Abstract
The preoptic area (POA) is a well-established regulator of body temperature, but its role in feeding behavior remains underexplored. Our study identifies leptin receptor (Lepr)-expressing neurons in the POA (POALepr) as critical component to suppress food intake (FI) and increase satiety in response to warm ambient temperatures. Utilizing chemogenetic activation in mice of both sexes, we demonstrate that selective activation of POALepr neurons mimics the effects of warm temperatures, leading to a significant reduction in FI. POALepr neurons project to the melanocortin pathway, where activation of melanocortin-4 receptors (MC4R) also suppresses FI in a temperature-dependent manner. Our findings suggest that POALepr neurons integrate thermal and metabolic cues, demonstrating that ambient temperature is an integral part of body weight homeostasis by modulating meal size and satiety via POALepr neurons. These results offer new insights into the neurochemical and functional properties of POA functions, expanding the traditional view that the POA is exclusively involved in thermoregulation and underscoring its broader role in energy balance.
Data availability
Raw images obtained by immunostaining are available upon reasonable request to the Corresponding Author. Code for processing feeding events and generating the related figures is available from https://doi.org/10.5281/zenodo.1843701277. Numerical source data for all graphs in the manuscript can be found in the Supplementary Data 1 file. Numerical source data for all Supplementary figures can be found in the Supplementary Data 2 file.
Code availability
Custom code used for the processing and visualization of feeding events is available at https://doi.org/10.5281/zenodo.1843701277.
References
Nakamura, K. Central circuitries for body temperature regulation and fever. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R1207–R1228 (2011).
Yu, S., Francois, M., Huesing, C. & Munzberg, H. The hypothalamic preoptic area and body weight control. Neuroendocrinology 106, 187–194 (2018).
Wechselberger, M., Wright, C. L., Bishop, G. A. & Boulant, J. A. Ionic channels and conductance-based models for hypothalamic neuronal thermosensitivity. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291, R518–R529 (2006).
Ambroziak, W. et al. Thermally induced neuronal plasticity in the hypothalamus mediates heat tolerance. Nat. Neurosci. https://doi.org/10.1038/s41593-024-01830-0 (2024).
Qian, S. et al. A temperature-regulated circuit for feeding behavior. Nat. Commun. 13, 4229 (2022).
Yang, S. et al. An mPOA-ARC(AgRP) pathway modulates cold-evoked eating behavior. Cell Rep. 36, 109502 (2021).
Hankenson, F. C., Marx, J. O., Gordon, C. J. & David, J. M. Effects of rodent thermoregulation on animal models in the research environment. Comp. Med 68, 425–438 (2018).
Yu, S. et al. Glutamatergic preoptic area neurons that express leptin receptors drive temperature-dependent body weight homeostasis. J. Neurosci. 36, 5034–5046 (2016).
Munzberg, H., Singh, P., Heymsfield, S. B., Yu, S. & Morrison, C. D. Recent advances in understanding the role of leptin in energy homeostasis. F1000Res. https://doi.org/10.12688/f1000research.24260.1 (2020).
Zhang, Y. et al. Leptin-receptor-expressing neurons in the dorsomedial hypothalamus and median preoptic area regulate sympathetic brown adipose tissue circuits. J. Neurosci. 31, 1873–1884 (2011).
Saper, C. B. & Machado, N. L. The search for thermoregulatory neurons is heating up. Cell Metab. 33, 1269–1271 (2021).
Moffitt, J. R. et al. Molecular, spatial, and functional single-cell profiling of the hypothalamic preoptic region. Science 362, eaau5324 (2018).
Hrvatin, S. et al. Neurons that regulate mouse torpor. Nature 583, 115–121 (2020).
Nakamura, Y. et al. Direct pyrogenic input from prostaglandin EP3 receptor-expressing preoptic neurons to the dorsomedial hypothalamus. Eur. J. Neurosci. 22, 3137–3146 (2005).
Yoshida, K., Li, X., Cano, G., Lazarus, M. & Saper, C. B. Parallel preoptic pathways for thermoregulation. J. Neurosci. 29, 11954–11964 (2009).
Jais, A. & Bruning, J. C. Arcuate nucleus-dependent regulation of metabolism-pathways to obesity and diabetes mellitus. Endocr. Rev. 43, 314–328 (2022).
