Whole-brain Mapping Reveals Diet-dependent Neuronal Activation and Selective Resistance to Exogenous FGF21

Authors: MENG, JIEYI - Children'S Nutrition Research Center (CNRC); CHEN, XI - Children'S Nutrition Research Center (CNRC); ZHU, YI - Children'S Nutrition Research Center (CNRC)

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/9/2025
Publication Date: 11/25/2025
Citation: Meng, J., Chen, X., Zhu, Y. 2025. Whole-brain Mapping Reveals Diet-dependent Neuronal Activation and Selective Resistance to Exogenous FGF21. Endocrinology. 167(1). Article bqaf176. https://doi.org/10.1210/endocr/bqaf176.
DOI: https://doi.org/10.1210/endocr/bqaf176

Interpretive Summary: Obesity changes how the brain responds to FGF21, a hormone that helps control metabolism and energy balance. In obesity, FGF21 becomes less active in important parts of the hypothalamus that normally help keep metabolism stable. This reduced response may explain why FGF21-based treatments do not work as well in people with obesity. Understanding this problem may help scientists develop better treatments for metabolic diseases.

Technical Abstract: Fibroblast growth factor 21 (FGF21) is a liver-derived hormone that regulates metabolism across multiple tissues. It can cross the blood-brain barrier and activate its receptor FGFR1c, in conjunction with co-receptor ß-Klotho, modulating neuronal activity. Previous studies have mapped the brain-wide distribution of FGFR1c and ß-Klotho, suggesting potential FGF21 target regions. Notably, FGF21 has been shown to act on the hypothalamus to regulate feeding behavior and macronutrient preference, positioning it as a promising candidate for antiobesity therapies. In this study, we found that under a diet of normal chow, FGF21 primarily activated hypothalamic regions involved in metabolic control and suppressed activity in cortical areas related to cognition. Prolonged high-fat diet (HFD) treatment increased neuronal activity in regions involved in sensory processing, memory, and reward. In HFD-fed mice, FGF21 broadly activated additional regions linked to reproduction, thermoregulation, sensory function, and arousal. However, its ability to stimulate key metabolic nuclei, such as the periventricular hypothalamic nucleus, was impaired, suggesting the existence of selective central FGF21 resistance. These findings reveal that FGF21 modulates brain activity in a diet-dependent manner and that obesity alters its central effects.