Biology subjects

Goergen, A.

Publications and source records attributed to Goergen, A..

2 recordsLinked to original sources

bioRxiv2025

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.

physiology↗

bioRxiv2025

High fat high sucrose exposure during lactation but not during the post-weaning period programs impaired glucose homeostasis

Nutrition during critical developmental windows plays a pivotal role in shaping long-term metabolic health. Exposure to a Western diet in early life may lead to altered metabolic programing, potentially influencing the risk to develop obesity and type 2 diabetes. In particular, an early exposure to an obesogenic diet may induce a metabolic program that only emerges upon dietary challenges later in life. Accordingly, understanding the long-term impact of nutritional insults in different stages of early life may provide strategies for primary prevention. Therefore, the present study aimed to determine which time window in the post-natal period is most critical for long-term metabolic health. To this end, pups born to lean mouse dams were exposed to a high-fat, high-sucrose (HFHS) diet for 3 weeks during lactation or in the post-weaning period. Thereafter, mice were either fed a regular chow diet until the age of 30 weeks or exposed to a second bout of HFHS diet for the last 12 weeks. Metabolic health and development of obesity was assessed by regular monitoring of glucose homeostasis and body weight gain. 12 week-old mice with lactational exposure to a HFHS diet revealed a significantly impaired glucose tolerance compared to control mice, while glucose tolerance of post -weaning exposed mice was similar to the control group. Moreover, a second bout of HFHS diet impaired glucose tolerance and increased body and adipose tissue weight in mice with lactational exposure to a significant greater extent than in post-weaning exposed mice. Hence, exposure to HFHS during lactation but not during the post-weaning period programs impaired glucose homeostasis, suggesting that the lactational window may be more critical in terms of metabolic programing.

physiology↗