Central FGF19 reduces hypothalamic inflammation and improves leptin signaling in obese mice

Obesity is a chronic metabolic disorder characterized by systemic and hypothalamic inflammation that impairs neuronal signaling and disrupts the fine-tuning of energy balance regulation. Leptin resistance, a hallmark of obesity, arises from this inflammatory state and contributes to increased food intake and reduced energy expenditure (EE). Fibroblast growth factor 19 (FGF19), a gut-derived hormone with beneficial metabolic effects in peripheral tissues, also acts centrally to reduce body weight. However, the mechanisms underlying its hypothalamic action remain unclear. In this study, we investigated whether central administration of FGF19 attenuates hypothalamic inflammation and restores leptin signaling in diet-induced obese (DIO) mice, thereby improving energy homeostasis. DIO mice received FGF19 via intracerebroventricular delivery using a cerebral infusion kit connected to an osmotic pump for 10 days. FGF19 treatment increased EE and reduced food intake in DIO mice, resulting in improved energy balance without changes in locomotor activity. These effects were accompanied by a marked reduction in hypothalamic inflammatory markers and glial activation, including reactive astrocytes. Notably, FGF19 restored hypothalamic leptin-induced Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) phosphorylation and normalized expression of anorexigenic neuropeptides. Our findings position FGF19 as a central regulator of leptin sensitivity and hypothalamic inflammation, highlighting its therapeutic potential for obesity through modulation of appetite and EE.