Brain circuits for satiety and nausea
Authors: Huang Kuei-Pin , Mcknight Aaron , Acosta Alisha , Ghidewon Misgana , Alhadeff Amber 
Published: May 2023

Long-acting glucagon-like peptide 1 receptor (GLP1R) agonists are currently the most effective pharmacotherapies for weight loss, although adverse effects (e.g., nausea and vomiting) limit treatment efficacy. What brain circuits do these pharmacotherapies engage to reduce body weight? Our data demonstrate that acute chemogenetic activation of GLP1R neurons in the hindbrain dorsal vagal complex (DVC) suppressed food intake (p<0.001), and chronic activation of GLP1RDVC neurons attenuated weight gain in high-fat diet-fed mice (p<0.001). Here, we sought to determine whether there are separable subpopulations of hindbrain GLP1RDVC neurons that mediate satiety and adverse effects (i.e., nausea). To determine whether GLP1RDVC neurons cause nausea-like behavior, we tested if GLP1RDVC neuron activation conditions a taste avoidance or aversive orofacial taste reactivity responses. Activation of GLP1RDVC neurons both conditioned a robust taste avoidance (p<0.001) and aversive taste reactivity responses (p<0.001), which was strikingly correlated to activation of GLP1R neurons in the area of postrema (AP, R2=0.545), but not in the nucleus of solitary tract (NTS, R2=0.036), which are both subregions of the DVC. These data raised the possibility that there are discrete anatomical subpopulations of GLP1RDVC neurons within the DVC that have dissociable effects on behavior. Indeed, while activation of either GLP1RAP or GLP1RNTS neurons reduced food intake (p<0.001), only activation of GLP1RAP neurons induced a conditioned taste avoidance (p<0.001). To determine the downstream projection of GLP1RAP and GLP1RNTS neurons, we used two complementary approaches: (1) virally-expressed fluorophore tracing to label axonal projections, and (2) pseudorabies virus (PRV) to retrogradely label distinct populations of GLP1RDVC neurons. Results from both experiments demonstrated that the two subpopulations have parallel projections, where GLP1RAP neurons project to the lateral parabrachial nucleus (lPBN) and GLP1RNTS neurons project to the paraventricular hypothalamus (PVH). To test the functional relevance of these parallel GLP1RDVC projections, we optogenetically activated axonal terminals of GLP1RDVC neurons in either the lPBN or the PVH. Activation of the terminals in either lPBN or PVH suppressed food intake (p<0.01), but only activation of lPBN terminals induced avoidance (p<0.01). These data demonstrate that there are two anatomically- and functionally-discrete subpopulations of GLP1RDVC neurons, where GLP1RNTS->PVH neurons mediate satiety and GLP1RAP->lPBN neurons induce nausea. Moving forward, targeting obesity therapeutics to neuron populations that suppress food intake without nausea will increase treatment adherence and facilitate more effective long-term weight loss. American Heart Association 898990 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.