Spinal Cord Injury Reduces Serum Levels of Fibroblast Growth Factor-21 and Impairs Its Signaling Pathways in Liver and Adipose Tissue in Mice.

Xin-Hua Liu,Daniella Azulai,Christopher P Cardozo,Jiangping Pan,William A Bauman,Lauren Harlow,Joshua Yarrow,Zachary A Graham

doi:10.3389/fendo.2021.668984

Abstract

Spinal cord injury (SCI) results in dysregulation of carbohydrate and lipid metabolism; the underlying cellular and physiological mechanisms remain unclear. Fibroblast growth factor 21 (FGF21) is a circulating protein primarily secreted by the liver that lowers blood glucose levels, corrects abnormal lipid profiles, and mitigates non-alcoholic fatty liver disease. FGF21 acts via activating FGF receptor 1 and ß-klotho in adipose tissue and stimulating release of adiponectin from adipose tissue which in turn signals in the liver and skeletal muscle. We examined FGF21/adiponectin signaling after spinal cord transection in mice fed a high fat diet (HFD) or a standard mouse chow. Tissues were collected at 84 days after spinal cord transection or a sham SCI surgery. SCI reduced serum FGF21 levels and hepatic FGF21 expression, as well as β-klotho and FGF receptor-1 (FGFR1) mRNA expression in adipose tissue. SCI also reduced serum levels and adipose tissue mRNA expression of adiponectin and leptin, two major adipokines. In addition, SCI suppressed hepatic type 2 adiponectin receptor (AdipoR2) mRNA expression and PPARα activation in the liver. Post-SCI mice fed a HFD had further suppression of serum FGF21 levels and hepatic FGF21 expression. Elevated serum free fatty acid (FFA) levels after HFD feeding were observed in post-SCI mice but not in sham-mice, suggesting defective FFA uptake after SCI. Moreover, after SCI several genes that are implicated in insulin’s action had reduced expression in tissues of interest. These findings suggest that downregulated FGF21/adiponectin signaling and impaired responsiveness of adipose tissues to FGF21 may, at least in part, contribute to the overall picture of metabolic dysfunction after SCI.

Highlights

Spinal cord injury (SCI) causes partial or total interruption of neural signal transmission between the brain and the periphery, thereby limiting physical activity
We observed that sham mice fed with high fat diet (HFD) had reduced Fibroblast growth factor 21 (FGF21) serum levels and hepatic FGF21 mRNA expression; serum FGF21 and hepatic FGF21 mRNA were further decreased in SCI-HFD mice compared to SCIConD mice (Figure 1B)
The central question addressed in this study was whether SCI per se has an impact to change serum FGF21 levels or activity of FGF21-dependent signaling, including that through adiponectin, in a mouse model of complete spinal cord transection

Summary

INTRODUCTION

Spinal cord injury (SCI) causes partial or total interruption of neural signal transmission between the brain and the periphery, thereby limiting physical activity. FGF21 improves systemic insulin sensitivity by promoting the healthy expansion of SAT [34], thereby increasing serum levels of adiponectin, a major adipokine produced by adipose tissue, which mediates the beneficial effects of FGF21 on the liver and muscle [35, 36]. To understand the possible role of FGF21 in altered fat, carbohydrate and energy metabolism following SCI, blood and tissue samples collected from SCI mice fed either a high fat diet (HFD) or control diet (ConD) were used to determine circulating FGF21 levels and expression of FGF21 mRNA. The cause of the potential perturbations in FGF21 levels and, if altered, the probable impact on lipid and carbohydrate metabolism was investigated by analyses of relevant signaling and molecular changes in fat, liver and muscle

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ETHICS STATEMENT