ASK1-induced FGF21 synthesis in the liver prevents obesity in mice

Objective Fibroblast growth factor 21 (FGF21) is a stress‐induced hormone secreted by the liver. It has a beneficial role in the regulation of glucose and energy metabolism. Herein, we identify apoptosis signal regulating kinase 1 (ASK1) as an inducer of hepatic FGF21 synthesis. Methods Glucose and energy metabolism were assessed in liver‐specific ASK1 overexpressing (ASK1 $^{+hep}$ ) and control littermate (ASK1 $^{f/f}$ ) mice fed a regular chow or high fat diet (HFD) for 20 weeks. Liver and fat depots were analyzed using RNA sequencing. Hepatic Fgf21 expression was downregulated using adeno‐associated virus (AAV) expressing short‐hairpin RNA sequences. ASK1 and FGF21 expression was determined in human liver samples. Results HFD‐fed ASK1 $^{+hep}$ mice exhibited improved glucose metabolism, elevated energy expenditure, and reduced body weight. FGF21 plasma levels were increased in HFD‐fed ASK1 $^{+hep}$ mice, and its reduction in vivo blunted beneficial effects on obesity. Mechanistically, ASK1 promoted hepatic Fgf21 gene expression via the transcription factor ATF4. In humans, hepatic ASK1 expression correlated positively with FGF21 and negatively with BMI and visceral fat area. Conclusions We describe a novel role of hepatic ASK1 in the synthesis of FGF21. Hence, increasing hepatic ASK1 expression might be a novel strategy to combat obesity‐associated metabolic complications.