POMC neuronal heterogeneity in energy balance and beyond: an integrated view.
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
16
11
2020
accepted:
13
01
2021
pubmed:
27
2
2021
medline:
24
4
2021
entrez:
26
2
2021
Statut:
ppublish
Résumé
Hypothalamic AgRP and POMC neurons are conventionally viewed as the yin and yang of the body's energy status, since they act in an opposite manner to modulate appetite and systemic energy metabolism. However, although AgRP neurons' functions are comparatively well understood, a unifying theory of how POMC neuronal cells operate has remained elusive, probably due to their high level of heterogeneity, which suggests that their physiological roles might be more complex than initially thought. In this Perspective, we propose a conceptual framework that integrates POMC neuronal heterogeneity with appetite regulation, whole-body metabolic physiology and the development of obesity. We highlight emerging evidence indicating that POMC neurons respond to distinct combinations of interoceptive signals and food-related cues to fine-tune divergent metabolic pathways and behaviours necessary for survival. The new framework we propose reflects the high degree of developmental plasticity of this neuronal population and may enable progress towards understanding of both the aetiology and treatment of metabolic disorders.
Identifiants
pubmed: 33633406
doi: 10.1038/s42255-021-00345-3
pii: 10.1038/s42255-021-00345-3
pmc: PMC8085907
mid: NIHMS1694295
doi:
Substances chimiques
AGRP protein, human
0
Agouti-Related Protein
0
MC4R protein, human
0
RNA, Messenger
0
Receptor, Melanocortin, Type 4
0
Pro-Opiomelanocortin
66796-54-1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
299-308Subventions
Organisme : NIA NIH HHS
ID : P01 AG032959
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK107293
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH113353
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK125094
Pays : United States
Organisme : Medical Research Council
ID : MR/S026193/1
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK120321
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_00014/5
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12012/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12012/5
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00014/1
Pays : United Kingdom
Références
Friedman, J. M. & Halaas, J. L. Leptin and the regulation of body weight in mammals. Nature 395, 763–770 (1998).
pubmed: 9796811
doi: 10.1038/27376
Harno, E., Gali Ramamoorthy, T., Coll, A. P. & White, A. POMC: The physiological power of hormone processing. Physiol. Rev. 98, 2381–2430 (2018).
pubmed: 30156493
pmcid: 6170974
doi: 10.1152/physrev.00024.2017
Quarta, C., Fioramonti, X. & Cota, D. POMC neurons dysfunction in diet-induced metabolic disease: hallmark or mechanism of disease? Neuroscience 447, 3–14 (2019).
pubmed: 31689486
doi: 10.1016/j.neuroscience.2019.09.031
Andermann, M. L. & Lowell, B. B. Toward a wiring diagram understanding of appetite control. Neuron 95, 757–778 (2017).
pubmed: 28817798
pmcid: 5657399
doi: 10.1016/j.neuron.2017.06.014
Cowley, M. A. et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–484 (2001).
pubmed: 11373681
doi: 10.1038/35078085
Tong, Q., Ye, C.-P., Jones, J. E., Elmquist, J. K. & Lowell, B. B. Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat. Neurosci. 11, 998–1000 (2008).
pubmed: 19160495
pmcid: 2662585
doi: 10.1038/nn.2167
Ollmann, M. M. et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135–138 (1997).
pubmed: 9311920
doi: 10.1126/science.278.5335.135
Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141 (1997).
pubmed: 9019399
doi: 10.1016/S0092-8674(00)81865-6
Lee, Y. S. et al. A POMC variant implicates β-melanocyte-stimulating hormone in the control of human energy balance. Cell Metab. 3, 135–140 (2006).
pubmed: 16459314
doi: 10.1016/j.cmet.2006.01.006
Krude, H. et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat. Genet. 19, 155–157 (1998).
pubmed: 9620771
doi: 10.1038/509
Biebermann, H. et al. A role for β-melanocyte-stimulating hormone in human body-weight regulation. Cell Metab. 3, 141–146 (2006).
pubmed: 16459315
doi: 10.1016/j.cmet.2006.01.007
Kühnen, P. et al. Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist. N. Engl. J. Med. 375, 240–246 (2016).
pubmed: 27468060
doi: 10.1056/NEJMoa1512693
Kievit, P. et al. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes 62, 490–497 (2013).
