Abstract
Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue (BAT). Using high-throughput library screening of secreted peptides, we identify two fibroblast growth factors (FGF), FGF6 and FGF9, as potent inducers of UCP1 expression in adipocytes and preadipocytes. Surprisingly, this occurs through a mechanism independent of adipogenesis and involves FGF receptor-3 (FGFR3), prostaglandin-E2 and interaction between estrogen receptor-related alpha, flightless-1 (FLII) and leucine-rich-repeat-(in FLII)-interacting-protein-1 as a regulatory complex for UCP1 transcription. Physiologically, FGF6/9 expression in adipose is upregulated by exercise and cold in mice, and FGF9/FGFR3 expression in human neck fat is significantly associated with UCP1 expression. Loss of FGF9 impairs BAT thermogenesis. In vivo administration of FGF9 increases UCP1 expression and thermogenic capacity. Thus, FGF6 and FGF9 are adipokines that can regulate UCP1 through a transcriptional network that is dissociated from brown adipogenesis, and act to modulate systemic energy metabolism.
Highlights
Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue (BAT)
Contrary to the classical view of brown adipogenesis, here we find that fibroblast growth factor 6 (FGF6) and FGF9 can induce a high level of Ucp[1] expression in brown and white preadipocytes independent of adipogenic differentiation
The present study reveals the discovery of two adipokines, FGF6 and FGF9, in the regulation of UCP1 expression in mouse and human adipose systems
Summary
Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue (BAT). Using high-throughput library screening of secreted peptides, we identify two fibroblast growth factors (FGF), FGF6 and FGF9, as potent inducers of UCP1 expression in adipocytes and preadipocytes This occurs through a mechanism independent of adipogenesis and involves FGF receptor-3 (FGFR3), prostaglandin-E2 and interaction between estrogen receptor-related alpha, flightless-1 (FLII) and leucine-rich-repeat-(in FLII)interacting-protein-1 as a regulatory complex for UCP1 transcription. The conventional view of brown adipocyte differentiation from preadipocytes involves the activation of adipogenic/thermogenic transcriptional cascades, including peroxisome proliferatoractivated receptor gamma (Pparg), CCAAT/enhancer binding proteins, PR domain containing 16 (Prdm16), and peroxisome proliferative activated receptor, gamma, coactivator 1 alpha (Ppargc1a)[3,20] This activation results in the expression of genes characteristic of fully differentiated brown adipocytes, including fatty acid binding protein 4 (Fabp4), deiodinase 2 (Dio2), cell death-inducing DNA fragmentation factor A (Cidea), and the brown fat defining marker Ucp[1]. These data establish the mechanism for the induction of UCP1 expression and thermogenic activity by FGF6/9
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