Chemokine-like receptor 1 deficiency does not affect the development of insulin resistance and nonalcoholic fatty liver disease in mice

• Published in: PloS one 2014-04, Vol.9 (4), p.e96345
• Main Authors: Gruben, Nanda, Aparicio Vergara, Marcela, Kloosterhuis, Niels J, van der Molen, Henk, Stoelwinder, Stefan, Youssef, Sameh, de Bruin, Alain, Delsing, Dianne J, Kuivenhoven, Jan Albert, van de Sluis, Bart, Hofker, Marten H, Koonen, Debby P Y
• Format: Article
• Language: English
• Subjects: Accumulation; Animals; Biology and Life Sciences; Body Weight; Body weight gain; Bone marrow; Bone marrow transplantation; Cholesterol; Fatty liver; Fatty Liver - genetics; Fatty Liver - pathology; Fibrosis; Food intake; Gene Deletion; Gene expression; Glucose; Glucose tolerance; Health aspects; High cholesterol diet; Immunological tolerance; Infiltration; Inflammation; Insulin; Insulin resistance; Insulin Resistance - genetics; Liver; Liver - metabolism; Liver - pathology; Liver diseases; Liver transplantation; Low density lipoprotein receptors; Low density lipoproteins; Macrophages; Male; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Milk; Non-alcoholic Fatty Liver Disease; Obesity; Pathogenesis; Pathology; Receptor density; Receptors, G-Protein-Coupled - genetics; Research and Analysis Methods; Rodents; Steatosis; Stem cell transplantation; Studies; Tumor necrosis factor-TNF
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0096345

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.