pubmed: 23048186
pmcid: 3554387
doi: 10.2337/db12-0598
Collet, T.-H. et al. Evaluation of a melanocortin-4 receptor (MC4R) agonist (setmelanotide) in MC4R deficiency. Mol. Metab. 6, 1321–1329 (2017).
pubmed: 29031731
pmcid: 5641599
doi: 10.1016/j.molmet.2017.06.015
Koch, M. et al. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519, 45–50 (2015).
pubmed: 25707796
pmcid: 4496586
doi: 10.1038/nature14260
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).
pubmed: 21209617
doi: 10.1038/nn.2739
Atasoy, D., Betley, J. N., Su, H. H. & Sternson, S. M.Deconstruction of a neural circuit for hunger. Nature 488, 172–177 (2012).
pubmed: 22801496
pmcid: 3416931
doi: 10.1038/nature11270
Krashes, M. J. et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J. Clin. Invest. 121, 1424–1428 (2011).
pubmed: 21364278
pmcid: 3069789
doi: 10.1172/JCI46229
Williams, K. W. et al. Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. J. Neurosci. 30, 2472–2479 (2010).
pubmed: 20164331
pmcid: 2836776
doi: 10.1523/JNEUROSCI.3118-09.2010
Sohn, J.-W. et al. Serotonin 2C receptor activates a distinct population of arcuate pro-opiomelanocortin neurons via TRPC channels. Neuron 71, 488–497 (2011).
pubmed: 21835345
pmcid: 3184528
doi: 10.1016/j.neuron.2011.06.012
Lam, B. Y. H. et al. Heterogeneity of hypothalamic pro-opiomelanocortin-expressing neurons revealed by single-cell RNA sequencing. Mol. Metab. 6, 383–392 (2017).
pubmed: 28462073
pmcid: 5404100
doi: 10.1016/j.molmet.2017.02.007
Campbell, J. N. et al. A molecular census of arcuate hypothalamus and median eminence cell types. Nat. Neurosci. 20, 484–496 (2017).
pubmed: 28166221
pmcid: 5323293
doi: 10.1038/nn.4495
Chen, R., Wu, X., Jiang, L. & Zhang, Y. Single-cell RNA-seq reveals hypothalamic cell diversity. Cell Rep. 18, 3227–3241 (2017).
pubmed: 28355573
pmcid: 5782816
doi: 10.1016/j.celrep.2017.03.004
Mizuno, T. M. et al. Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting in ob/ob and db/db mice, but is stimulated by leptin. Diabetes 47, 294–297 (1998).
pubmed: 9519731
doi: 10.2337/diab.47.2.294
Brandt, C. et al. Food perception primes hepatic ER homeostasis via melanocortin-dependent control of mTOR activation. Cell 175, 1321–1335.e20 (2018).
pubmed: 30445039
pmcid: 6541012
doi: 10.1016/j.cell.2018.10.015
Quarta, C. et al. Functional identity of hypothalamic melanocortin neurons depends on Tbx3. Nat. Metab. 1, 222–235 (2019).
pubmed: 32694784
pmcid: 8291379
doi: 10.1038/s42255-018-0028-1
Wu, Q. et al. The temporal pattern of cfos activation in hypothalamic, cortical, and brainstem nuclei in response to fasting and refeeding in male mice. Endocrinology 155, 840–853 (2014).
pubmed: 24424063
doi: 10.1210/en.2013-1831
Fekete, C. et al. Activation of anorexigenic pro-opiomelanocortin neurones during refeeding is independent of vagal and brainstem inputs. J. Neuroendocrinol. 24, 1423–1431 (2012).
pubmed: 22734660
doi: 10.1111/j.1365-2826.2012.02354.x
Knight, Z. A. et al. Molecular profiling of activated neurons by phosphorylated ribosome capture. Cell 151, 1126–1137 (2012).
pubmed: 23178128
doi: 10.1016/j.cell.2012.10.039
Mandelblat-Cerf, Y. et al. Arcuate hypothalamic AgRP and putative POMC neurons show opposite changes in spiking across multiple timescales. eLife 4, e07122 (2015).
pmcid: 4498165
doi: 10.7554/eLife.07122
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).
pubmed: 25703096
pmcid: 4373539
doi: 10.1016/j.cell.2015.01.033
Seeley, R. J. & Berridge, K. C. The hunger games. Cell 160, 805–806 (2015).
