Chemokine-like receptor 1 deficiency does not affect the development of insulin resistance and nonalcoholic fatty liver disease in mice.
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.
University of Groningen, University Medical Center Groningen, Department of Pediatrics, Molecular Genetics Section, Groningen, the Netherlands.
Nanda
N
Gruben
University of Groningen, University Medical Center Groningen, Department of Pediatrics, Molecular Genetics Section, Groningen, the Netherlands.
Marcela
M
Aparicio Vergara
University of Groningen, University Medical Center Groningen, Department of Pediatrics, Molecular Genetics Section, Groningen, the Netherlands.
Niels J
NJ
Kloosterhuis
University of Groningen, University Medical Center Groningen, Department of Pediatrics, Molecular Genetics Section, Groningen, the Netherlands.
Henk
H
van der Molen
University of Groningen, University Medical Center Groningen, Department of Pediatrics, Molecular Genetics Section, Groningen, the Netherlands.
Stefan
S
Stoelwinder
Utrecht University, Faculty of Veterinary Medicine, Dutch Molecular Pathology Center, Utrecht, the Netherlands.
Sameh
S
Youssef
Utrecht University, Faculty of Veterinary Medicine, Dutch Molecular Pathology Center, Utrecht, the Netherlands.
Alain
A
de Bruin
Merck Research Laboratories, MSD, Department of Immune Therapeutics, Oss, the Netherlands.
Dianne J
DJ
Delsing
University of Groningen, University Medical Center Groningen, Department of Pediatrics, Molecular Genetics Section, Groningen, the Netherlands.
Jan Albert
JA
Kuivenhoven
University of Groningen, University Medical Center Groningen, Department of Pediatrics, Molecular Genetics Section, Groningen, the Netherlands.
Bart
B
van de Sluis
University of Groningen, University Medical Center Groningen, Department of Pediatrics, Molecular Genetics Section, Groningen, the Netherlands.
Marten H
MH
Hofker
University of Groningen, University Medical Center Groningen, Department of Pediatrics, Molecular Genetics Section, Groningen, the Netherlands.
Debby P Y
DP
Koonen
D000818:Animals; D001835:Body Weight; D005234:Fatty Liver / Q000235:genetics* / Q000473:pathology; D017353:Gene Deletion; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*
C486456:CMKLR1 protein, mouse; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled