Ups and downs: The PPARγ/p-PPARγ seesaw of follistatin-like 1 and integrin receptor signaling in adipogenesis

Abstract

Objective Although Follistatin-like protein 1 (FSTL1), as an “adipokine”, is highly expressed in preadipocytes, the detail role of FSTL1 in adipogenesis and obesity remains not fully understood. Methods In vitro differentiation of both Fstl1 −/− murine embryonic fibroblasts (MEFs) and stromal vascular fraction (SVF) were measured to assess the specific role of FSTL1 in adipose differentiation. Fstl1 adipocyte-specific knockout mice were generated to evaluate its role in obesity development. Gene expression analysis and phosphorylation patterns were performed to check out the molecular mechanism of the biological function of FSTL1. Results FSTL1 deficiency inhibited preadipocytes differentiation in vitro and obesity development in vivo. Glycosylation at N142 site was pivotal for the biological effect of FSTL1 during adipogenesis; the conversion between PPARγ and p-PPARγ was the key factor for the function of FSTL1. Molecular mechanism studies showed that FSTL1 functions through the integrin/FAK/ERK signaling pathway. Conclusions Our results suggest that FSTL1 promotes adipogenesis by inhibiting the conversion of PPARγ to p-PPARγ through the integrin/FAK/ERK signaling pathway. Glycosylated modification at N142 of FSTL1 is the key site to exert its biological effect.

Adipokines, Hepatokines and Myokines: Focus on Their Role and Molecular Mechanisms in Adipose Tissue Inflammation

“…Follistatin-like 1 (FSTL1) is a novel pro-inflammatory cytokine that is ~37 kDa in size and is highly expressed in AT, and mainly in the stromal vascular fraction 121 ). Moreover, FSTL1 expression is high in preadipocytes with a transient upregulation in early differentiated cells and then declines to basal levels after differentiation ( 121 – 123 ). Hence, FSTL1 has a potential role in adipogenesis.…”

“…Hence, FSTL1 has a potential role in adipogenesis. Indeed, a recent study found that FSTL1 deficiency inhibited preadipocyte differentiation in vitro and obesity development in vivo ( 123 ). In addition, FSTL1 has been shown to act as a novel stimulator of β-adrenergic signaling and promote BAT thermogenesis ( 124 ).…”

“…in the stromal vascular fraction 121). Moreover, FSTL1 expression is high in preadipocytes with a transient upregulation in early differentiated cells and then declines to basal levels after differentiation (121)(122)(123). Hence, FSTL1 has a potential role in adipogenesis.…”

New Discovered Adipokines Associated with the Pathogenesis of Obesity and Type 2 Diabetes

“… 8 During the switch from chow diet to high fat diet (HFD), FSTL1 deletion mice gained less body weight, fat mass, and glucose level than the control group. FSTL1 promoted adipogenesis by inhibiting the conversion of PPARγ to p-PPARγ through the integrin/FAK/ERK signaling pathway, 9 and could activate NFκB and JNK signaling pathways, critical in obesity-induced inflammation and IR, in adipocytes and macrophages. 8 Insulin-stimulated phosphorylation of both Akt and IRS-1 was markedly reduced by FSTL1 treatment, which impaired insulin signal transduction in 3T3-L1 adipocytes.…”

FSTL1 is an antagonist of ERK1/2 phosphorylation during ciliogenesis and preadipocyte differentiation

“…We showed that both high levels of FSTL1 at the onset and its subsequent reduction during the process are required for normal differentiation in this cell line [13]. Importantly, in vivo experiments by others confirmed that differentiation to adipocytes of Fstl1-/- mouse embryonic fibroblasts (MEFs) and stromal vascular cells (SVCs) was impaired [14]. Moreover, different reports are starting to link FSTL1 with obesity in humans (see for example [15, 16]).…”