# Selective deletion of FGFR1 in AgRP neurons impairs energy homeostasis under high-fat diet in mice

## TL;DR

Deleting FGFR1 in specific brain neurons worsens weight gain on a high-fat diet and disrupts energy balance in mice.

## Contribution

This study identifies FGFR1 in AgRP neurons as a key regulator of energy homeostasis and α-Klotho signaling.

## Key findings

- FGFR1 deletion in AgRP neurons leads to high-fat diet-induced weight gain.
- Loss of FGFR1 increases AgRP neuron firing and blocks α-Klotho's suppressive effect.
- FGFR1 knockdown reduces FOXO1 phosphorylation and elevates AgRP expression.

## Abstract

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.

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.

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.

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.

Proposed mechanisms by which FGFR1 regulates AgRP neuron activity and FOXO1 phosphorylation in the hypothalamic cell line.Image 1

•Deleting FGFR1 in adult mouse AgRP neurons via AAV CRISPR-Cas9 reveals its critical role in energy balance.•AgRP neuron FGFR1 deletion disrupts energy balance, causing high-fat diet-induced weight gain.•FGFR1 is essential for AgRP neuron excitability; its loss increases firing and blocks α-Klotho suppression.•FGFR1 loss reduces FOXO1 phosphorylation and elevates AgRP expression.•FGFR1 signaling coordinates AgRP neuron firing and gene expression to control body weight.

Deleting FGFR1 in adult mouse AgRP neurons via AAV CRISPR-Cas9 reveals its critical role in energy balance.

AgRP neuron FGFR1 deletion disrupts energy balance, causing high-fat diet-induced weight gain.

FGFR1 is essential for AgRP neuron excitability; its loss increases firing and blocks α-Klotho suppression.

FGFR1 loss reduces FOXO1 phosphorylation and elevates AgRP expression.

FGFR1 signaling coordinates AgRP neuron firing and gene expression to control body weight.