CMKLR1 deficiency attenuates androgen-induced lipid accumulation in mice

Excess androgen-induced obesity has become a public health problem, and its prevalence has increased substantially in recent years. Chemokine-like receptor 1 (CMKLR1), a receptor of chemerin secreted by adipose tissue, is linked to adipocyte differentiation, adipose tissue development, and obesity. However, the effect of CMKLR1 signaling on androgen-mediated adiposity in vivo remains unclear. Using CMKLR1-knockout mice, we constructed an androgen-excess female mouse model through 5α-dihydrotestosterone (DHT) treatment and an androgen-deficient male mouse model by orchidectomy (ORX). For mechanism investigation, we used 2-(α-Naphthoyl) ethyltrimethylammonium iodide (α-NETA), an antagonist of CMKLR1, to suppress CMKLR1 in vivo and wortmannin, a PI3K signaling antagonist, to treat brown adipose tissue (BAT) explant cultures in vitro. Furthermore, we used histological examination and quantitative PCR, as well as Western blot analysis, glucose tolerance tests, and biochemical analysis of serum, to describe the phenotypes and the changes in gene expression. We demonstrated that excess androgen in the female mice resulted in larger cells in the white adipose tissue (WAT) and the BAT, whereas androgen deprivation in the male mice induced a reduction in cell size. Both of these adipocyte size effects could be attenuated in the CMKLR1-knockout mice. CMKLR1 deficiency influenced the effect of androgen treatment on adipose tissue by regulating the mRNA expression of the androgen receptor (AR) and adipocyte markers (such as Fabp4 and Cidea). Moreover, suppression of CMKLR1 by α-NETA could also reduce the extent of the adipocyte cell enlargement caused by DHT. Furthermore, we found that DHT could reduce the levels of phosphorylated ERK (pERK) in the BAT, while CMKLR1 inactivation inhibited this effect, which had been induced by DHT, through the PI3K signaling pathway. These findings reveal an antiobesity role of CMKLR1 deficiency in regulating lipid accumulation, highlighting the scientific importance for the further development of small-molecule CMKLR1 antagonists as fundamental research tools and/or as potential drugs for use in the treatment of adiposity.