pubmed: 25723156
doi: 10.1016/j.cell.2015.02.028
Üner, A. G. et al. Role of POMC and AgRP neuronal activities on glycaemia in mice. Sci. Rep. 9, 13068 (2019).
pubmed: 31506541
pmcid: 6736943
doi: 10.1038/s41598-019-49295-7
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).
pubmed: 23426689
pmcid: 6619547
doi: 10.1523/JNEUROSCI.2742-12.2013
Fenselau, H. et al. A rapidly-acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by α-MSH. Nat. Neurosci. 20, 42–51 (2017).
pubmed: 27869800
doi: 10.1038/nn.4442
Woods, S. C. The eating paradox: how we tolerate food. Psychol. Rev. 98, 488–505 (1991).
pubmed: 1961770
doi: 10.1037/0033-295X.98.4.488
Clasadonte, J. & Prevot, V. The special relationship: glia–neuron interactions in the neuroendocrine hypothalamus. Nat. Rev. Endocrinol. 14, 25–44 (2018).
pubmed: 29076504
doi: 10.1038/nrendo.2017.124
Wang, D. et al. Whole-brain mapping of the direct inputs and axonal projections of POMC and AgRP neurons. Front. Neuroanat. 9, 40 (2015).
pubmed: 25870542
pmcid: 4375998
doi: 10.3389/fnana.2015.00040
Elias, C. F. et al. Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron 21, 1375–1385 (1998).
pubmed: 9883730
doi: 10.1016/S0896-6273(00)80656-X
Baker, R. A. & Herkenham, M. Arcuate nucleus neurons that project to the hypothalamic paraventricular nucleus: neuropeptidergic identity and consequences of adrenalectomy on mRNA levels in the rat. J. Comp. Neurol. 358, 518–530 (1995).
pubmed: 7593746
doi: 10.1002/cne.903580405
Lemus, M. B. et al. A stereological analysis of NPY, POMC, Orexin, GFAP astrocyte, and Iba1 microglia cell number and volume in diet-induced obese male mice. Endocrinology 156, 1701–1713 (2015).
pubmed: 25742051
doi: 10.1210/en.2014-1961
Georgescu, T. et al. Neurochemical characterization of brainstem pro-opiomelanocortin cells. Endocrinology 161, bqaa032 (2020).
pubmed: 32166324
pmcid: 7102873
doi: 10.1210/endocr/bqaa032
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).
pubmed: 22902836
pmcid: 4862653
doi: 10.1016/j.cmet.2012.06.015
Gao, Y. et al. TrpC5 mediates acute leptin and serotonin effects via Pomc neurons. Cell Rep. 18, 583–592 (2017).
pubmed: 28099839
pmcid: 5324780
doi: 10.1016/j.celrep.2016.12.072
Könner, A. C. et al. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab. 5, 438–449 (2007).
pubmed: 17550779
doi: 10.1016/j.cmet.2007.05.004
Shin, A. C. et al. Insulin receptor signaling in POMC, but not AgRP, neurons controls adipose tissue insulin action. Diabetes 66, 1560–1571 (2017).
pubmed: 28385803
pmcid: 5440019
doi: 10.2337/db16-1238
Balthasar, N. et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42, 983–991 (2004).
pubmed: 15207242
doi: 10.1016/j.neuron.2004.06.004
Huo, L. et al. Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metab. 9, 537–547 (2009).
pubmed: 19490908
pmcid: 2730605
doi: 10.1016/j.cmet.2009.05.003
Berglund, E. D. et al. Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. J. Clin. Invest. 122, 1000–1009 (2012).
pubmed: 22326958
pmcid: 3287225
doi: 10.1172/JCI59816
Huang, H. et al. Rho-kinase regulates energy balance by targeting hypothalamic leptin receptor signaling. Nat. Neurosci. 15, 1391–1398 (2012).
pubmed: 22941110
pmcid: 3458121
doi: 10.1038/nn.3207
Xu, J. et al. Genetic identification of leptin neural circuits in energy and glucose homeostases. Nature 556, 505–509 (2018).
pubmed: 29670283
pmcid: 5920723
doi: 10.1038/s41586-018-0049-7
Padilla, S. L., Carmody, J. S. & Zeltser, L. M. Pomc-expressing progenitors give rise to antagonistic neuronal populations in hypothalamic feeding circuits. Nat. Med. 16, 403–405 (2010).
