2026/03/31 by Redin A. Spann, Sora Q. Kim, Md Shahjalal Hossain Khan +8 · 1 voice
Biochemistry, Genetics and Molecular Biology · Neuroscience · #Fibroblast Growth Factor Research #Regulation of Appetite and Obesity #Genetics, Aging, and Longevity in Model Organisms
paper · doi:10.1016/j.celrep.2026.117218
openalex publication_date 2026/03/31 · openalex created_date 2026/04/01 · openalex updated_date 2026/08/01
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.