Adipocyte FGF1 Signaling in Systemic Metabolism

About This Grant

Project Summary/Abstract Hyperlipidemia, characterized by elevated levels of lipids in the blood, causes significant abnormal metabolism such as lipid accumulation, insulin resistance, mitochondrial dysfunction, and inflammation. These alterations contribute to or are associated with various metabolic disorders, obesity, and diabetes, and become a leading cause of atherosclerotic cardiovascular diseases (ASCVD). However, there is no compelling alternative to replace conventional lipid-lowering therapies, which are still risky to many patients due to their associated adverse effects. Therefore, developing more specific and efficient lipid-lowering therapies is essential. Fibroblast growth factor 1 (FGF1) exhibits unexpected and potent glucose-lowering and insulin-sensitizing effects in diabetic mice, leading to increasing attention to FGF1 in metabolic diseases. Nevertheless, the pathophysiological roles of FGF1 in lipid homeostasis and atherogenesis remain unclear. Moreover, there is a significant gap in the field regarding the underlying mechanism of FGF1 action on systemic metabolism. My preliminary studies showed chronic administration of FGF1 and a non-mitogenic FGF1 variant (FGF1ΔHBS). ameliorated atherosclerotic phenotypes associated with rectified hyperlipidemia, promoted insulin sensitivity, and enhanced brown adipose tissue (BAT) activation in ApoEKO mice. Notably, FGF1 treatment accelerated the plasma lipid clearance and distinctively enhanced lipid uptake in BAT, accompanied by significant increases in lipoprotein lipase (LPL) activity and expression in BAT. My data further indicated brown adipocyte LPL-specific deletion (LPLBAT-KO) abolishes FGF1’s benefits in lipid-lowering and glucose intolerance in ApoEKO mice. Currently, activating BAT in adult humans has fueled substantial interest in exploring its potential as a ‘metabolic sink’ in mice. The FGFR1 in adipose tissue is essential for FGF1’s anti-diabetic effects. These findings lead me to central hypothesize that the FGF1/FGFR1 axis promotes LPL-mediated signaling in BAT to modulate systemic metabolism and prevent atherosclerosis. Aim 1 will define BAT as a mediator for FGF1 effects on systemic lipid homeostasis. Systematic assessment of the effects of FGF1 on lipid clearance and BAT activation in ApoEKO, LDLRKO, and ApoEKO/LPLBAT-KO mice. FGF1 treated-BAT suppression and BAT ablation mouse models will be subject to metabolic characterization. Aim 2 aims to determine whether brown adipocyte FGF1/FGFR1-LPL plays a critical role in regulating metabolic homeostasis and preventing the progression of atherosclerosis. The gain and/or loss of function of FGF1 will be investigated through BAT-specific FGF1 overexpression using the AAV/Rec2-mADIPOQP-Fgf1 vector in ApoEKO/FGF1KO and brown adipocyte-specific FGFR1 knockout (ApoEKO/Fgfr1BAT-KO) mice. These studies aim to uncover the mechanistic role of FGF1 in BAT in systemic homeostasis. Additionally, brown adipocyte-specific knockout mice will be used to assess the clinical translatability of FGF1ΔHBS in protecting against atherosclerosis. This proposed study will reveal that FGF1/FGFR1-LPL signaling in BAT plays critical roles in modulating systemic metabolism, paving the way for novel therapeutic strategies to address dyslipidemia-related metabolic diseases.