Abstract
Fibroblast growth factor 21 (FGF21) is a recently discovered hepatokine that regulates lipid and glucose metabolism and is upregulated in response to numerous physiological and pathological stimuli. Herein, we demonstrate that both physical and chemical hypoxia increase the systemic and hepatic expression of FGF21 in mice; by contrast, hypoxia induces a reduction of FGF21 expression in hepatocytes, indicating that hypoxia-induced FGF21 expression is differentially regulated in intact animals and in hepatocytes. Furthermore, we demonstrate that hypoxia treatment increases hormone-sensitive lipase-mediated adipose tissue lipolysis in mice, which is reduced in Fgf21 knockout mice, thereby implying that FGF21 plays a critical role in hypoxia-related adipose lipolysis. Adipose tissue lipolysis causes an increase in the amount of circulating free fatty acids, which leads to the activation of peroxisome proliferators-activated receptor alpha and an increased expression of FGF21 in hepatocytes. We further show that hypoxia-induced elevation of reactive oxygen species, but not the hypoxia-inducible factor, is responsible for the lipolysis and FGF21 expression. In conclusion, our data clearly demonstrate that FGF21 plays a critical role in hypoxia-induced adipose lipolysis, which induces hepatic expression of FGF21. Clarification of hypoxia-regulated FGF21 regulation will enhance our understanding of the pathophysiology of hypoxia-related diseases, such as sleep disorders and metabolic diseases.
Highlights
Adipose tissue functions as the major fat storage site in the form of triglycerides (TGs)
We found that the increase in Fibroblast growth factor 21 (FGF21) expression is not due to the activation of hypoxia-inducible factor (HIF) by hypoxia in hepatocytes, but through hypoxiainduced adipose tissue lipolysis leading to the mobilization of free fatty acids (FFAs) and the activation peroxisome proliferators-activated receptor alpha (PPARa) in the liver and hypoxia-induced oxidative stress
Unlike the in vivo study, hypoxia treatment did not increase, rather decreased the cellular Fgf21 mRNA expression and protein secretion in the HepG2 cells (Figures 2E, F). These results suggest that FGF21 expression is differentially regulated in hepatocytes and in animal
Summary
Adipose tissue functions as the major fat storage site in the form of triglycerides (TGs). While lipolysis is a physiological response to metabolic changes, excess lipolysis may lead to increased circulating FFA levels, which is a risk factor for a variety of metabolic diseases. Previous studies have shown that adipose tissue lipolysis is associated with tissue hypoxia (Mahat et al, 2016), which is a pathophysiological state existing in Adipose Lipolysis Requires FGF21 many disease conditions (Famulla et al, 2012; Plihalova et al, 2016; Zhang et al, 2017). Lipolysis and hypoxia have been linked to fibroblast growth factor 21 (FGF21), respectively (Arner et al, 2008; Cai et al, 2019). FGFs require heparin to promote binding to the tyrosine kinase FGF receptors (FGFRs) and act in a paracrine or autocrine fashion (Beenken and Mohammadi, 2009). FGF21 does not possess a heparinbinding domain and is secreted into the circulation, where it exerts its functions through the activation of a unique dual receptor system consisting of FGFRs and a co-receptor, bklotho (Ding et al, 2012); in this way, it can function in an endocrine fashion
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