The glycoprotein follistatin-like 1 promotes brown adipose thermogenesis

Metabolism. 2019 Sep:98:16-26. doi: 10.1016/j.metabol.2019.05.008. Epub 2019 May 24.

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.

Keywords: Adaptive thermogenesis; Brown adipose tissue; FSTL1; Protein glycosylation; β3-adrenergic receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / physiology*
  • Adrenergic beta-3 Receptor Agonists / pharmacology
  • Animals
  • Cell Line
  • Cold Temperature
  • Energy Metabolism / physiology
  • Follistatin-Related Proteins / biosynthesis
  • Follistatin-Related Proteins / genetics
  • Follistatin-Related Proteins / metabolism*
  • Gene Expression / genetics
  • Gene Expression / physiology
  • Gene Knockdown Techniques
  • Glycosylation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • PPAR gamma / metabolism
  • Signal Transduction
  • Thermogenesis / physiology*
  • Uncoupling Protein 1 / metabolism

Substances

  • Adrenergic beta-3 Receptor Agonists
  • Follistatin-Related Proteins
  • Fstl1 protein, mouse
  • PPAR gamma
  • Ucp1 protein, mouse
  • Uncoupling Protein 1