pubmed: 20348924
pmcid: 2854504
doi: 10.1038/nm.2126
Caron, A. et al. POMC neurons expressing leptin receptors coordinate metabolic responses to fasting via suppression of leptin levels. eLife 7, e33710 (2018).
pubmed: 29528284
pmcid: 5866097
doi: 10.7554/eLife.33710
Berglund, E. D. et al. Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis. J. Clin. Invest. 123, 5061–5070 (2013).
pubmed: 24177424
pmcid: 3859401
doi: 10.1172/JCI70338
Dodd, G. T. et al. Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 160, 88–104 (2015).
pubmed: 25594176
pmcid: 4453004
doi: 10.1016/j.cell.2014.12.022
Dicken, M. S., Tooker, R. E. & Hentges, S. T. Regulation of GABA and glutamate release from proopiomelanocortin neuron terminals in intact hypothalamic networks. J. Neurosci. 32, 4042–4048 (2012).
pubmed: 22442070
pmcid: 3321840
doi: 10.1523/JNEUROSCI.6032-11.2012
Hentges, S. T., Otero-Corchon, V., Pennock, R. L., King, C. M. & Low, M. J. Proopiomelanocortin expression in both GABA and glutamate neurons. J. Neurosci. 29, 13684–13690 (2009).
pubmed: 19864580
pmcid: 2785088
doi: 10.1523/JNEUROSCI.3770-09.2009
Hentges, S. T. et al. GABA release from proopiomelanocortin neurons. J. Neurosci. 24, 1578–1583 (2004).
pubmed: 14973227
pmcid: 6730447
doi: 10.1523/JNEUROSCI.3952-03.2004
Jarvie, B. C. & Hentges, S. T. Expression of GABAergic and glutamatergic phenotypic markers in hypothalamic proopiomelanocortin neurons. J. Comp. Neurol. 520, 3863–3876 (2012).
pubmed: 22522889
pmcid: 4114021
doi: 10.1002/cne.23127
Wittmann, G., Hrabovszky, E. & Lechan, R. M. Distinct glutamatergic and GABAergic subsets of hypothalamic pro-opiomelanocortin neurons revealed by in situ hybridization in male rats and mice. J. Comp. Neurol. 521, 3287–3302 (2013).
pubmed: 23640796
pmcid: 4003895
doi: 10.1002/cne.23350
Atasoy, D., Aponte, Y., Su, H. H. & Sternson, S. M. A FLEX switch targets channelrhodopsin-2 to multiple cell types for imaging and long-range circuit mapping. J. Neurosci. 28, 7025–7030 (2008).
pubmed: 18614669
pmcid: 2593125
doi: 10.1523/JNEUROSCI.1954-08.2008
Trotta, M. et al. Hypothalamic Pomc expression restricted to GABAergic neurons suppresses Npy overexpression and restores food intake in obese mice. Mol. Metab. 37, 100985 (2020).
pubmed: 32311511
pmcid: 7292867
doi: 10.1016/j.molmet.2020.100985
Zhu, C. et al. Profound and redundant functions of arcuate neurons in obesity development. Nat. Metab. 2, 763–774 (2020).
pubmed: 32719538
pmcid: 7687864
doi: 10.1038/s42255-020-0229-2
Saucisse, N. et al. POMC neurons functional heterogeneity relies on mTORC1 signaling. Preprint at bioRxiv https://doi.org/10.1101/2020.03.25.007765 (2020).
Wei, Q. et al. Uneven balance of power between hypothalamic peptidergic neurons in the control of feeding. Proc. Natl Acad. Sci. USA 115, E9489–E9498 (2018).
pubmed: 30224492
pmcid: 6176613
doi: 10.1073/pnas.1802237115
Zeng, H. & Sanes, J. R. Neuronal cell-type classification: challenges, opportunities and the path forward. Nat. Rev. Neurosci. 18, 530–546 (2017).
pubmed: 28775344
doi: 10.1038/nrn.2017.85
Dodd, G. T. et al. Insulin regulates POMC neuronal plasticity to control glucose metabolism. eLife 7, e38704 (2018).
