Selective Deletion of FGFR1 in AgRP Neurons Impairs Energy Homeostasis Under High-Fat Diet in Mice

Authors

Daniel Shookster
Shea O'Connell
Patel Darshan
Taylor Landry
Wyatt Bunner
Zhiying Jiang
Qingchun Tong
Hu Huang

Language

English

Publication Date

3-1-2026

Journal

Molecular Metabolism

DOI

10.1016/j.molmet.2026.102332

PMID

41679434

PMCID

PMC12936525

PubMedCentral® Posted Date

2-10-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Background: The global obesity crisis and the limited success of current treatments underscore the need to identify novel regulatory pathways. While central administration of α-Klotho exerts anti-obesity effects in rodents through AgRP neurons, the intracellular signaling mechanisms that mediate this process remain undefined.

Methods: To define the role of FGFR1 within the α-Klotho signaling pathway in AgRP neurons, we performed a targeted deletion of the receptor in adult mice using an AAV-mediated CRISPR/Cas9 system alongside transgenic models.

Results: Deletion of FGFR1 in AgRP neurons disrupted energy homeostasis, promoting weight gain induced by a high-fat diet. Electrophysiological recordings revealed that FGFR1 loss increased the intrinsic firing rate of AgRP neurons and abolished the suppressive effect of α-Klotho on their activity. At the molecular level, FGFR1 knockdown decreased phosphorylation of the transcription factor FOXO1 and elevated AgRP mRNA expression.

Conclusions: Our results define a crucial FGFR1 signaling axis in AgRP neurons that coordinately regulates their electrical activity and peptide expression, thereby establishing FGFR1 as an essential regulator of energy homeostasis.

Keywords

Animals, Receptor, Fibroblast Growth Factor, Type 1, Diet, High-Fat, Neurons, Mice, Agouti-Related Protein, Energy Metabolism, Homeostasis, Male, Mice, Inbred C57BL, Klotho Proteins, Signal Transduction, Forkhead Box Protein O1, Obesity, Mice, Transgenic, FGFR1, AgRP neuron, Energy homeostasis, High fat diet

Published Open-Access

yes

Recommended Citation

Shookster, Daniel; O'Connell, Shea; Darshan, Patel; et al., "Selective Deletion of FGFR1 in AgRP Neurons Impairs Energy Homeostasis Under High-Fat Diet in Mice" (2026). Faculty, Staff and Student Publications. 6598.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6598