ASK1 overexpression protects from HFD-induced body weight gain via FGF21

People with obesity are at high risk to develop metabolic complications such as type 2 diabetes and metabolic dysfunction-associated fatty liver disease (MAFLD). We previously reported that the apoptosis signal-regulating kinase 1 (ASK1) regulates the development of MAFLD, since high fat diet (HFD)-fed mice with liver-specific ASK1 depletion and overexpression revealed increased and blunted development of MAFLD, respectively. Herein we identify a protective role of liver-expressed ASK1 in the context of diet-induced obesity. When fed a HFD for 20 weeks, liver-specific ASK1 overexpressing mice (ASK1 ^+hep ) were resistant to obesity and showed improved glucose metabolism as well as increased energy expenditure compared to control animals. Moreover, HFD-fed ASK1 ^+hep mice had higher BAT activity as well as increased browning of inguinal WAT, as suggested by increased UCP1 levels. The latter may be induced by the hepatokine fibroblast growth factor (FGF21), a hormone that is mainly produced in the liver and is known to reduce body weight via increasing energy expenditure. In line with an important role of FGF21, its plasma levels were significantly increased in HFD-fed ASK1 ^+hep mice and they negatively correlated with body weight. Mechanistically, we propose that the transcription factor ATF4 is activated via HFD-induced ASK1-p38 signaling in hepatocytes, subsequently promoting hepatic Fgf21 gene expression. Supporting this hypothesis, p38 inhibition resulted in a more pronounced reduction in Fgf21 expression in ASK1 ^+hep hepatocytes compared to controls, while silencing of ATF4 in primary hepatocytes significantly decreased Fgf21 transcript levels in ASK1 ^+hep hepatocytes but not in hepatocytes derived from control mice. In conclusion, we have uncovered a yet undescribed axis between hepatic ASK1 and FGF21 which positively affects body weight and glucose metabolism.