Chemokine-Like Receptor 1 Deficiency Does Not Affect the Development of Insulin Resistance and Nonalcoholic Fatty Liver Disease in Mice

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.

Reduced expression of chemerin in visceral adipose tissue associates with hepatic steatosis in patients with obesity

“…It has been described as a chemoattractant of innate immune cells such as Kupffer cells, which in turn are believed to be key players in the pathophysiology of NAFLD . However, while a mouse model with diminished chemerin action showed no effects on insulin resistance and NAFLD compared with wild type , the administration of recombinant chemerin attenuated the inflammatory response in another model . Although the associations were moderate, the anti‐inflammatory effects of chemerin and its negative association with NAS suggest that this lower VAT expression of chemerin in patients with obesity may be involved in the pathophysiology of NAFLD.…”

Chemerin in Liver Diseases

“…A high fat, high cholesterol diet does not affect body weight, food intake, insulin resistance, hepatic inflammation and hepatic expression of fibrotic genes in CMKLR1-/-mice [50].…”

Adipokines in Liver Cirrhosis

“…Though chemerin may exert autocrine and/or paracrine activities in the liver, its function in this organ is still unclear. Indeed, chemerin, GPR1 and CMKLR1 knock-out mice do not display gross hepatic abnormalities even when fed diets to produce obesity or NAFLD [ 93 , 94 , 95 ]. Chemerin and GPR1 seem to stimulate insulin secretion and knock-out animals consequently display hyperglycemia [ 94 , 95 ].…”