Chen, Y., Lin, Y. C., Kuo, T. W. & Knight, Z. A. Sensory detection of food rapidly modulates arcuate feeding circuits. Cell 160, 829–841 (2015).
Baldini, G. & Phelan, K. D. The melanocortin pathway and control of appetite-progress and therapeutic implications. J. Endocrinol. 241, R1–R33 (2019).
Wang, D. et al. Whole-brain mapping of the direct inputs and axonal projections of POMC and AgRP neurons. Front Neuroanat. 9, 40 (2015).
Deem, J. D. et al. Cold-induced hyperphagia requires AgRP neuron activation in mice. Elife 9, e58764 (2020).
Jeong, J. H. et al. Activation of temperature-sensitive TRPV1-like receptors in ARC POMC neurons reduces food intake. PLoS Biol. 16, e2004399 (2018).
Suwannapaporn, P., Chaiyabutr, N., Wanasuntronwong, A. & Thammacharoen, S. Arcuate proopiomelanocortin is part of a novel neural connection for short-term low-degree of high ambient temperature effects on food intake. Physiol. Behav. 245, 113687 (2022).
Rathod, Y. D. & Di Fulvio, M. The feeding microstructure of male and female mice. PLoS ONE 16, e0246569 (2021).
Zorrilla, E. P. et al. Measuring meals: structure of prandial food and water intake of rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, R1450–R1467 (2005).
Faber, C. L. et al. Leptin receptor neurons in the dorsomedial hypothalamus regulate diurnal patterns of feeding, locomotion, and metabolism. Elife 10, e63671 (2021).
Garfield, A. S. et al. Dynamic GABAergic afferent modulation of AgRP neurons. Nat. Neurosci. 19, 1628–1635 (2016).
Richard, C. D., Tolle, V. & Low, M. J. Meal pattern analysis in neural-specific proopiomelanocortin-deficient mice. Eur. J. Pharm. 660, 131–138 (2011).
Azzara, A. V., Sokolnicki, J. P. & Schwartz, G. J. Central melanocortin receptor agonist reduces spontaneous and scheduled meal size but does not augment duodenal preload-induced feeding inhibition. Physiol. Behav. 77, 411–416 (2002).
Zheng, H., Patterson, L. M., Phifer, C. B. & Berthoud, H. R. Brain stem melanocortinergic modulation of meal size and identification of hypothalamic POMC projections. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R247–R258 (2005).
Balthasar, N. et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 123, 493–505 (2005).
Berthoud, H. R., Sutton, G. M., Townsend, R. L., Patterson, L. M. & Zheng, H. Brainstem mechanisms integrating gut-derived satiety signals and descending forebrain information in the control of meal size. Physiol. Behav. 89, 517–524 (2006).
Andermann, M. L. & Lowell, B. B. Toward a wiring diagram understanding of appetite control. Neuron 95, 757–778 (2017).
Mountjoy, K. G., Mortrud, M. T., Low, M. J., Simerly, R. B. & Cone, R. D. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol. Endocrinol. 8, 1298–1308 (1994).
Cansell, C., Denis, R. G., Joly-Amado, A., Castel, J. & Luquet, S. Arcuate AgRP neurons and the regulation of energy balance. Front Endocrinol. 3, 169 (2012).
Doring, H., Schwarzer, K., Nuesslein-Hildesheim, B. & Schmidt, I. Leptin selectively increases energy expenditure of food-restricted lean mice. Int. J. Obes. Relat. Metab. Disord. 22, 83–88 (1998).
Rosenbaum, M. et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J. Clin. Invest. 115, 3579–3586 (2005).
Bing, C. et al. Hyperphagia in cold-exposed rats is accompanied by decreased plasma leptin but unchanged hypothalamic NPY. Am. J. Physiol. 274, R62–R68 (1998).
Concannon, P., Levac, K., Rawson, R., Tennant, B. & Bensadoun, A. Seasonal changes in serum leptin, food intake, and body weight in photoentrained woodchucks. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281, R951–R959 (2001).
Yu, S. et al. Preoptic leptin signaling modulates energy balance independent of body temperature regulation. Elife 7, e33505 (2018).
