Fibroblast Growth Factor and Energy Metabolism

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Project Summary/Abstract Obesity is growing at epidemic rates worldwide and leads to a broad spectrum of other disorders, which collectively form metabolic syndrome. Central to these pathologies is the adipose tissue. In mammals, there are two functionally distinct types of fat: white adipose tissue, which stores excess calories, and brown and its related beige adipose tissue, which dissipates energy for thermogenesis. Numerous studies in rodents have demonstrated that increasing the amount or activity of brown or beige fat holds excellent therapeutic potential for obesity-related metabolic diseases. Adipose tissue undergoes dramatic remodeling in response to environmental challenges. Cold exposure is an effective way to increase brown fat mass and activity. as well as to induce browning of white adipose tissue. While it has long been postulated that growth factors produced by the adipose niche play a critical role in the remodeling of brown and white fat upon cold challenge, the identity of such factors have remained mostly unidentified. Recently, we discovered that fibroblast growth factor (FGF) 9 is a cold-induced adipokine and can induce UCP1 expression independent of brown adipogenesis. In addition to adipose progenitors, FGF9 also stimulates thermogenic program in mature adipocytes. Importantly, expression of FGF receptor 3 (FGFR3), the receptor that mediates FGF9’s effects, is also induced by cold in both the stromal vascular fraction (SVF) cells and adipocytes, suggesting that FGF9 functions as an autocrine/endocrine factor within the adipose niche. Using single-cell RNA sequencing of the adipose SVF, we identify FGFR3’s abundant expression in the vascular endothelial cells. Based on these exciting findings, we hypothesize that FGF9, produced by adipocytes, functions as a niche factor to promote brown and white adipose tissue remodeling and modulate thermogenic program in mature adipocytes, in response to cold challenge. The primary goals of this grant are to 1) determine the role of FGF9 in regulation of thermogenic program in mature adipocytes and delineate the underlying transcriptional and epigenetic mechani, 2) determine the role of FGF9-induced angiogenesis in adipose remodeling, and 3) use both gain- and loss-of-function mouse models and nanotechnology to define the in vivo role of the FGF9-FGFR3 axis in energy metabolism and explore the potential of targeting this pathway to develop new therapies to treat obesity and its many related co-morbidities. Completion of the proposed studies will lead to a new understanding of adipose remodeling and could provide potential therapeutic approaches for obesity, type 2 diabetes, and other related metabolic diseases.