FGF6 and FGF9 regulate UCP1 expression independent of brown adipogenesis

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.

Multifunctional Roles of the Actin-Binding Protein Flightless I in Inflammation, Cancer and Wound Healing

“…Conversely, overexpression of Flii reduced both the amount of triglycerides and the expression of desalt1, which was replicated in mammalian preadipocytes (Park et al, 2018b). Flii is also a transcriptional coactivator of Uncoupling protein-1 (UCP1), a key regulator of brown fat adipogenesis, and acts to modulate systemic energy metabolism (Shamsi et al, 2020). A number of other enzymes related to the metabolic pathways of glycolysis, lipogenesis, lypolysis and the pentose phosphate pathway are also increased in the Drosophila Flii mutants (Park et al, 2018a).…”

Identification and characterization of adipose surface epitopes

“…FGFR1/βKlotho signaling also mediates the FGF21 effects on BAT thermogenesis [ 213 , 223 , 225 ], albeit its action includes non-adipocyte cells within BAT [ 226 , 227 ]. In contrast, FGFR3 regulates UCP1 dependent thermogenesis in brown adipocytes [ 228 ].…”

Exploiting oxidized lipids and the lipid‐binding GPCRs against cardiometabolic diseases

“…In general, COX‐1 is constitutively and ubiquitously expressed, whereas COX‐2 expression can be inducible mainly under inflammatory insults, via NF‐κB signalling. Although COX‐2 was previously established as an inducible enzyme, it is currently known that COX‐2 is actually constitutively expressed in a number of tissues and cell types, such as in uterus, endothelium, adipose tissue, kidney, and brain (Oksuz et al, 2016; Shamsi et al, 2020). These enzymes have two distinct catalytic sites.…”

“…One important factor that may explain such controversies may be that animal models of COX‐2 deletion or overexpression can differentially affect the concentration of many lipid species in addition to PGE 2 , and in such scenarios, other prostanoids can counteract the pro‐thermogenic actions of PGE 2 . It is important to recall that PGE 2 primarily stimulates the G s ‐protein coupled receptors EP 2 and EP 4 in adipocytes and macrophages, thus triggering a cAMP‐dependent pathway upstream of the activation of UCP1 (Shamsi et al, 2020). Consistently, studies in which PGE 2 pro‐thermogenic activity is assessed have indicated that indeed the addition of PGE 2 to adipocytes induces UCP1 expression in human white adipocytes (García‐Alonso et al, 2016) and in murine pre‐adipocytes (Shamsi et al, 2020), while deletion of the rate‐limiting enzyme for PGE 2 biosynthesis, microsomal PGE synthase‐1, decreased thermogenic gene expression, including UCP1 (García‐Alonso et al, 2013).…”

“…It is important to recall that PGE 2 primarily stimulates the G s ‐protein coupled receptors EP 2 and EP 4 in adipocytes and macrophages, thus triggering a cAMP‐dependent pathway upstream of the activation of UCP1 (Shamsi et al, 2020). Consistently, studies in which PGE 2 pro‐thermogenic activity is assessed have indicated that indeed the addition of PGE 2 to adipocytes induces UCP1 expression in human white adipocytes (García‐Alonso et al, 2016) and in murine pre‐adipocytes (Shamsi et al, 2020), while deletion of the rate‐limiting enzyme for PGE 2 biosynthesis, microsomal PGE synthase‐1, decreased thermogenic gene expression, including UCP1 (García‐Alonso et al, 2013). Furthermore, Shamsi et al (2020) have recently shown that PGE 2 biosynthesis is induced by FGFs (FGF‐6 and FGF‐9) in classical brown adipocytes to mediate an adipogenesis‐independent transcriptional regulation of UCP1 that relies on the activation of EP 2 /EP 4 receptors and consequent activation of oestrogen‐related receptor α (ERR‐α), which in turn translocate to the nucleus where in co‐operation with the co‐transcription factors, flightless‐1 (FLII) and leucine reach repeat (in FLII)‐interacting protein (LRRFIP1), promotes the enhancement of UCP1 transcription, ultimately leading to higher‐energy expenditure in vivo (Shamsi et al, 2020).…”