; Sakoda, Hideyuki; Kushiyama, Akifumi; Katagiri, Hideki; Anai, Motonobu; Ono, Hiraku; Fukushima, Yasushi; Horike, Nanao; Viana, Amelia Y.I.; Uchijima, Yasunobu; Kurihara, Hiroki; Asano, Tomohiko

doi:10.1007/s00125-005-1735-1

Cited by 40 publications

(48 citation statements)

References 36 publications

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“…Indeed, it was reported that injecting mice with either resistin or RELM␤ induced insulin resistance (11). In addition, we found the intestinal expression and serum concentration of RELM␤ to be increased in insulin resistant models such as high fat fed and db/db mice (12). Thus, we speculated that the inflammatory state of the intestine, overeating, bowel movements, and/or nutrient absorption might regulate the intestinal expression and serum level of RELM␤ and thereby regulate whole-body insulin sensitivity.…”

supporting

confidence: 54%

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

Kushiyama

Shojima

Ogihara

et al. 2005

Journal of Biological Chemistry

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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.

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supporting

confidence: 54%

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

Kushiyama

Shojima

Ogihara

et al. 2005

Journal of Biological Chemistry

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“…These resistin family proteins share a cysteine-rich domain at their C terminus (Cx11Cx8CxCx2Cx10CxCxCx9CC), and the roles of RELMα, RELMβ, and RELMγ have been extensively studied. [6][7][8][9][10] Unlike the situation in mice, resistin and RELMβ, but not RELMα and RELMγ, are present in humans. 9,11 To date, expression of RELMβ has been reported to be limited to the gut or bronchi.…”

mentioning

confidence: 99%

Resistin-Like Molecule β Is Abundantly Expressed in Foam Cells and Is Involved in Atherosclerosis Development

Kushiyama

Sakoda

Oue

et al. 2013

ATVB

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Objective-Resistin-like molecule (RELM) β is a secretory protein homologous to resistin and reportedly contributes to local immune response regulation in gut and bronchial epithelial cells. However, we found that activated macrophages also express RELMβ and thus investigated the role of RELMβ in the development of atherosclerosis. Approach and Results-It was demonstrated that foam cells in atherosclerotic lesions of the human coronary artery abundantly express RELMβ. RELMβ knockout ( −/− ) and wild-type mice were mated with apolipoprotein E-deficient background mice. RELMβ −/− apolipoprotein E-deficient mice exhibited less lipid accumulation in the aortic root and wall than RELMβ +/+ apolipoprotein E-deficient mice, without significant changes in serum lipid parameters. In vitro, RELMβ −/− primary cultured peritoneal macrophages (PCPMs) exhibited weaker lipopolysaccharide-induced nuclear factor-κB classical pathway activation and inflammatory cytokine secretion than RELMβ

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“…In mice, resistin is primarily produced in adipocytes, whereas in humans, resistin is mainly derived from monocytes and macrophages 19,46 . Retnlg is expressed abundantly in the colon, lung and spleen 47 . HFD consumption induced secretion of Retnlb, resistin and Retnlg into the serum of C57BL/6J mice 47 , but the HFD-induced secretion of Retnla has not been reported.…”

Section: Discussionmentioning

confidence: 99%

“…Retnlg is expressed abundantly in the colon, lung and spleen 47 . HFD consumption induced secretion of Retnlb, resistin and Retnlg into the serum of C57BL/6J mice 47 , but the HFD-induced secretion of Retnla has not been reported. In this study, we found that Retnla concentrations in serum were increased in HFD-fed C57BL/6J…”

Section: Discussionmentioning

confidence: 99%

The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice

et al. 2014

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Hyperlipidemia is a well-recognized risk factor for atherosclerosis and can be regulated by adipokines. Expression of the adipokine resistin-like molecule alpha (Retnla) is regulated by food intake; whether Retnla has a role in the pathogenesis of hyperlipidemia and atherosclerosis is unknown. Here we report that Retnla has a cholesterol-lowering effect and protects against atherosclerosis in low-density lipoprotein receptor-deficient mice. On a high-fat diet, Retnla deficiency promotes hypercholesterolaemia and atherosclerosis, whereas Retnla overexpression reverses these effects and improves the serum lipoprotein profile, with decreased cholesterol in the very low-density lipoprotein fraction concomitant with reduced serum apolipoprotein B levels. We show that Retnla upregulates cholesterol-7-a-hydroxylase, a key hepatic enzyme in the cholesterol catabolic pathway, through induction of its transcriptional activator liver receptor homologue-1, leading to increased excretion of cholesterol in the form of bile acids. These findings define Retnla as a novel therapeutic target for treating hypercholesterolaemia and atherosclerosis.

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Serum concentrations of resistin-like molecules β and γ are elevated in high-fat-fed and obese db/db mice, with increased production in the intestinal tract and bone marrow

Cited by 40 publications

References 36 publications

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

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

Resistin-Like Molecule β Is Abundantly Expressed in Foam Cells and Is Involved in Atherosclerosis Development

The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice

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