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The TGFβ cytokine family member, GDF-15, reduces food intake and body weight and represents a potential treatment for obesity. Because the brainstem-restricted expression pattern of its receptor, GDNF Family Receptor α–like (GFRAL), presents an exciting opportunity to understand mechanisms of action for area postrema neurons in food intake; we generated GfralCre and conditional GfralCreERT mice to visualize and manipulate GFRAL neurons. We found infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons. TRAP-Seq analysis of GFRAL neurons revealed their expression of a wide range of neurotransmitters and neuropeptides. Artificially activating GfralCre-expressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). GFRAL neurons most strongly innervate the parabrachial nucleus (PBN), where they target CGRP-expressing (CGRPPBN) neurons. Silencing CGRPPBN neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non–meal-associated pathophysiologic signals to suppress nutrient uptake and absorption.

The brainstem dorsal vagal complex (DVC) is known to regulate energy balance and is the target of appetite-suppressing hormones, such as glucagon-like peptide 1 (GLP-1). Here we provide a comprehensive genetic map of the DVC and identify neuronal populations that control feeding. Combining bulk and single-nucleus gene expression and chromatin profiling of DVC cells, we reveal 25 neuronal populations with unique transcriptional and chromatin accessibility landscapes and peptide receptor expression profiles. GLP-1 receptor (GLP-1R) agonist administration induces gene expression alterations specific to two distinct sets of Glp1r neurons—one population in the area postrema and one in the nucleus of the solitary tract that also expresses calcitonin receptor ( Calcr ). Transcripts and regions of accessible chromatin near obesity-associated genetic variants are enriched in the area postrema and the nucleus of the solitary tract neurons that express Glp1r and/or Calcr , and activating several of these neuronal populations decreases feeding in rodents. Thus, DVC neuronal populations associated with obesity predisposition suppress feeding and may represent therapeutic targets for obesity. Ludwig et al. map transcription and chromatin accessibility in single cells across the brainstem dorsal vagal complex, thereby identifying neuronal populations, including some that control feeding.

Signals from the gut act in the dorsal vagal complex (DVC) to slow the flow of food from the stomach into the intestine, promote meal termination, and mediate aversive responses to gastrointestinal malaise. The DVC consists of the area postrema (AP), which lies outside of the blood-brain barrier, the adjacent nucleus tractus solitarius (NTS), and the dorsal motor nucleus of the vagus (DMV). While AP neurons are postulated to play crucial roles in appetite suppression and aversive responses (e.g., nausea) by anti-obesity peptides, individual populations of AP neurons remain relatively unstudied due to the difficulty of stereotaxically targeting them in mice. Because calcitonin receptor (Calcr)-expressing AP neurons specifically may be targets for anti-obesity treatments, but mice respond poorly to these compounds, we generated and validated a CalcrCre rat model to target AP Calcr neurons and understand their circuitry and function. Intra-AP injection of viruses to Cre-dependently express synaptic tracers in these animals revealed major projections to the NTS and DMV. AP Calcr neurons also sent sparse projections to the lateral parabrachial nucleus (lPBN). We injected a Cre-dependent AAV virus into the AP to express activating (hM3Dq) Designer Receptor Exclusively Activated by Designer Drugs (DREADD) in CalcrCre rats (CalcrAP-hM3Dq-mCherry rats) to permit the activation of AP Calcr neurons in response to CNO. CNO-dependent activation of AP Calcr neurons in these rats delayed gastric emptying and decreased food intake over 24 hours but did not provoke a conditioned taste avoidance (CTA) response. Interestingly, prolonged (multi-day) CNO-dependent activation of AP Calcr neurons in CalcrAP-hM3Dq-mCherry rats did not promote the prolonged suppression of food intake and failed to reduce body weight. Hence, non-aversive AP Calcr neurons delay gastric emptying and inhibit food intake over the short term but do not mediate the long-term suppression of food intake and body weight, suggesting that they may not represent useful targets for treating obesity.

Body weight and adiposity represent biologically controlled parameters that are influenced by a combination of genetic, developmental and environmental variables. Although the hypothalamus plays a crucial role in matching caloric intake with energy expenditure to achieve a stable body weight, it is now recognized that neuronal circuits in the hindbrain not only serve to produce nausea and to terminate feeding in response to food consumption or during pathological states, but also contribute to the long-term control of body weight. Additionally, recent work has identified hindbrain neurons that are capable of suppressing food intake without producing aversive responses like those associated with nausea. Here we review recent advances in our understanding of the hindbrain neurons that control feeding, particularly those located in the area postrema and the nucleus tractus solitarius. We frame this information in the context of new atlases of hindbrain neuronal populations and develop a model of the hindbrain circuits that control food intake and energy balance, suggesting important areas for additional research. The hindbrain is mostly known to participate in eating behaviour by controlling short-term meal parameters and aversive responses to gut malaise. Cheng et al. review current evidence revealing non-aversive neuronal circuits in the hindbrain that are relevant for initiation and termination of homeostatic feeding, as well as for the long-term control of body weight.

