Wadden, T. A. et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: The STEP 3 Randomized Clinical Trial. JAMA 325, 1403–1413 (2021).
Wilding, J. P. H. et al. Once-weekly semaglutide in adults with overweight or obesity. N. Engl. J. Med. 384, 989–1002 (2021).
World Obesity Federation. World Obesity Atlas 2023 (World Obesity Federation, 2023).
Jastreboff, A. M. et al. Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N. Engl. J. Med. 389, 514–526 (2023).
Jastreboff, A. M. et al. Tirzepatide once Wweekly for the treatment of obesity. N. Engl. J. Med. 387, 205–216 (2022).
Muller, T. D. et al. Glucagon-like peptide 1 (GLP-1). Mol. Metab. 30, 72–130 (2019).
Hayes, M. R., De Jonghe, B. C. & Kanoski, S. E. Role of the glucagon-like-peptide-1 receptor in the control of energy balance. Physiol. Behav. 100, 503–510 (2010).
Krieger, J.-P. et al. Knockdown of GLP-1 receptors in vagal afferents affects normal food iIntake and glycemia. Diabetes 65, 34–43 (2016).
Kanoski, S. E., Fortin, S. M., Arnold, M., Grill, H. J. & Hayes, M. R. Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, liraglutide and exendin-4. Endocrinology 152, 3103–3112 (2011).
Gabery, S. et al. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight 5, https://doi.org/10.1172/jci.insight.133429 (2020).
Jensen, C. B. et al. Characterization of the glucagonlike peptide-1 receptor in male mouse brain using a novel antibody and in situ hybridization. Endocrinology 159, 665–675 (2018).
Merchenthaler, I., Lane, M. & Shughrue, P. Distribution of pre-pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system. J. Comp. Neurol. 403, 261–280 (1999).
Zhang, C. et al. Area postrema cell types that mediate nausea-associated behaviors. Neuron 109, 461–472 (2021).
Xie, Z. et al. The gut-to-brain axis for toxin-induced defensive responses. Cell 185, 4298–4316 (2022).
Grill, H. J. & Hayes, M. R. Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance. Cell Metab. 16, 296–309 (2012).
Ludwig, M. Q. et al. A genetic map of the mouse dorsal vagal complex and its role in obesity. Nat. Metab. 3, 530–545 (2021).
Adriaenssens, A. et al. Hypothalamic and brainstem glucose-dependent insulinotropic polypeptide receptor neurons employ distinct mechanisms to affect feeding. 8, https://doi.org/10.1172/jci.insight.164921 (2023).
Lindberg, J. S. et al. Cinacalcet HCl, an oral calcimimetic agent for the treatment of secondary hyperparathyroidism in hemodialysis and peritoneal dialysis: a randomized, double-blind, multicenter study. J. Am. Soc. Nephrol. 16, 800–807 (2005).
Harrington, P. E. & Fotsch, C. Calcium sensing receptor activators: calcimimetics. Curr. Med. Chem. 14, 3027–3034 (2007).
Kanoski, S. E., Rupprecht, L. E., Fortin, S. M., De Jonghe, B. C. & Hayes, M. R. The role of nausea in food intake and body weight suppression by peripheral GLP-1 receptor agonists, exendin-4 and liraglutide. Neuropharmacology 62, 1916–1927 (2012).
Pelchat, M. L., Grill, H. J., Rozin, P. & Jacobs, J. Quality of acquired responses to tastes by Rattus norvegicus depends on type of associated discomfort. J. Comp. Psychol. 97, 140–153 (1983).
Grill, H. J. & Norgren, R. The taste reactivity test. I. Mimetic responses to gustatory stimuli in neurologically normal rats. Brain Res. 143, 263–279 (1978).
Watakabe, A. et al. Comparative analyses of adeno-associated viral vector serotypes 1, 2, 5, 8 and 9 in marmoset, mouse and macaque cerebral cortex. Neurosci. Res. 93, 144–157 (2015).
Wilson-Pérez, H. E. et al. Vertical sleeve gastrectomy is effective in two genetic mouse models of glucagon-like Peptide 1 receptor deficiency. Diabetes 62, 2380–2385 (2013).
Murphy, S. et al. Nucleus of the solitary tract A2 neurons control feeding behaviors via projections to the paraventricular hypothalamus. Neuropsychopharmacology 48, 351–361 (2023).
Rinaman, L. Ascending projections from the caudal visceral nucleus of the solitary tract to brain regions involved in food intake and energy expenditure. Brain Res. 1350, 18–34 (2010).
