# Divergent Mechanisms Underlying Anorexic and Antidiabetic Actions of FGF1 in the Brain

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2022 · $603,559

## Abstract

PROJECT SUMMARY
With support from this program, we reported in 2016 that across multiple rodent models of type 2 diabetes
(T2D), remission of hyperglycemia lasting for weeks or months can be achieved with a single
intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1). In the years since, our investigation
into mechanisms underlying this effect has consistently shown that in addition to sustained glucose lowering,
FGF1 also induces a potent but transient anorexic response. In a primate model, this effect is sufficiently
intense as to suspend ongoing efforts to translate FGF1-based diabetes therapy to the clinic.
 Studies in this proposal will clarify mechanisms underlying both the anorexic response and sustained
glucose lowering induced by the central action of FGF1, with a focus on neurons in the hypothalamic arcuate
nucleus (ARC) that express agouti-related peptide (AgRP neurons). Inhibition of these neurons by FGF1 is
implicated in both the feeding and glucose-lowering effects of FGF1, although distinct projections and signaling
molecules appear to mediate these divergent effects. Thus, whereas diabetes remission induced by icv FGF1
injection is blocked by Mc4r deletion or blockade, these interventions have no impact on FGF1-induced
anorexia. Instead, we hypothesize that the anorexic response involves activation of neurons in the parabrachial
nucleus that express calcitonin gene-related peptide (PBNCGRP neurons) via a melanocortin-independent
mechanism. These neurons are 1) highly anorexigenic, 2) tonically inhibited by GABAergic projections from
AgRP neurons, and 3) robustly activated following icv FGF1 injection. SA1 investigates the hypothesis that
FGF1-induced anorexia results from PBNCGRP neuron activation secondary to reduced GABAergic input
from AgRP neurons. We will also determine if FGF1-induced PBNCGRP neuron activation can be blocked
by pharmacological intervention with a GABA receptor agonist, while having no effect on the
associated remission of hyperglycemia.
 A second goal of this proposal is to delineate the mechanism(s) underlying prolonged inhibition of AgRP
neurons by FGF1. Perineuronal nets (PNNs) are extracellular matrix specializations that enmesh most AgRP
neurons, and loss of these PNNs is hypothesized to contribute to diabetes-associated AgRP neuron activation.
Since these PNNs are rapidly reformed following icv FGF1 injection, SA 2 tests the hypothesis that
sustained inhibition of AgRP neurons by FGF1 requires reassembly of the PNNs that enmesh them.
1

## Key facts

- **NIH application ID:** 10518971
- **Project number:** 2R01DK083042-26
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Michael W Schwartz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $603,559
- **Award type:** 2
- **Project period:** 1994-09-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10518971

## Citation

> US National Institutes of Health, RePORTER application 10518971, Divergent Mechanisms Underlying Anorexic and Antidiabetic Actions of FGF1 in the Brain (2R01DK083042-26). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10518971. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*