pubmed: 30230471
pmcid: 6170188
doi: 10.7554/eLife.38704
Greenman, Y. et al. Postnatal ablation of POMC neurons induces an obese phenotype characterized by decreased food intake and enhanced anxiety-like behavior. Mol. Endocrinol. 27, 1091–1102 (2013).
pubmed: 23676213
pmcid: 5415244
doi: 10.1210/me.2012-1344
Parton, L. E. et al. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449, 228–232 (2007).
pubmed: 17728716
doi: 10.1038/nature06098
Fioramonti, X. et al. Characterization of glucosensing neuron subpopulations in the arcuate nucleus: integration in neuropeptide Y and pro-opio melanocortin networks? Diabetes 56, 1219–1227 (2007).
pubmed: 17261674
doi: 10.2337/db06-0567
Claret, M. et al. AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J. Clin. Invest. 117, 2325–2336 (2007).
pubmed: 17671657
pmcid: 1934578
doi: 10.1172/JCI31516
Levin, B. E. Neuronal glucose sensing: still a physiological orphan? Cell Metab. 6, 252–254 (2007).
pubmed: 17908553
doi: 10.1016/j.cmet.2007.09.005
Santoro, A. et al. DRP1 suppresses leptin and glucose sensing of POMC neurons. Cell Metab. 25, 647–660 (2017).
pubmed: 28190775
pmcid: 5366041
doi: 10.1016/j.cmet.2017.01.003
Ramírez, S. et al. Mitochondrial dynamics mediated by mitofusin 1 is required for POMC neuron glucose-sensing and insulin release control. Cell Metab. 25, 1390–1399.e6 (2017).
pubmed: 28591639
doi: 10.1016/j.cmet.2017.05.010
Hu, J., Jiang, L., Low, M. J. & Rui, L. Glucose rapidly induces different forms of excitatory synaptic plasticity in hypothalamic POMC neurons. PLoS ONE 9, e105080 (2014).
pubmed: 25127258
pmcid: 4134273
doi: 10.1371/journal.pone.0105080
Perez-Tilve, D. et al. Melanocortin signaling in the CNS directly regulates circulating cholesterol. Nat. Neurosci. 13, 877–882 (2010).
pubmed: 20526334
pmcid: 3100172
doi: 10.1038/nn.2569
Nogueiras, R. et al. The central melanocortin system directly controls peripheral lipid metabolism. J. Clin. Invest. 117, 3475–3488 (2007).
pubmed: 17885689
pmcid: 1978426
doi: 10.1172/JCI31743
Jo, Y.-H., Su, Y., Gutierrez-Juarez, R. & Chua, S. Oleic acid directly regulates POMC neuron excitability in the hypothalamus. J. Neurophysiol. 101, 2305–2316 (2009).
pubmed: 19261705
pmcid: 2681442
doi: 10.1152/jn.91294.2008
Michael, N. J. & Watt, M. J.Long chain fatty acids differentially regulate sub-populations of arcuate POMC and NPY neurons. Neuroscience 451, 164–173 (2020).
pubmed: 33002557
doi: 10.1016/j.neuroscience.2020.09.045
Sanz, E. et al. Fertility-regulating Kiss1 neurons arise from hypothalamic Pomc-expressing progenitors. J. Neurosci. 35, 5549–5556 (2015).
pubmed: 25855171
pmcid: 4388920
doi: 10.1523/JNEUROSCI.3614-14.2015
Pelling, M. et al. Differential requirements for neurogenin 3 in the development of POMC and NPY neurons in the hypothalamus. Dev. Biol. 349, 406–416 (2011).
pubmed: 21074524
doi: 10.1016/j.ydbio.2010.11.007
Lee, B. et al. Dlx1/2 and Otp coordinate the production of hypothalamic GHRH- and AgRP-neurons. Nat. Commun. 9, 2026 (2018).
pubmed: 29795232
pmcid: 5966420
doi: 10.1038/s41467-018-04377-4
Zeltser, L. M. Developmental influences on circuits programming susceptibility to obesity. Front. Neuroendocrinol. 39, 17–27 (2015).
pubmed: 26206662
pmcid: 4681591
doi: 10.1016/j.yfrne.2015.07.002
Croizier, S., Park, S., Maillard, J. & Bouret, S. G. Central Dicer-miR-103/107 controls developmental switch of POMC progenitors into NPY neurons and impacts glucose homeostasis. eLife 7, e40429 (2018).