Kaiyala, K. J., Ogimoto, K., Nelson, J. T., Schwartz, M. W. & Morton, G. J. Leptin signaling is required for adaptive changes in food intake, but not energy expenditure, in response to different thermal conditions. PLoS ONE 10, e0119391 (2015).
Gutierrez, E., Garcia, N. & Carrera, O. Disordered eating in anorexia nervosa: give me heat, not just food. Front Public Health 12, 1433470 (2024).
Carrera, O. & Gutierrez, E. Hyperactivity in anorexia nervosa: to warm or not to warm. That is the question (a translational research one). J. Eat. Disord. 6, 4 (2018).
Song, K. et al. The TRPM2 channel is a hypothalamic heat sensor that limits fever and can drive hypothermia. Science 353, 1393–1398 (2016).
Tan, C. L. et al. Warm-sensitive neurons that control body temperature. Cell 167, 47–59.e15 (2016).
Zhang, K. X. et al. Violet-light suppression of thermogenesis by opsin 5 hypothalamic neurons. Nature 585, 420–425 (2020).
Zhang, Z. et al. Estrogen-sensitive medial preoptic area neurons coordinate torpor in mice. Nat. Commun. 11, 6378 (2020).
Laque, A. et al. Leptin receptor neurons in the mouse hypothalamus are colocalized with the neuropeptide galanin and mediate anorexigenic leptin action. Am. J. Physiol. Endocrinol. Metab. 304, E999–E1011 (2013).
Kroeger, D. et al. Galanin neurons in the ventrolateral preoptic area promote sleep and heat loss in mice. Nat. Commun. 9, 4129 (2018).
Pinol, R. A. et al. Brs3 neurons in the mouse dorsomedial hypothalamus regulate body temperature, energy expenditure, and heart rate, but not food intake. Nat. Neurosci. 21, 1530–1540 (2018).
Alcantara, I. C., Tapia, A. P. M., Aponte, Y. & Krashes, M. J. Acts of appetite: neural circuits governing the appetitive, consummatory, and terminating phases of feeding. Nat. Metab. 4, 836–847 (2022).
Sternson, S. M. & Eiselt, A. K. Three pillars for the neural control of appetite. Annu Rev. Physiol. 79, 401–423 (2017).
Berrios, J. et al. Food cue regulation of AGRP hunger neurons guides learning. Nature 595, 695–700 (2021).
Rau, A. R. & Hentges, S. T. GABAergic inputs to POMC neurons originating from the dorsomedial hypothalamus are regulated by energy state. J. Neurosci. 39, 6449–6459 (2019).
Tran, L. T. et al. Hypothalamic control of energy expenditure and thermogenesis. Exp. Mol. Med. 54, 358–369 (2022).
Rezai-Zadeh, K. et al. Leptin receptor neurons in the dorsomedial hypothalamus are key regulators of energy expenditure and body weight, but not food intake. Mol. Metab. 3, 681–693 (2014).
Cai, H. et al. Neural circuits regulation of satiation. Appetite 200, 107512 (2024).
Yeo, G. S. H. et al. The melanocortin pathway and energy homeostasis: from discovery to obesity therapy. Mol. Metab. 48, 101206 (2021).
Matsumura, S. et al. Stimulation of G(s) signaling in MC4R cells by DREADD increases energy expenditure, suppresses food intake, and increases locomotor activity in mice. Am. J. Physiol. Endocrinol. Metab. 322, E436–E445 (2022).
Singh, U. et al. Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations. Mol. Metab. 55, 101401 (2022).
Krashes, M. J., Shah, B. P., Koda, S. & Lowell, B. B. Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Cell Metab. 18, 588–595 (2013).
Suwanapaporn, P., Chaiyabutr, N. & Thammacharoen, S. A low degree of high ambient temperature decreased food intake and activated median preoptic and arcuate nuclei. Physiol. Behav. 181, 16–22 (2017).
Aponte, Y., Atasoy, D. & Sternson, S. M. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat. Neurosci. 14, 351–355 (2011).
Koch, M. et al. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519, 45–50 (2015).
Zhan, C. et al. Acute and long-term suppression of feeding behavior by POMC neurons in the brainstem and hypothalamus, respectively. J. Neurosci. 33, 3624–3632 (2013).