Growth and differentiation factor 15 (GDF15), an anorexigenic peptide that represents a promising candidate for anti-obesity treatment, acts via GDNF Family Receptor Alpha Like (GFRAL), which is expressed almost exclusively on a subset of neurons in the area postrema (AP). To determine the function and mechanisms of action for GFRAL neurons, we generated Gfralcre and conditional GfralCreERT mice. Although their chemogenetic (DREADD-mediated) activation promoted FOS in a variety of brainstem, hypothalamic, and limbic nuclei, GFRAL neurons projected only to the nucleus of the solitary tract (NTS) and the parabrachial nucleus (PBN), where they innervated and activated aversive/anorexigenic GCRP-expressing cells. Tetanus-toxin-mediated silencing of PBN CGRP neurons abrogated the aversive and anorexic effects of GDF15. Furthermore, while non-gastrointestinal (GI) stimuli (e.g., GDF15 and LPS, but not feeding or gut peptide mimetics) activated GFRAL neurons, chemogenetically activating these cells decreased gastric emptying, suppressed feeding, and promoted a conditioned taste aversion. These findings suggest that GFRAL neurons link non-GI anorexigenic signals to the control of gut physiology and to the aversive suppression of food intake. Additionally, because the chemogenetic activation of GFRAL neurons suppressed food intake more strongly than GDF15 in lean mice, additional modes of activating GFRAL neurons may augment the anorectic potential of GDF15.

Amylin analogs, including potential anti-obesity therapies like cagrilintide, act on neurons in the brainstem dorsal vagal complex (DVC) that express calcitonin receptors (CALCR). These receptors, often combined with receptor activity-modifying proteins (RAMPs), mediate the suppression of food intake and body weight. To understand the molecular and neural mechanisms of cagrilintide action, we used single-nucleus RNA sequencing to define 89 cell populations across the rat, mouse, and non-human primate caudal brainstem. We then integrated spatial profiling to reveal neuron distribution in the rat DVC. Furthermore, we compared the acute and long-term transcriptional responses to cagrilintide across DVC neurons of rats, which exhibit strong cagrilintide responsiveness, and mice, which respond poorly to cagrilintide over the long term. We found that cagrilintide promoted long-term transcriptional changes, including increased prolactin releasing hormone ( expression, in the nucleus of the solitary tract (NTS) cells in rats, but not in mice, suggesting the importance of NTS cells for sustained weight loss. Indeed, activating rat area postrema cells briefly reduced food intake but failed to decrease food intake or body weight over the long term. Overall, these results not only provide a cross-species and spatial atlas of DVC cell populations but also define the molecular and neural mediators of acute and long-term cagrilintide action.

Amylin analogs, including potential anti-obesity therapies like cagrilintide, act on neurons in the brainstem dorsal vagal complex (DVC) that express calcitonin receptors (CALCR). These receptors, often combined with receptor activity-modifying proteins (RAMPs), mediate the suppression of food intake and body weight. To understand the molecular and neural mechanisms of cagrilintide action, we used single-nucleus RNA sequencing to define 89 cell populations across the rat, mouse, and non-human primate caudal brainstem. We then integrated spatial profiling to reveal neuron distribution in the rat DVC. Furthermore, we compared the acute and long-term transcriptional responses to cagrilintide across DVC neurons of rats, which exhibit strong cagrilintide responsiveness, and mice, which respond poorly to cagrilintide over the long term. We found that cagrilintide promoted long-term transcriptional changes, including increased prolactin releasing hormone (Prlh) expression, in the nucleus of the solitary tract (NTS) Calcr/Prlh cells in rats, but not in mice, suggesting the importance of NTS Calcr/Prlh cells for sustained weight loss. Indeed, activating rat area postrema Calcr cells briefly reduced food intake but failed to decrease food intake or body weight over the long term. Overall, these results not only provide a cross-species and spatial atlas of DVC cell populations but also define the molecular and neural mediators of acute and long-term cagrilintide action.Competing Interest StatementM.G.M receives research support from AstraZeneca, Eli Lilly, and Novo Nordisk, has served as a paid consultant for Merck, and has received speaking honoraria from Novo Nordisk. T.H.P., T.A.L., P.K., and M.G.M. have received research support from Novo Nordisk and T.H.P holds stocks in the company. M.Q.L, D.M.R., S.L., M.K.G., A.S., K.R. are employees at Novo Nordisk. All other authors have no competing interests to declare.Footnotes* https://github.com/perslab/ludwig-coester-Gordian-2025* https://cbmr-rmpp.shinyapps.io/spatial_dvc_app/

To determine the function and mechanisms of action for hindbrain neurons that express GFRAL, the receptor for the anorexigenic peptide, GDF-15, we generated GfralCre and conditional GfralCreERT mice. While signals of infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons, the artificial activation of GfralCre-expressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). Additionally, activation of the smaller population of GFRAL neurons captured by the GfralCreERT allele decreased gastric emptying and produced a CTA without suppressing food intake, suggesting that GFRAL neurons primarily modulate gastric physiology and stimulate aversive responses. GFRAL neurons most strongly innervated the parabrachial nucleus (PBN), where they targeted CGRP-expressing (CGRPPBN) neurons. Silencing CGRPPBN neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non-meal-associated, pathophysiologic signals to the aversive suppression of nutrient uptake and absorption. Competing Interest Statement SBJ is an employee of Novo Nordisk. DPO, MGM, and RJS receive research support from Novo Nordisk. RJS and MGM receive research support from AstraZeneca. RJS receives research support from Pfizer, Kintai and Ionis. RJS also serves as a paid consultant for Novo Nordisk, Kintai, Ionis and Scohia. RJS has equity positions in Zafgen and ReDesign Health.