pubmed: 30311908
pmcid: 6203430
doi: 10.7554/eLife.40429
Messina, A. et al. A microRNA switch regulates the rise in hypothalamic GnRH production before puberty. Nat. Neurosci. 19, 835–844 (2016).
pubmed: 27135215
doi: 10.1038/nn.4298
Bouret, S. G., Draper, S. J. & Simerly, R. B. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304, 108–110 (2004).
pubmed: 15064420
doi: 10.1126/science.1095004
Steculorum, S. M. et al. Neonatal ghrelin programs development of hypothalamic feeding circuits. J. Clin. Invest. 125, 846–858 (2015).
pubmed: 25607843
pmcid: 4319433
doi: 10.1172/JCI73688
Fuente-Martín, E. et al. Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes. J. Clin. Invest. 122, 3900–3913 (2012).
pubmed: 23064363
pmcid: 3484452
doi: 10.1172/JCI64102
Vogt, M. C. et al. Neonatal insulin action impairs hypothalamic neurocircuit formation in response to maternal high-fat feeding. Cell 156, 495–509 (2014).
pubmed: 24462248
pmcid: 4101521
doi: 10.1016/j.cell.2014.01.008
Haddad-Tóvolli, R. et al. Pro-opiomelanocortin (POMC) neuron translatome signatures underlying obesogenic gestational malprogramming in mice. Mol. Metab. 36, 100963 (2020).
pubmed: 32283518
pmcid: 7152705
doi: 10.1016/j.molmet.2020.02.006
Dennison, C. S., King, C. M., Dicken, M. S. & Hentges, S. T. Age-dependent changes in amino acid phenotype and the role of glutamate release from hypothalamic proopiomelanocortin neurons. J. Comp. Neurol. 524, 1222–1235 (2016).
pubmed: 26361382
doi: 10.1002/cne.23900
Nasif, S. et al. Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood. Proc. Natl Acad. Sci. USA 112, E1861–E1870 (2015).
pubmed: 25825735
pmcid: 4403183
doi: 10.1073/pnas.1500672112
Mirzadeh, Z. et al. Perineuronal net formation during the critical period for neuronal maturation in the hypothalamic arcuate nucleus. Nat. Metab. 1, 212–221 (2019).
pubmed: 31245789
pmcid: 6594569
doi: 10.1038/s42255-018-0029-0
Reichelt, A. C., Hare, D. J., Bussey, T. J. & Saksida, L. M. Perineuronal nets: plasticity, protection, and therapeutic potential. Trends Neurosci. 42, 458–470 (2019).
pubmed: 31174916
doi: 10.1016/j.tins.2019.04.003
Li, J., Tang, Y. & Cai, D. IKKβ/NF-κB disrupts adult hypothalamic neural stem cells to mediate a neurodegenerative mechanism of dietary obesity and pre-diabetes. Nat. Cell Biol. 14, 999–1012 (2012).
pubmed: 22940906
pmcid: 3463771
doi: 10.1038/ncb2562
Yoo, S. & Blackshaw, S. Regulation and function of neurogenesis in the adult mammalian hypothalamus. Prog. Neurobiol. 170, 53–66 (2018).
pubmed: 29631023
pmcid: 6173995
doi: 10.1016/j.pneurobio.2018.04.001
Piazza, P. V., Cota, D. & Marsicano, G. The CB1 receptor as the cornerstone of exostasis. Neuron 93, 1252–1274 (2017).
pubmed: 28334603
doi: 10.1016/j.neuron.2017.02.002
Sutton, A. K. & Krashes, M. J. Integrating hunger with rival motivations. Trends Endocrinol. Metab. 31, 495–507 (2020).
pubmed: 32387196
doi: 10.1016/j.tem.2020.04.006
Mandela, P., Yan, Y., LaRese, T., Eipper, B. A. & Mains, R. E. Elimination of Kalrn expression in POMC cells reduces anxiety-like behavior and contextual fear learning. Horm. Behav. 66, 430–438 (2014).
pubmed: 25014196
pmcid: 4127147
doi: 10.1016/j.yhbeh.2014.07.001
Qu, N. et al. A POMC-originated circuit regulates stress-induced hypophagia, depression, and anhedonia. Mol. Psychiatry 25, 1006–1021 (2020).
