Objectives: The thermogenic brown adipose tissue (BAT) has been proposed as a potential target to prevent or treat obesity and related metabolic diseases. BAT secretes adipokines to regulate the thermogenic program in an autocrine or paracrine manner. Follistatin-like 1 (FSTL1), a glycoprotein involved in adipogenesis and obesity, however, the function of FSTL1 in BAT thermogenesis and in the regulation of systemic energy homeostasis are not fully understood. Methods: Whole-body ablation Fstl1 heterozygous mice (Fstl1+/−) and its littermates control were injected with CL316,243 to assess energy balance. A series of FSTL1 overexpression and knockdown experiments were carried out to evaluate its function in regulating thermogenic gene expression in brown adipocytes. Results: FSTL1 expression was induced upon BAT activation during cold challenge or β3-adrenergic activation. FSTL1 haploinsufficiency in mice led to reduced thermogenic gene expression, impaired BAT recruitment, and decreased heat production. FSTL1 cell-autonomously promoted the β3-adrenergic signaling, which was required to upregulate PPARγ and UCP1 in brown adipocytes. Furthermore, only glycosylated FSTL1 could be secreted from brown adipocytes to induce the β3-adrenergic activation. Conclusions: Our results suggest FSTL1 as a novel stimulator of the β-adrenergic signaling and BAT thermogenesis.
Bibliographical noteFunding Information:
The present study was supported by National Natural Science Foundation of China (grant no. 81602532 ); Beijing Municipal Organization Department Talents Project (grant no. 2015000020124G113 ); Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five - year Plan (grant no. IDHT20170516 ).
- Adaptive thermogenesis
- Brown adipose tissue
- Protein glycosylation
- β3-adrenergic receptor