Disruption of the Chemokine-Like Receptor-1 (CMKLR1) Gene Is Associated with Reduced Adiposity and Glucose Intolerance

Abstract

Adipose tissue secretes a variety of bioactive signaling molecules, termed adipokines, which regulate numerous biological functions including appetite, energy balance, glucose homeostasis, and inflammation. Chemerin is a novel adipokine that regulates adipocyte differentiation and metabolism by binding to and activating the G protein-coupled receptor, chemokine like receptor-1 (CMKLR1). In the present study, we investigated the impact of CMKLR1 deficiency on adipose development, glucose homeostasis, and inflammation in vivo. Herein we report that regardless of diet (low or high fat), CMKLR1(-/-) mice had lower food consumption, total body mass, and percent body fat compared with wild-type controls. CMKLR1(-/-) mice also exhibited decreased hepatic and white adipose tissue TNFα and IL-6 mRNA levels coincident with decreased hepatic dendritic cell infiltration, decreased adipose CD3+ T cells, and increased adipose natural killer cells. CMKLR1(-/-) mice were glucose intolerant compared with wild-type mice, and this was associated with decreased glucose stimulated insulin secretion as well as decreased skeletal muscle and white adipose tissue glucose uptake. Collectively these data provide compelling evidence that CMKLR1 influences adipose tissue development, inflammation, and glucose homeostasis and may contribute to the metabolic derangement characteristic of obesity and obesity-related diseases.

Elevated hepatic chemerin mRNA expression in human non-alcoholic fatty liver disease

“…This hypothesis is supported by the suggestion that the activity of the chemerin-CMKLR1 system may depend on the nature of stimuli in the local microenvironment (47). Accordingly, a recent study has reported decreased serum IL6 levels and reduced hepatic inflammatory cell invasion in Cmklr1 K/K mice (22). Complementarily, we found a significant association between the hepatic mRNA levels of IL6 and those of CMKLR1 in our NAFLD subjects, and accordingly when exposing the PHHs to IL6, a significant upregulation of CMKLR1 mRNA expression was observed.…”

“…Interestingly, hepatic CMKLR1 protein expression is reduced in the liver of patients suffering from hepatic steatosis and is upregulated by adiponectin (21), suggesting a protective role of the receptor under conditions of hepatic steatosis. On the other hand, a recent report has indicated decreased serum IL6 levels and reduced hepatic inflammatory cell invasion in Cmklr1 K/K mice (22). Thus, the chemerin-CMKLR1 system seems to be involved in tissue inflammation, which also represents a hallmark of NASH (1,23), but whether the chemerin-CMKLR1 system exerts pro-or anti-inflammatory effects is currently under discussion (19,24,25).…”

Genetic Determination of Serum Levels of Diabetes-Associated Adipokines

“…It seems that increased chemerin levels represent a compensatory mechanism in metabolic diseases. It has also been shown in mice that a disruption of the CMKLR1 gene is associated with reduced adiposity, but the mice were glucose-intolerant and had a decreased glucose-stimulated insulin secretion [140]. Unfortunately, except for the CMKLR1 intron variant rs1878022 A/G, which was found in a GWAS for the survival rate of patients with nonsmall cell lung cancer [141], no other "common" CMKLR1 genetic variant has been investigated.…”

La chémérine

“…Une pré-prochémérine est synthé-tisée, sécrétée ensuite sous la forme d'un précurseur inactif, la prochémérine (Figure 1). Celle-ci est activée par clivage de sa partie carboxy-terminale par diffé-rentes enzymes (cathepsine G, plasmine, élastase, ainsi la souris, une invalidation du gène Cmklr1 entraîne une diminution de l'adiposité et une augmentation de l'intolérance au glucose [27] bien que Rouger et al aient observé une augmentation de l'adiposité chez des souris Cmklr1 -/- [28]. L'invalidation de Gpr1, codant le second récepteur de la chémérine, entraîne aussi une intolérance au glucose, mais uniquement au cours d'un régime enrichi en lipides [29].…”