pubmed: 31485012
doi: 10.1038/s41380-019-0506-1
Rubinstein, M. et al. Absence of opioid stress-induced analgesia in mice lacking β-endorphin by site-directed mutagenesis. Proc. Natl Acad. Sci. USA 93, 3995–4000 (1996).
pubmed: 8633004
pmcid: 39474
doi: 10.1073/pnas.93.9.3995
Cerritelli, S., Hirschberg, S., Hill, R., Balthasar, N. & Pickering, A. E. Activation of brainstem pro-opiomelanocortin neurons produces opioidergic analgesia, bradycardia and bradypnoea. PLoS ONE 11, e0153187 (2016).
pubmed: 27077912
pmcid: 4831707
doi: 10.1371/journal.pone.0153187
Comeras, L. B., Herzog, H. & Tasan, R. O. Neuropeptides at the crossroad of fear and hunger: a special focus on neuropeptide Y. Ann. NY Acad. Sci. 1455, 59–80 (2019).
pubmed: 31271235
doi: 10.1111/nyas.14179
He, Z. et al. Cellular and synaptic reorganization of arcuate NPY/AgRP and POMC neurons after exercise. Mol. Metab. 18, 107–119 (2018).
pubmed: 30292523
pmcid: 6308029
doi: 10.1016/j.molmet.2018.08.011
Lim, B. K., Huang, K. W., Grueter, B. A., Rothwell, P. E. & Malenka, R. C. Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature 487, 183–189 (2012).
pubmed: 22785313
pmcid: 3397405
doi: 10.1038/nature11160
Klawonn, A. M. et al. Motivational valence is determined by striatal melanocortin 4 receptors. J. Clin. Invest. 128, 3160–3170 (2018).
pubmed: 29911992
pmcid: 6026003
doi: 10.1172/JCI97854
Bruschetta, G., Jin, S., Liu, Z.-W., Kim, J. D. & Diano, S. MC4R signaling in dorsal raphe nucleus controls feeding, anxiety, and depression. Cell Rep. 33, 108267 (2020).
pubmed: 33053350
doi: 10.1016/j.celrep.2020.108267
Bell, B. B. et al. Differential contribution of POMC and AgRP neurons to the regulation of regional autonomic nerve activity by leptin. Mol. Metab. 8, 1–12 (2018).
pubmed: 29289646
doi: 10.1016/j.molmet.2017.12.006
Do Carmo, J. M. et al. Control of blood pressure, appetite, and glucose by leptin in mice lacking leptin receptors in proopiomelanocortin neurons. Hypertension 57, 918–926 (2011).
pubmed: 21422382
doi: 10.1161/HYPERTENSIONAHA.110.161349
Jiang, J., Morgan, D. A., Cui, H. & Rahmouni, K. Activation of hypothalamic AgRP and POMC neurons evokes disparate sympathetic and cardiovascular responses. Am. J. Physiol. Heart Circ. Physiol. https://doi.org/10.1152/ajpheart.00411.2020 (2020).
Van der Klaauw, A. A. & Farooqi, I. S. The hunger genes: pathways to obesity. Cell 161, 119–132 (2015).
pubmed: 25815990
doi: 10.1016/j.cell.2015.03.008
Paeger, L. et al. Energy imbalance alters Ca
pubmed: 28762947
pmcid: 5538824
doi: 10.7554/eLife.25641
Thaler, J. P. et al. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 122, 153–162 (2012).
pubmed: 22201683
doi: 10.1172/JCI59660
Yi, C.-X. et al. TNFα drives mitochondrial stress in POMC neurons in obesity. Nat. Commun. 8, 15143 (2017).
pubmed: 28489068
pmcid: 5436136
doi: 10.1038/ncomms15143
Kim, J. D., Yoon, N. A., Jin, S. & Diano, S. Microglial UCP2 mediates inflammation and obesity induced by high-fat feeding. Cell Metab. 30, 952–962.e5 (2019).
pubmed: 31495690
pmcid: 7251564
doi: 10.1016/j.cmet.2019.08.010
Jais, A. & Brüning, J. C. Hypothalamic inflammation in obesity and metabolic disease. J. Clin. Invest. 127, 24–32 (2017).
pubmed: 28045396
pmcid: 5199695
doi: 10.1172/JCI88878
Purkayastha, S., Zhang, G. & Cai, D. Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB. Nat. Med. 17, 883–887 (2011).
