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

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.