233-LB: Spinal Cord Injury Inhibited-FGF21 Signaling Is Associated with Dysregulation of Metabolic Gene Expression in Mouse Liver and Adipose Tissue

Abstract

Spinal cord injury (SCI) causes deleterious changes in the metabolic profile due to muscle atrophy and sedentary lifestyle. SCI is associated with increased risk for cardiovascular disease, liver disorders and type 2 diabetes mellitus (T2DM). Understanding of the mechanisms for these disorders in those with SCI is poor. Fibroblast growth factor 21 (FGF-21), a hepatic hormone, is reported to have beneficial effects on glucose/lipid metabolism in animal models and human subjects with T2DM. However, the expression levels and the potential effect of FGF-21 on SCI related metabolic dysfunction have not been studied. To address this issue, we compared FGF-21 serum and hepatic mRNA levels in sham and SCI mice fed control or high fat diet (HFD) at 84d after SCI. SCI reduced serum FGF-21 levels by 60% and hepatic FGF-21 mRNA levels by 50% compared to sham mice; levels were further suppressed by HFD. These changes were associated with elevated serum levels of alanine aminotransferase, a liver damage marker. In adipose tissue (AT), SCI decreased mRNA expression of FGF-21 receptor (FGFR1), β-Klotho, adiponectin, PPARγ, and leptin. In addition, SCI reduced IRS1 and Glut4 mRNA levels in AT, indicating impaired insulin signaling. Moreover, elevated levels of TNFα in AT and CD11b (a macrophage marker) in the liver were observed, implying a proinflammatory state after SCI. Finally, post-SCI mice fed a HFD had elevated free fatty acid (FFA) levels in serum and liver compared to sham-mice fed a HFD, suggesting defective FFA uptake and metabolism. These data suggest that reduced FGF-21 signaling after SCI may, at least in part, be contributing to the metabolic dysfunction after SCI, and that FGF-21 may be a candidate for the treatment of SCI-related metabolic dysfunction. Disclosure X. Liu: None. L. Harlow: None. Z. Graham: None. J.F. Yarrow: None. K. Cusi: Consultant; Self; Allergan plc., AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., Gilead Sciences, Inc., Merck & Co., Inc. Research Support; Self; Cirius Therapeutics, Echosens, Eli Lilly and Company, Inventiva Pharma, Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Poxel SA, Zydus Pharmaceuticals, Inc. W.A. Bauman: None. C.P. Cardozo: None. Funding U.S. Department of Veterans Affairs (B9212C, B2020C)