Wang, D. et al. Whole-brain mapping of the direct inputs and axonal projections of POMC and AgRP neurons. Front. Neuroanat. 9, 40 (2015).
Carter, M. E., Han, S. & Palmiter, R. D. Parabrachial calcitonin gene-related peptide neurons mediate conditioned taste aversion. J. Neurosci. 35, 4582–4586 (2015).
Campos, C. A., Bowen, A. J., Schwartz, M. W. & Palmiter, R. D. Parabrachial CGRP neurons control meal termination. Cell Metab 23, 811–820 (2016).
Carter, M. E., Soden, M. E., Zweifel, L. S. & Palmiter, R. D. Genetic identification of a neural circuit that suppresses appetite. Nature 503, 111–114 (2013).
Li, M. M. et al. The paraventricular hypothalamus regulates satiety and prevents obesity via two genetically distinct circuits. Neuron 102, 653–667 (2019).
Zhang, S. X. et al. Competition between stochastic neuropeptide signals calibrates the rate of satiation. Preprint at bioRxiv https://doi.org/10.1101/2023.07.11.548551 (2023).
Fenselau, H. et al. A rapidly acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by α-MSH. Nat. Neurosci. 20, 42–51 (2017).
Spector, A. C., Breslin, P. & Grill, H. J. Taste reactivity as a dependent measure of the rapid formation of conditioned taste aversion: a tool for the neural analysis of taste-visceral associations. Behav. Neurosci. 102, 942–952 (1988).
Dowsett, G. K. C. et al. A survey of the mouse hindbrain in the fed and fasted states using single-nucleus RNA sequencing. Mol Metab 53, 101240 (2021).
Cork, S. C. et al. Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain. Mol. Metab. 4, 718–731 (2015).
Göke, R., Larsen, P. J., Mikkelsen, J. D. & Sheikh, S. P. Distribution of GLP-1 binding sites in the rat brain: evidence that exendin-4 is a ligand of brain GLP-1 binding sites. Eur. J. Neurosci. 7, 2294–2300 (1995).
Alhadeff, A. L. & Grill, H. J. Hindbrain nucleus tractus solitarius glucagon-like peptide-1 receptor signaling reduces appetitive and motivational aspects of feeding. Am. J. Physiol. Regul. Integr. Comp. Physiol. 307, R465–R470 (2014).
Fortin, S. M. GABA neurons in the nucleus tractus solitarius express GLP-1 receptors and mediate anorectic effects of liraglutide in rats., Sci. Transl. Med. 12, eaay8071 (2020).
Hayes, M. R. et al. Intracellular signals mediating the food intake-suppressive effects of hindbrain glucagon-like peptide-1 receptor activation. Cell Metab. 13, 320–330 (2011).
Alhadeff, A. L. et al. Endogenous glucagon-like peptide-1 receptor signaling in the nucleus tractus solitarius is required for food intake control. Neuropsychopharmacology 42, 1471–1479 (2017).
Costa, A. et al. Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation. Mol. Metab. 55, 101407 (2022).
Ilanges, A. et al. Brainstem ADCYAP1+ neurons control multiple aspects of sickness behaviour. Nature 609, 761–771 (2022).
Secher, A. et al. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J. Clin. Invest. 124, 4473–4488 (2014).
Burmeister, M. A. et al. The hypothalamic glucagon-like peptide 1 receptor Is sufficient but not necessary for the regulation of energy balance and glucose homeostasis in mice. Diabetes 66, 372–384 (2017).
Hayes, M. R., Skibicka, K. P. & Grill, H. J. Caudal brainstem processing is sufficient for behavioral, sympathetic, and parasympathetic responses driven by peripheral and hindbrain glucagon-like-peptide-1 receptor stimulation. Endocrinology 149, 4059–4068 (2008).
D’Agostino, G. et al. Nucleus of the solitary tract serotonin 5-HT2C receptors modulate food intake. Cell Metab. 28, 619–630 (2018).
Webster, A. N. et al. Molecular connectomics reveals a glucagon-like peptide 1 sensitive neural circuit for satiety. Preprint at bioRxiv https://doi.org/10.1101/2023.10.31.564990 (2023).
D’Agostino, G. et al. Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit., eLife 5, e12225 (2016).
Roman, C. W., Sloat, S. R. & Palmiter, R. D. A tale of two circuits: CCKNTS neuron stimulation controls appetite and induces opposing motivational states by projections to distinct brain regions. Neuroscience 358, 316–324 (2017).
