Mauvais-Jarvis, F., Clegg, D. J. & Hevener, A. L. The role of estrogens in control of energy balance and glucose homeostasis. Endocr. Rev. 34, 309–338 (2013).
Google Scholar
Carr, M. C. The emergence of the metabolic syndrome with menopause. J. Clin. Endocrinol. Metab. 88, 2404–2411 (2003).
Google Scholar
Correa, S. M. et al. An estrogen-responsive module in the ventromedial hypothalamus selectively drives sex-specific activity in females. Cell Rep. 10, 62–74 (2015).
Google Scholar
Herber, C. B. et al. Estrogen signaling in arcuate Kiss1 neurons suppresses a sex-dependent female circuit promoting dense strong bones. Nat. Commun. 10, 163 (2019).
Google Scholar
Martinez de Morentin, P. B. et al. Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK. Cell Metab. 20, 41–53 (2014).
Google Scholar
Xu, Y. et al. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab. 14, 453–465 (2011).
Google Scholar
van Veen, J. E. et al. Hypothalamic estrogen receptor alpha establishes a sexually dimorphic regulatory node of energy expenditure. Nat. Metab. 2, 351–363 (2020).
Google Scholar
Farooqi, I. S. et al. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J. Clin. Invest. 106, 271–279 (2000).
Google Scholar
Qi, L., Kraft, P., Hunter, D. J. & Hu, F. B. The common obesity variant near MC4R gene is associated with higher intakes of total energy and dietary fat, weight change and diabetes risk in women. Hum. Mol. Genet. 17, 3502–3508 (2008).
Google Scholar
Thammacharoen, S., Lutz, T. A., Geary, N. & Asarian, L. Hindbrain administration of estradiol inhibits feeding and activates estrogen receptor-α-expressing cells in the nucleus tractus solitarius of ovariectomized rats. Endocrinology 149, 1609–1617 (2008).
Google Scholar
Villanueva, E. C. et al. Complex regulation of mammalian target of rapamycin complex 1 in the basomedial hypothalamus by leptin and nutritional status. Endocrinology 150, 4541–4551 (2009).
Google Scholar
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).
Google Scholar
Ste Marie, L., Miura, G. I., Marsh, D. J., Yagaloff, K. & Palmiter, R. D. A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Proc. Natl Acad. Sci. USA 97, 12339–12344 (2000).
Google Scholar
Chen, A. S. et al. Role of the melanocortin-4 receptor in metabolic rate and food intake in mice. Transgenic Res. 9, 145–154 (2000).
Google Scholar
Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141 (1997).
Google Scholar
Sina, M. et al. Phenotypes in three pedigrees with autosomal dominant obesity caused by haploinsufficiency mutations in the melanocortin-4 receptor gene. Am. J. Hum. Genet. 65, 1501–1507 (1999).
Google Scholar
Skene, P. J., Henikoff, J. G. & Henikoff, S. Targeted in situ genome-wide profiling with high efficiency for low cell numbers. Nat. Protoc. 13, 1006–1019 (2018).
Google Scholar
Lin, C. Y. et al. Whole-genome cartography of estrogen receptor α binding sites. PLoS Genet. 3, e87 (2007).
Google Scholar
Lo, L. et al. Connectional architecture of a mouse hypothalamic circuit node controlling social behavior. Proc. Natl Acad. Sci. USA 116, 7503–7512 (2019).
Google Scholar
Fuhrmann, F. et al. Locomotion, theta oscillations, and the speed-correlated firing of hippocampal neurons are controlled by a medial septal glutamatergic circuit. Neuron 86, 1253–1264 (2015).
Google Scholar
Góis, Z. H. T. D. & Tort, A. B. L. Characterizing speed cells in the rat hippocampus. Cell Rep. 25, 1872–1884 (2018).
Google Scholar
Evans, D. A. et al. A synaptic threshold mechanism for computing escape decisions. Nature 558, 590–594 (2018).
Google Scholar
Tovote, P. et al. Midbrain circuits for defensive behaviour. Nature 534, 206–212 (2016).
Google Scholar
Carter, M. E. et al. Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nat. Neurosci. 13, 1526–1533 (2010).
