Abstract
The adipokine chemerin and its receptor, chemokine-like receptor 1 (Cmklr1), are associated with insulin resistance and nonalcoholic fatty liver disease (NAFLD), which covers a broad spectrum of liver diseases, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). It is possible that chemerin and/or Cmklr1 exert their effects on these disorders through inflammation, but so far the data have been controversial. To gain further insight into this matter, we studied the effect of whole-body Cmklr1 deficiency on insulin resistance and NAFLD. In view of the primary role of macrophages in hepatic inflammation, we also transplanted bone marrow from Cmklr1 knock-out (Cmklr1-/-) mice and wild type (WT) mice into low-density lipoprotein receptor knock-out (Ldlr-/-) mice, a mouse model for NASH. All mice were fed a high fat, high cholesterol diet containing 21% fat from milk butter and 0.2% cholesterol for 12 weeks. Insulin resistance was assessed by an oral glucose tolerance test, an insulin tolerance test, and by measurement of plasma glucose and insulin levels. Liver pathology was determined by measuring hepatic inflammation, fibrosis, lipid accumulation and the NAFLD activity score (NAS). Whole-body Cmklr1 deficiency did not affect body weight gain or food intake. In addition, we observed no differences between WT and Cmklr1-/- mice for hepatic inflammatory and fibrotic gene expression, immune cell infiltration, lipid accumulation or NAS. In line with this, we detected no differences in insulin resistance. In concordance with whole-body Cmklr1 deficiency, the absence of Cmklr1 in bone marrow-derived cells in Ldlr-/- mice did not affect their insulin resistance or liver pathology. Our results indicate that Cmklr1 is not involved in the pathogenesis of insulin resistance or NAFLD. Thus, we recommend that the associations reported between Cmklr1 and insulin resistance or NAFLD should be interpreted with caution.
Highlights
Obesity is accompanied by the development of the metabolic syndrome, a cluster of metabolic abnormalities, which includes low-grade inflammation, dyslipidemia and insulin resistance
As chemokine-like receptor 1 (Cmklr1) is known to be necessary for adipocyte differentiation [20] and Cmklr1-/- mice were shown to have reduced body weight and fat mass compared to wild type (WT) mice [15], we evaluated body weight gain and food intake in mice fed a HFC diet for 12 weeks
We observed no differences in the number of adipocytes per mm2 in visceral and subcutaneous adipose tissue (VAT and SAT) (VAT: WT, 143 cells/mm2610; Cmklr1-/, 155 cells/ mm264, SAT: WT, 301 cells/mm2610; Cmklr1-/, 345 cells/ mm2631), indicating that adipose tissue morphology was similar in WT and Cmklr1-/- mice (Fig. 1C)
Summary
Obesity is accompanied by the development of the metabolic syndrome, a cluster of metabolic abnormalities, which includes low-grade inflammation, dyslipidemia and insulin resistance. Since nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome, its increasing prevalence follows the increasing rates of obesity seen worldwide. NAFLD has become one of the main causes of chronic liver disease in Western societies [1]. NAFLD describes a broad spectrum of liver diseases, ranging from simple steatosis (intrahepatic fat accumulation) to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis [2]. NASH can be distinguished from simple steatosis by the presence of inflammation. It is unknown how NAFLD develops or which factors provoke its progression into NASH
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