CMKLR1 deficiency attenuates androgen-induced lipid accumulation in mice

Binbin Huang,Linlin Wu,Liang Xiang,Jianmin Niu,Jian V Zhang,Jie Chen,Tianxia Xiao,Lirong Ren,Huashan Zhao,Mengxia Li,Baobei Wang,Chen Huang

doi:10.1152/ajpendo.00176.2019

Abstract

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. Here, using pharmacological method, orchidectomized model and CMKLR1 knockout mice, we demonstrated that androgen excess in female mice resulted in a larger cell size in white adipose tissue (WAT) and brown adipose tissue (BAT), whereas androgen deprivation of male mice induced a smaller cell size. Both effects relating to the adipocytes size were both attenuated in CMKLR1 knockout mice. CMKLR1 deficiency influenced the effect of androgen on adipose tissue by regulating the mRNA expression of androgen receptor (AR) and adipocyte markers (such as Fabp4 and Cidea). Moreover, in vivo suppression of CMKLR1 by its antagonist α-NETA can also weaken the enlargement of the adipocyte cell size caused by 5α-dihydrotestosterone (DHT). Furthermore, using in vitro BAT explants culture and PI3K signaling antagonist wortmannin, we found DHT could reduce the phosphorylated ERK (pERK) in BAT, whereas CMKLR1 inactivation inhibited this effect caused by DHT through PI3K signaling pathway. Taken together, these findings reveal an anti-obesity role of CMKLR1 deficiency in regulating lipid accumulation, highlighting the scientific importance for further development of small molecule CMKLR1 antagonists as fundamental scientific tools or a potential drug for the treatment of adiposity.

Highlights

A growing obesity epidemic is threatening the health of people around the world [14], leading to several secondary diseases such as Type 2 diabetes, hyperlipidemia, atherosclerosis, dyslipidemia, cardiovascular diseases, and fatty liver [22, 42]
We demonstrated that excess androgen in the female mice resulted in larger cells in the white adipose tissue (WAT) and the brown adipose tissue (BAT), whereas androgen deprivation in the male mice induced a reduction in cell size
We found that DHT could reduce the levels of phosphorylated ERK in the BAT, while Chemokine-like receptor 1 (CMKLR1) inactivation inhibited this effect, which had been induced by DHT, through the PI3K signaling pathway

Summary

Introduction

A growing obesity epidemic is threatening the health of people around the world [14], leading to several secondary diseases such as Type 2 diabetes, hyperlipidemia, atherosclerosis, dyslipidemia, cardiovascular diseases, and fatty liver [22, 42]. Adipose tissue hypertrophy and hyperplasia contribute to obesity, resulting in increased risk of developing secondary diseases. Androgen deficiency in men leads to obesity, and treatment of hypogonadal men with testosterone reduces fat content [25]. Androgen excess in women with polycystic ovary syndrome (PCOS) is related to obesity [29, 43]. Serum testosterone is positively associated with the body mass index in women with PCOS and obesity [34]. Because of the conflicting results from different studies [4, 7, 23, 28, 37], the mechanism through which androgen induces adiposity remains largely unknown

Methods

Results

Discussion

Conclusion