The Central GIPR Signalling Axis: New Insights, New Questions
Dr Alice Adriaenssens (University College London)
C42 Biomedical Sciences Building
A Snapshot seminar hosted by the School of Physiology, Pharmacology and Neuroscience
Abstract: Intact glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) signalling in the CNS is critical for the ability of GIP-based therapeutics to lower body weight. Though progress has been made in determining the localisation and molecular identity of Gipr neurons in both mouse and humans, the pathways leveraged by GIPR pharmacology in the brain remain incompletely understood. Previously, we have explored the role of Gipr neurons in the hypothalamus and dorsal vagal complex (DVC)—brain regions critical to the control of energy balance—in the regulation of feeding. While chemogenetic stimulation of both hypothalamic and DVC Gipr neurons suppressed food intake, hypothalamic and brainstem Gipr neuronal populations oppositely regulated energy expenditure, activity, and avoidance, indicating that divergent neurocircuitry is leveraged by Gipr neurons depending on their neuroanatomical location. 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. Similarly, our current analyses comparing hypothalamic subpopulations demonstrated that Gipr neurons within the paraventricular and the mediobasal hypothalamus (PVH, and cMBH, respectively) exhibit distinct projection patterns and recruit different brain centres following chemogenetic activation. Chemogenetic targeting of PVH or cMBH Gipr populations also resulted in distinct meal pattern profiles. Collectively these data demonstrate that subpopulations of Gipr neurons differ in their connectivity, transcriptomic profile, and appetite-controlling mechanisms, highlighting the heterogeneity Gipr neurocircuits in key feeding centres of the brain. A key challenge for future work will be to understand which Gipr neurocircuits are engaged by peripherally administered pharmacology, and how these circuits influence the efficacy of GIP based therapeutics to control energy balance.