Dongliang Fang1, Xinyi Shi1, Tao Lu1, Haibin Ruan2, Yan Gao3. 1. Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China. 2. Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA. 3. Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China. Electronic address: gy1003@ccmu.edu.cn.
Abstract
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.
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. FSTL1haploinsufficiency 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.
Authors: Marijn C Peters; Sofia Di Martino; Thomas Boelens; Jiabin Qin; Alain van Mil; Pieter A Doevendans; Steven A J Chamuleau; Joost P G Sluijter; Klaus Neef Journal: Mol Ther Methods Clin Dev Date: 2022-02-23 Impact factor: 6.698
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