FGF21 reverses MASH through coordinated actions on the CNS and liver – ScienceDirect

When I combine these findings with the work of Prof. Brüning and his colleagues on the central regulation of the hypothalamus–liver axis (https://lnkd.in/embCm_9x), it gives the impression that FGF1 functions as a postprandial regulator of this axis. It appears to be secreted by the liver in response to nutrient absorption—possibly triggered by short- and medium-chain fatty acids, which are absorbed directly into the portal vein—and signals to glutamatergic neurons in the CNS to suppress hepatic de novo lipogenesis, which may be active during fasting, and to increase energy expenditure.

It seems that the pre-absorptive (conditional) rapid phase of hypothalamus–liver axis activation is more focused on hepatic glucose metabolism, whereas FGF21 may play a critical role in regulating lipid and cholesterol metabolism during the absorptive and post-absorptive phases.

Jesse P. Rose, Donald A. Morgan, Andrew I. Sullivan, Xiaorong Fu, Melissa Inigo-Vollmer, Shawn C. Burgess, David K. Meyerholz, Kamal Rahmouni, Matthew J. Potthoff,
FGF21 reverses MASH through coordinated actions on the CNS and liver,
Cell Metabolism,
2025,
,
ISSN 1550-4131,
https://doi.org/10.1016/j.cmet.2025.04.014.
(https://www.sciencedirect.com/science/article/pii/S1550413125002529)
Abstract: Summary
Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a growing public health burden with limited therapeutic options. Recent studies have revealed that fibroblast growth factor 21 (FGF21)-based analogs can significantly improve MASH, but the mechanisms for this effect are not well understood. Here, we demonstrate that the beneficial metabolic effects of FGF21 to reverse MASH are mediated through distinct mechanisms to independently lower hepatic triglyceride and cholesterol levels. Specifically, FGF21 signaling directly to glutamatergic neurons in the central nervous system (CNS) stimulates hepatic triglyceride reduction and reversal of fibrosis, whereas FGF21 signaling directly to hepatocytes is necessary and sufficient to reduce hepatic cholesterol levels in mice. Mechanistically, we show that FGF21 acts in the CNS to increase sympathetic nerve activity to the liver, which suppresses hepatic de novo lipogenesis. These results provide critical insights into a promising pharmacological target to treat MASH.