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

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 β-Klotho, modulating neuronal activity. Previous studies have mapped the brain-wide distribution of FGFR1c and β-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.