Central GHSR inverse agonism by a LEAP2 analog regulates thermometabolic and behavioral responses via catecholamine signaling.

Authors

Isac Cardoso Dos Santos, Hanniely Thais Menezes Dos Santos, Juliana Vila Verde Ribeiro, João Pedro Maciel Machado Leite, Aline Rezende Ribeiro de Abreu, Michelle Mendanha Mendonça, Elder Sales da Silva, Eduardo Colombari, Gustavo Rodrigues Pedrino, Rodrigo Mello Gomes, James Fajemiroye, Paulo Marcelo Andrade Lima, Mario Perelló, Stefanne Madalena Marques, Carlos Henrique Xavier

Published in

Physiology & behavior. Pages 115521. Oct 06, 2026. Epub Oct 06, 2026.

Abstract

Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous GHSR inverse agonist that antagonizes ghrelin-mediated signaling, thereby opposing several of the physiological actions elicited by ghrelin. Evidence indicates that GHSR participates in autonomic, cardiovascular, renal, and psychogenic regulation, interacts with dopaminergic signaling and interplays with adrenergic pathways during sympathetically driven hypertension. Here, we investigated whether catecholaminergic mechanisms mediate behavioral and thermometabolic effects evoked from central GHSR inverse agonism by a LEAP2 analog.
Adult male Wistar rats were systemically pretreated with either the tyrosine hydroxylase inhibitor α-methyl-para-tyrosine (AMPT; 200 mg/kg) or the non-selective dopamine receptor antagonist chlorpromazine (CLP; 2 mg/kg) and then centrally pretreated with LEAP2[1-14] (6 nmol) or vehicle. Rats were evaluated across a range of paradigms, including anxiety- and panic-like behaviors, open-field exploration, ingestive activity, treadmill performance with VO₂ recorders and infrared thermography of caudal heat dissipation.
Central LEAP2 analog impaired the expression of anxiety- and panic-like responses and attenuated heat-conservation mechanisms triggered by aversion. Behavioral and food ingestive effects were largely dependent on dopaminergic receptor signaling, whereas thermoregulatory responses during exercise required the entire catecholaminergic pathways inhibited by AMPT.
LEAP2 analog regulates specific behavioral and thermometabolic responses through neurobiological mechanisms involving catecholaminergic pathways and dopamine receptors, highlighting central GHSR as a potential pharmacological target for neuroendocrine defense mechanisms.

PMID:
42838183
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.

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