FGF1 is required for adipose metabolic homeostasis and mitochondrial fuel flexibility Taehee Jo, Heewon Jung, Hyemi Shin, Duseok Kang, Jae Myoung Suh, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
The metabolic flexibility and remodeling capacity of fat tissues is a feature essential to the maintenance of systemic metabolic homeostasis. The plasticity of mitochondrial substrate preference to glucose or fatty acids, underlies the dynamic nature of adipose tissue physiology whereas chronic nutrient overload leads to mitochondrial dysfunction and attendant metabolic sequelae. Within this context, the PPARγ-FGF1 axis is a critical regulator of adipose remodeling and responds to chronic metabolic stress as well as acute nutrient cues. To elucidate the fat autonomous mechanisms of FGF1 in metabolic flexibility and tissue remodeling, we newly generated adipose-specific Fgf1 knockout (Fgf1 FKO) mice. Upon high fat diet (HFD) stress, Fgf1 FKO mice displayed severe diabetic phenotype with atrophic visceral adipose tissue. Gross examination of Fgf1 FKO visceral fat revealed atrophic and dysmorphic alterations indicative of a failure of adipose tissues to undergo proper adaptive remodeling. Detailed histopathological analyses revealed polarized distribution of adipocyte lipid droplet size accompanied by marked tissue fibrosis. Consequently, Fgf1 FKO mice had more severe hepatic steatosis and increased pancreatic islet hyperplasia when compared with control. By microarray analysis, we show that HFD challenged FGF1 null (Fgf1 KO) visceral fat, in comparison to wild-type visceral fat, failed to undergo the metabolic shift from β-oxidation to glycolysis observed under HFD stress. Moreover, induction of lipogenesis and lipolysis genes was not observed in HFD Fgf1 KO, suggesting mitochondrial fuel inflexibility plays a causative role in defective adipose fatty acid metabolism of HFD Fgf1 KO. Previous findings show that PPARγ agonists increase adipose mitochondrial oxidative phosphorylation (OXPHOS) capacity, which may contribute to the insulin sensitizing effects of PPARγ agonists. Extracellular flux analyses with cultured adipocytes showed that FGF-FGFR signaling is required to relay PPARγ agonist induced mitochondrial OXPHOS increase. Moreover, treatment of recombinant FGF1 to 3T3-L1 adipocytes was sufficient to increase extracellular acidification rate, suggesting a direct effect on cellular glycolysis. Taken together, we propose that upregulation of adipose FGF1 triggered by HFD is required for proper adaptive remodeling of adipose tissues, and that the maladaptive phenotypes of FGF1 null adipose tissue is, in part, due to defective mitochondrial fuel flexibility.
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