Cheon, D. H. et al. Lateral hypothalamus and eating: cell types, molecular identity, anatomy, temporal dynamics and functional roles. Exp. Mol. Med 57, 925–937 (2025).
Shi, H., Strader, A. D., Woods, S. C. & Seeley, R. J. Sexually dimorphic responses to fat loss after caloric restriction or surgical lipectomy. Am. J. Physiol. Endocrinol. Metab. 293, E316–E326 (2007).
Yang, Y., Smith, D. L. Jr., Keating, K. D., Allison, D. B. & Nagy, T. R. Variations in body weight, food intake and body composition after long-term high-fat diet feeding in C57BL/6J mice. Obesity 22, 2147–2155 (2014).
Luo, P. et al. Medial preoptic area FoxO1 controls metabolic adaptation in a sexually dimorphic manner. bioRxiv https://doi.org/10.1101/2025.06.25.661575 (2025).
Bellefontaine, N. et al. Leptin-dependent neuronal NO signaling in the preoptic hypothalamus facilitates reproduction. J. Clin. Invest. 124, 2550–2559 (2014).
Leshan, R. L., Bjornholm, M., Munzberg, H. & Myers, M. G. Jr. Leptin receptor signaling and action in the central nervous system. Obesity 14, 208S–212S (2006).
Cowley, M. A. et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–484 (2001).
Garfield, A. S. et al. A neural basis for melanocortin-4 receptor-regulated appetite. Nat. Neurosci. 18, 863–871 (2015).
Liu, J. et al. Cell-specific translational profiling in acute kidney injury. J. Clin. Invest. 124, 1242–1254 (2014).
Madisen, L. et al. Transgenic mice for intersectional targeting of neural sensors and effectors with high specificity and performance. Neuron 85, 942–958 (2015).
Paxinos, G. & Franklin, K. B. Paxinos and Franklin’s the Mouse Brain in Stereotaxic Coordinates 5th edn (Academic Press, 2019).
Strubbe, J. H. & Woods, S. C. The timing of meals. Psychol. Rev. 111, 128–141 (2004).
Kaiser, L. & Munzberg, H. MunzbeH/2025_published-code: Create FoodIntakeSuite.v24.0501.R Zenodo. https://doi.org/10.5281/zenodo.18437012 (2026).
Acknowledgements
This work was supported by P20 RR02195, P/F NORC #2P30-DK072476-06, 2R01DK092587, R01AT011683 (HM), 1-OT2OD023864-01 (H.M., H.R.B., and S.Y.). This work utilized the facilities of the Cell Biology and Bioimaging Core and Animal Metabolism and Behavior Core that are supported in part by COBRE (P20-RR021945) and NORC (1P30-DK072476) center grants from the National Institutes of Health, an NIH Equipment Grant (S10OD023703) and NIH Virus Center grant no. P40RR018604.
Author information
Authors and Affiliations
Contributions
L.K.: Experimental planning (All Fig.), data collection (All Fig.), curation, analysis (All Fig.), and manuscript draft. N.L.: Experiment planning (Figs. 2, 5, 6, 7), data collection (Figs. 2, 5, 6, 7), curation (Figs. 2, 5, 6, 7), and manuscript editing/review. K.Z.: Experimental planning (Fig. 7) and data collection (All Fig. 7). C.K.: Manuscript editing/review. J.W.: Histology imaging (Figs. 5, 6, 7), generally advised all histology in the paper, and manuscript editing/review. MS: Data collection (Fig. 6). Manuscript editing/review. R.C.N.: Experiment planning (Fig. 1), data collection (Fig. 1), and manuscript editing/review. S.Y.: Experiment planning (Figs. 1, 5), data collection (Figs. 1, 5), and curation (Figs. 1, 5). H.R.B.: Manuscript editing/review. C.D.M.: Manuscript editing/review. H.M.: Concept, supervision, manuscript writing, editing, and funding.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Communications Biology thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editors: Joao Valente. A peer review file is available.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Kaiser, L., Lee, N., Zaunbrecher, K. et al. Obesogenic effects of warm temperature involve feeding adaptation by preoptic area leptin receptor neurons. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09723-7
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s42003-026-09723-7
