Hypothalamic and brainstem glucose-dependent insulinotropic polypeptide receptor neurons employ distinct mechanisms to affect feeding.

Central glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) signaling is critical in GIP-based therapeutics' ability to lower body weight, but pathways leveraged by GIPR pharmacology in the brain remain incompletely understood. We explored the role of Gipr neurons in the hypothalamus and dorsal vagal complex (DVC) - brain regions critical to the control of energy balance. Hypothalamic Gipr expression was not necessary for the synergistic effect of GIPR/GLP-1R coagonism on body weight. While chemogenetic stimulation of both hypothalamic and DVC Gipr neurons suppressed food intake, activation of DVC Gipr neurons reduced ambulatory activity and induced conditioned taste avoidance, while there was no effect of a short-acting GIPR agonist (GIPRA). Within the DVC, Gipr neurons of the nucleus tractus solitarius (NTS), but not the area postrema (AP), projected to distal brain regions and were transcriptomically distinct. Peripherally dosed fluorescent GIPRAs revealed that access was restricted to circumventricular organs in the CNS. These data demonstrate that Gipr neurons in the hypothalamus, AP, and NTS differ in their connectivity, transcriptomic profile, peripheral accessibility, and appetite-controlling mechanisms. These results highlight the heterogeneity of the central GIPR signaling axis and suggest that studies into the effects of GIP pharmacology on feeding behavior should consider the interplay of multiple regulatory pathways.

Characterisation and antidiabetic utility of a novel hybrid peptide, exendin-4/gastrin/xenin-8-Gln.

Enteroendocrine derived hormones such as glucagon-like-peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), gastrin and xenin are known to exert complementary beneficial metabolic effects in diabetes. This study has assessed the biological activity and therapeutic utility of a novel GLP-1/gastrin/xenin hybrid peptide, namely exendin-4/gastrin/xenin-8-Gln hybrid, both alone and in combination with the stable GIP mimetic, (DAla2)GIP. Exendin-4/gastrin/xenin-8-Gln increased in vitro insulin secretion to a similar or superior extent, as the parent peptides. Insulinotropic effects were mainly linked to modulation of GLP-1 and neurotensin receptors. Exendin-4/gastrin/xenin-8-Gln also augmented the insulinotropic actions of (DAla2)GIP. Acute administration of exendin-4/gastrin/xenin-8-Gln in mice induced significant appetite suppressive, glucose lowering and insulin secretory effects, with a duration of biological action beyond 8 h. Twice daily administration of exendin-4, exendin-4/gastrin/xenin-8-Gln, either alone or in combination with (DAla2)GIP, reduced circulating glucose, increased plasma insulin as well as improving glucose tolerance, insulin sensitivity and metabolic response to GIP in high fat fed mice. Body weight, food intake, circulating glucagon and amylase activity were unaltered. All hybrid peptide treated high fat mice exhibited marked reductions in LDL-cholesterol and body fat mass. Energy expenditure and locomotor activity were increased in mice treated with exendin-4/gastrin/xenin-8-Gln in combination with (DAla2)GIP. Interestingly, exendin-4 and exendin-4/gastrin/xenin-8-Gln treatment, but not exendin-4/gastrin/xenin-8-Gln in combination with (DAla2)GIP, reduced pancreatic islet and beta-cell area when compared to high fat controls. These studies confirm that unimolecular multi-agonist peptide hormones exert beneficial metabolic effects in diabetes, highlighting their potential as novel treatment strategies.