Dissociable hindbrain GLP1R circuits for satiety and aversion.

The most successful obesity therapeutics, glucagon-like peptide-1 receptor (GLP1R) agonists, cause aversive responses such as nausea and vomiting, effects that may contribute to their efficacy. Here, we investigated the brain circuits that link satiety to aversion, and unexpectedly discovered that the neural circuits mediating these effects are functionally separable. Systematic investigation across drug-accessible GLP1R populations revealed that only hindbrain neurons are required for the efficacy of GLP1-based obesity drugs.

Topical application of a P2X2/P2X3 purine receptor inhibitor suppresses the bitter taste of medicines and other taste qualities.

Background And Purpose: Many medications taste intensely bitter. The innate aversion to bitterness affects medical compliance, especially in children. There is a clear need to develop bitter blockers to suppress the bitterness of vital medications.

Hindbrain ghrelin and liver-expressed antimicrobial peptide 2, ligands for growth hormone secretagogue receptor, bidirectionally control food intake.

Hindbrain growth hormone secretagogue receptor (GHSR) agonism increases food intake, yet the underlying neural mechanisms remain unclear. The functional effects of hindbrain GHSR antagonism by its endogenous antagonist liver-expressed antimicrobial peptide 2 (LEAP2) are also yet unexplored. To test the hypothesis that hindbrain GHSR agonism attenuates the food intake inhibitory effect of gastrointestinal (GI) satiation signals, ghrelin (at a feeding subthreshold dose) was administered to the fourth ventricle (4V) or directly to the nucleus tractus solitarius (NTS) before systemic delivery of the GI satiation signal cholecystokinin (CCK).

Hypophagia induced by salmon calcitonin, but not by amylin, is partially driven by malaise and is mediated by CGRP neurons.

Objective: The behavioral mechanisms and the neuronal pathways mediated by amylin and its long-acting analog sCT (salmon calcitonin) are not fully understood and it is unclear to what extent sCT and amylin engage overlapping or distinct neuronal subpopulations to reduce food intake. We here hypothesize that amylin and sCT recruit different neuronal population to mediate their anorectic effects.

Methods: Viral approaches were used to inhibit calcitonin gene-related peptide (CGRP) lateral parabrachial nucleus (LPBN) neurons and assess their role in amylin's and sCT's ability to decrease food intake in mice.

GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist-Induced Nausea and Emesis in Preclinical Models.

Glucagon-like peptide 1 receptor (GLP-1R) agonists decrease body weight and improve glycemic control in obesity and diabetes. Patient compliance and maximal efficacy of GLP-1 therapeutics are limited by adverse side effects, including nausea and emesis. In three different species (i.

GDF15 Induces an Aversive Visceral Malaise State that Drives Anorexia and Weight Loss.

The anorectic and weight-suppressive effects of growth differentiation factor-15 (GDF15) are attracting considerable attention for treating obesity. Current experiments in rats investigate whether GDF15 induces an aversive visceral malaise-based state that mediates its acute anorectic effect and, through aversion conditioning, exerts longer-term anorexia. Visceral malaise, conditioned affective food responses (taste reactivity), gastric emptying (GE), food intake, and body weight are evaluated after acute and chronic systemic dosing of GDF15 or long-acting Fc-GDF15.

GDF15 Induces Anorexia through Nausea and Emesis.

Growth differentiation factor 15 (GDF15) is a cytokine that reduces food intake through activation of hindbrain GFRAL-RET receptors and has become a keen target of interest for anti-obesity therapies. Elevated endogenous GDF15 is associated with energy balance disturbances, cancer progression, chemotherapy-induced anorexia, and morning sickness. We hypothesized that GDF15 causes emesis and that its anorectic effects are related to this function.