Cheng, W. et al. Calcitonin receptor neurons in the mouse nucleus tractus solitarius control energy balance via the non-aversive suppression of feeding. Cell Metab. 31, 301–312 (2020).
Ran, C., Boettcher, J. C., Kaye, J. A., Gallori, C. E. & Liberles, S. D. A brainstem map for visceral sensations. Nature 609, 320–326 (2022).
Ly, T. et al. Sequential appetite suppression by oral and visceral feedback to the brainstem. Nature 624, 130–137 (2023).
Shu, Y. et al. Gastrointestinal adverse events associated with semaglutide: a pharmacovigilance study based on FDA adverse event reporting system. Front. Public Health 10, 996179 (2022).
Atasoy, D., Betley, J. N., Su, H. H. & Sternson, S. M. Deconstruction of a neural circuit for hunger. Nature 488, 172–177 (2012).
Wu, Q., Boyle, M. P. & Palmiter, R. D. Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell 137, 1225–1234 (2009).
Egecioglu, E. et al. The glucagon-like peptide 1 analogue Exendin-4 attenuates alcohol mediated behaviors in rodents. Psychoneuroendocrinology 38, 1259–1270 (2013).
Tuesta, L. M. et al. GLP-1 acts on habenular avoidance circuits to control nicotine intake. Nat. Neurosci. 20, 708–716 (2017).
Schmidt, H. D. et al. Glucagon-like peptide-1 receptor activation in the ventral tegmental area decreases the reinforcing efficacy of cocaine. Neuropsychopharmacology 41, 1917–1928 (2016).
Wickham, R. J. Nausea and vomiting: a palliative care imperative. Curr. Oncol. Rep. 22, 1 (2020).
Williams, E. K. et al. Sensory neurons that detect stretch and nutrients in the digestive system. Cell 166, 209–221 (2016).
Madisen, L. et al. A toolbox of Cre-dependent optogenetic transgenic mice for light-induced activation and silencing. Nat. Neurosci. 15, 793–802 (2012).
Huang, K.-P. et al. Sex differences in response to short-term high fat diet in mice. Physiol. Behav. 221, 112894 (2020).
Alhadeff, A. L. et al. A neural circuit for the suppression of pain by a competing need state. Cell 173, 140–152 (2018).
Goldstein, N. et al. Hypothalamic detection of macronutrients via multiple gut-brain pathways. Cell Metab. 33, 676–687 (2021).
Min, S. et al. Arterial baroreceptors sense blood pressure through decorated aortic claws. Cell Rep. 29, 2192–2201 (2019).
Ghidewon, M. et al. Growth differentiation factor 15 (GDF15) and semaglutide inhibit food intake and body weight through largely distinct, additive mechanisms. Diabetes Obes. Metab. 24, 1010–1020 (2022).
Wyvell, C. L. & Berridge, K. C. Intra-accumbens amphetamine increases the conditioned incentive salience of sucrose reward: enhancement of reward “wanting” without enhanced “liking” or response reinforcement. J. Neurosci. 20, 8122–8130 (2000).
Berridge, K. C. & Peciña, S. Benzodiazepines, appetite, and taste palatability. Neurosci. Biobehav. Rev. 19, 121–131 (1995).
Ren, D. et al. A prokaryotic voltage-gated sodium channel. Science 294, 2372–2375 (2001).
Giovannucci, A. et al. CaImAn an open source tool for scalable calcium imaging data analysis., eLife 8, e38173 (2019).
Pnevmatikakis, E. A. & Giovannucci, A. NoRMCorre: an online algorithm for piecewise rigid motion correction of calcium imaging data. J. Neurosci. Methods 291, 83–94 (2017).
Stringer, C., Wang, T., Michaelos, M. & Pachitariu, M. Cellpose: a generalist algorithm for cellular segmentation. Nat. Methods 18, 100–106 (2021).
Pnevmatikakis, E. A. et al. Simultaneous denoising, deconvolution, and demixing of calcium imaging data. Neuron 89, 285–299 (2016).
Tan, H.-E. et al. The gut–brain axis mediates sugar preference. Nature 580, 511–516 (2020).
Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411–420 (2018).
Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573–3587 (2021).
Ludwig, M. Q., Todorov, P. V., Egerod, K. L., Olson, D. P. & Pers, T. H. Single-cell mapping of GLP-1 and GIP receptor expression in the dorsal vagal complex. Diabetes 70, 1945–1955 (2021).