Exercise Normalizes Dysfunctional Adipose Tissue Phenotype in FGF21-Null Mice: 3607 Board #54 June 3 9

Adipose tissue (AT) immunometabolic health predicts systemic metabolic health. Exercise improves metabolic function and insulin sensitivity and is thought to improve AT metabolism by reducing AT inflammation. Fibroblast growth factor 21 (FGF21) is a pleotropic hormone-like protein that has been shown to have beneficial effects by improving glucose and lipid metabolism and may have beneficial effects on AT immunometabolic function. However, it is unknown whether exercise-induced AT adaptations are mediated through FGF21. PURPOSE: To determine the role of FGF21 in exercise-induced adaptations in white (W) and brown (B) AT. METHODS: Male FGF21 knock-out (KO) and wild type (WT) mice were fed normal chow and either exercise trained via voluntary wheel running (EX) or kept sedentary (SED) for 8 weeks. Visceral (i.e., epididymal), subcutaneous (inguinal region) WAT, and BAT (interscapular region) depots were removed, weighed and flash-frozen in liquid nitrogen. Techniques used: EchoMRI - body composition, real-time PCR - gene expression, Western blotting - protein content, and H&E staining - histology. RESULTS: FGF21KO mice weighed more (p<0.05) and had greater overall adiposity. In addition to having greater systemic insulin resistance (IR) based on HOMA-IR (p<0.01), AT from FGF21KO mice was more insulin resistant (p<0.01) based on fasting plasma insulin and free fatty acids. EX decreased AT IR (p<0.01) but only tended to decrease HOMA-IR (p=0.112). Phospho-Akt and GLUT4 proteins were increased in AT of FGF21KO mice, combined with increased IR, is suggestive of dysregulated glucose uptake. In WAT and BAT, inflammatory and oxidative stress genes (e.g., MCP-1, TNFα, CD11c, P22phox) were significantly upregulated in FGF21KO and normalized by EX. Mitochondria content, indicated by COX III and IV protein, were significantly reduced in BAT of FGF21KO. CONCLUSION: Absence of FGF21 increases AT IR as well as WAT and BAT inflammation; EX rescues this phenotype. Normal WAT mitochondrial adaptations to EX may be adversely affected by loss of FGF21. Metabolic dysfunction in FGF21KO appears largely due to excess AT, and is almost completely normalized by EX. Supported by grant number R25GM056901 from the NIGMS of the NIH, VA-CDA2 IK2BX001299 (RSR), and MU Research Board, Corporate Advisory Board, and Research Council.