1527-P: Anorexia Induced by the Central Action of Fibroblast Growth Factor 1 (FGF1) Is Dependent on Reduced GABA Receptor Activation

• Published in: Diabetes (New York, N.Y.) Vol. 72; no. Supplement_1; p. 1
• Main Authors: SCARLETT, JARRAD M., ALONGE, KIMBERLY M., PHAN, BAO ANH N., MORTON, GREGORY J., SCHWARTZ, MICHAEL W.
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 20-06-2023
• Subjects: Agonists; Animal models; Anorexia; c-Fos protein; Calcitonin; Calcitonin gene-related peptide; Diabetes mellitus (non-insulin dependent); Fibroblast growth factor 1; Hyperglycemia; Hypothalamus; Hypotheses; Injection; Neurons; Parabrachial nucleus; Receptor mechanisms; Remission; γ-Aminobutyric acid A receptors
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db23-1527-P

Previously, we reported that in multiple rodent models of type 2 diabetes, remission of hyperglycemia lasting for weeks can be induced by a single intracerebroventricular (icv) injection of FGF1. This effect is accompanied by a potent but transient anorexic response that is sufficiently robust as to hinder efforts to translate these findings towards the clinic. To understand the mechanism underlying FGF1-induced anorexia, we considered 1) our recent finding that icv FGF1 induces acute and sustained inhibition of hypothalamic AgRP neurons, and 2) prior work showing that parabrachial nucleus that express calcitonin gene-related peptide (PBNCGRP neurons) are both highly anorexigenic and tonically inhibited by GABAergic projections from AgRP neurons. We therefore hypothesized that FGF1-induced anorexia involves activation PBNCGRPneurons arising from reduced GABAergic input. Consistent with this hypothesis, we report that PBNCGRPneurons are robustly activated following icv FGF1 injection (based on c-Fos staining) via a mechanism that appears to be indirect, since the c-Fos induction is not associated with FGF receptor (FGFR) activation (detected by pERK staining in the PBN). We next asked whether the anorexic response to icv FGF1 administration can be blunted by systemic administration of a GABAA receptor agonist. Consistent with this hypothesis, we found that continuous subcutaneous infusion of the GABAA receptor agonist Bretazenil blunts the anorexic response to icv FGF1 injection by ~50% at a dose that has no effect intake in control mice. Similarly, the effect of FGF1 to induce c-Fos in the PBN was largely blocked by Bretazenil, and our preliminary findings indicate that CGRP neurons are among those in which this effect occurred. Together, these data suggest that FGF1-induced anorexia results from reduced GABAergic inhibition of PBNCGRP neurons.
Disclosure
J.M.Scarlett: None. K.M.Alonge: None. B.N.Phan: None. G.J.Morton: Research Support; Novo Nordisk A/S. M.W.Schwartz: Consultant; NodThera, Research Support; Novo Nordisk A/S.
Funding
U.S. Department of Defense (PRMRP W81XWH-21-1-0635); National Institutes of Health (DK083042)