Google Scholar
Coimbra, B. et al. Role of laterodorsal tegmentum projections to nucleus accumbens in reward-related behaviors. Nat. Commun. 10, 4138 (2019).
Google Scholar
Balthasar, N. et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 123, 493–505 (2005).
Google Scholar
Matharu, N. et al. CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency. Science 363, eaau0629 (2019).
Google Scholar
Slonaker, J. R. The effect of pubescence, oestruation and menopause on the voluntary activity in the albino rat. Am. J. Physiol. 68, 294–315 (1924).
Google Scholar
Lotta, L. A. et al. Human gain-of-function MC4R variants show signaling bias and protect against obesity. Cell 177, 597–607 (2019).
Google Scholar
Pfaus, J. G., Shadiack, A., Van Soest, T., Tse, M. & Molinoff, P. Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist. Proc. Natl Acad. Sci. USA 101, 10201–10204 (2004).
Google Scholar
Clayton, A. H. et al. Bremelanotide for female sexual dysfunctions in premenopausal women: a randomized, placebo-controlled dose-finding trial. Womens Health 12, 325–337 (2016).
Google Scholar
Chandler, D. J. et al. Redefining noradrenergic neuromodulation of behavior: impacts of a modular locus coeruleus architecture. J. Neurosci. 39, 8239–8249 (2019).
Google Scholar
Duval, K. et al. Effects of the menopausal transition on energy expenditure: a MONET Group Study. Eur. J. Clin. Nutr. 67, 407–411 (2013).
Google Scholar
O’Neal, T. J., Friend, D. M., Guo, J., Hall, K. D. & Kravitz, A. V. Increases in physical activity result in diminishing increments in daily energy expenditure in mice. Curr. Biol. 27, 423–430 (2017).
Google Scholar
Duggal, N. A., Niemiro, G., Harridge, S. D. R., Simpson, R. J. & Lord, J. M. Can physical activity ameliorate immunosenescence and thereby reduce age-related multi-morbidity? Nat. Rev. Immunol. 19, 563–572 (2019).
Google Scholar
Garfield, A. S. et al. A neural basis for melanocortin-4 receptor-regulated appetite. Nat. Neurosci. 18, 863–871 (2015).
Google Scholar
Dhillon, H. et al. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 49, 191–203 (2006).
Google Scholar
Krashes, M. J. et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J. Clin. Invest. 121, 1424–1428 (2011).
Google Scholar
Cai, D., Cohen, K. B., Luo, T., Lichtman, J. W. & Sanes, J. R. Improved tools for the Brainbow toolbox. Nat. Methods 10, 540–547 (2013).
Google Scholar
Hu, Y. et al. Differential effects of unfolded protein response pathways on axon injury-induced death of retinal ganglion cells. Neuron 73, 445–452 (2012).
Google Scholar
Nagai, Y. et al. Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys. Nat. Neurosci. 23, 1157–1167 (2020).
Google Scholar
Kim, D., Langmead, B. & Salzberg, S. L. HISAT: a fast spliced aligner with low memory requirements. Nat. Methods 12, 357–360 (2015).
Google Scholar
Anders, S., Pyl, P. T. & Huber, W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166–169 (2015).
Google Scholar
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
Google Scholar
Mo, A. et al. Epigenomic signatures of neuronal diversity in the mammalian brain. Neuron 86, 1369–1384 (2015).
Google Scholar
Martin, M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J. 17, 10–12 (2011).
Google Scholar
Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012).
Google Scholar
Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).
Google Scholar
Ramirez, F. et al. deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 44, W160–W165 (2016).
Google Scholar
Zhang, Y. et al. Model-based analysis of ChIP–seq (MACS). Genome Biol. 9, R137.
Hahne, F. & Ivanek, R. Visualizing genomic data using Gviz and Bioconductor. Methods Mol. Biol. 1418, 335–351 (2016).
Google Scholar
Crane, J. D., Mottillo, E. P., Farncombe, T. H., Morrison, K. M. & Steinberg, G. R. A standardized infrared imaging technique that specifically detects UCP1-mediated thermogenesis in vivo. Mol Metab. 3, 490–494 (2014).
Edgar, R., Domrachev, M. & Lash, A. E. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30, 207–210 (2002).
Google Scholar