FGF21 signals through hindbrain neurons to alter food intake and energy expenditure during dietary protein restriction

The metabolic hormone fibroblast growth factor 21 (FGF21) is essential for adaptive responses to dietary protein restriction, but the precise neural circuit mediating these effects remains undefined. Here, we demonstrate that a discrete population of glutamatergic, Klb-expressing neurons in the nucleus of the solitary tract (NTS) mediates FGF21 action during protein restriction. Using a Klb-Flp mouse line combined with intersectional genetics, we show that NTS-beta-klotho (KLB) neurons are directly activated by FGF21. Systematic evaluation of previously implicated regions (suprachiasmatic nucleus SCN, paraventricular nucleus PVN, and ventromedial hypothalamus VMH) reveals these areas are not required for FGF21-mediated responses to protein restriction. In contrast, selective ablation of NTS-KLB neurons prevents metabolic adaptations to protein restriction, including changes in food intake, food choice, and energy expenditure, while their chemogenetic activation is sufficient to drive these responses. These findings establish that NTS-KLB neurons directly respond to FGF21 and coordinate adaptive changes during protein restriction, identifying the neural circuit linking dietary protein sensing to metabolic adaptation.