pubmed: 21642978
pmcid: 3134198
doi: 10.1038/nm.2372
GBD 2015 Obesity Collaborators. Health effects of overweight and obesity in 195 countries over 25 years. N. Engl. J. Med. 377, 13–27 (2017).
doi: 10.1056/NEJMoa1614362
Aberdein, N. et al. Role of PTP1B in POMC neurons during chronic high-fat diet: sex differences in regulation of liver lipids and glucose tolerance. Am. J. Physiol. Regul. Integr. Comp. Physiol. 314, R478–R488 (2018).
pubmed: 29351427
doi: 10.1152/ajpregu.00287.2017
Burke, L. K. et al. Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons. Mol. Metab. 5, 245–252 (2016).
pubmed: 26977396
pmcid: 4770275
doi: 10.1016/j.molmet.2016.01.005
Padilla, S. L., Reef, D. & Zeltser, L. M. Defining POMC neurons using transgenic reagents: impact of transient Pomc expression in diverse immature neuronal populations. Endocrinology 153, 1219–1231 (2012).
pubmed: 22166984
doi: 10.1210/en.2011-1665
Lein, E., Borm, L. E. & Linnarsson, S. The promise of spatial transcriptomics for neuroscience in the era of molecular cell typing. Science 358, 64–69 (2017).
pubmed: 28983044
doi: 10.1126/science.aan6827
Moffitt, J. R. et al. Molecular, spatial, and functional single-cell profiling of the hypothalamic preoptic region. Science 362, eaau5324 (2018).
pubmed: 30385464
pmcid: 6482113
doi: 10.1126/science.aau5324
Hanchate, N. K. et al. Connect-seq to superimpose molecular on anatomical neural circuit maps. Proc. Natl Acad. Sci. USA 117, 4375–4384 (2020).
pubmed: 32034095
pmcid: 7049128
doi: 10.1073/pnas.1912176117
Fenno, L. E. et al. Targeting cells with single vectors using multiple-feature Boolean logic. Nat. Methods 11, 763–772 (2014).
pubmed: 24908100
pmcid: 4085277
doi: 10.1038/nmeth.2996
Fenno, L. E. et al. Comprehensive dual- and triple-feature intersectional single-vector delivery of diverse functional payloads to cells of behaving mammals. Neuron 107, 836–853.e11 (2020).
pubmed: 32574559
pmcid: 7687746
doi: 10.1016/j.neuron.2020.06.003
Grienberger, C. & Konnerth, A. Imaging calcium in neurons. Neuron 73, 862–885 (2012).
pubmed: 22405199
doi: 10.1016/j.neuron.2012.02.011
Betley, J. N. et al. Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature 521, 180–185 (2015).
pubmed: 25915020
pmcid: 4567040
doi: 10.1038/nature14416
Xu, Y. et al. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab. 29, 1232 (2019).
pubmed: 31067449
pmcid: 6553462
doi: 10.1016/j.cmet.2019.04.006
Wang, C. et al. TAp63 contributes to sexual dimorphism in POMC neuron functions and energy homeostasis. Nat. Commun. 9, 1544 (2018).
pubmed: 29670083
pmcid: 5906443
doi: 10.1038/s41467-018-03796-7
Müller, T. D., Clemmensen, C., Finan, B., DiMarchi, R. D. & Tschöp, M. H. Anti-obesity therapy: from rainbow pills to polyagonists. Pharmacol. Rev. 70, 712–746 (2018).
pubmed: 30087160
doi: 10.1124/pr.117.014803
Quarta, C. et al. Molecular integration of incretin and glucocorticoid action reverses immunometabolic dysfunction and obesity. Cell Metab. 26, 620–632.e6 (2017).
pubmed: 28943448
doi: 10.1016/j.cmet.2017.08.023
He, Z. et al. Direct and indirect effects of liraglutide on hypothalamic POMC and NPY/AgRP neurons—implications for energy balance and glucose control. Mol. Metab. 28, 120–134 (2019).
pubmed: 31446151
pmcid: 6822260
doi: 10.1016/j.molmet.2019.07.008
Secher, A. et al. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J. Clin. Invest. 124, 4473–4488 (2014).
pubmed: 25202980
pmcid: 4215190
doi: 10.1172/JCI75276
D’Agostino, G. et al. Nucleus of the solitary tract serotonin 5-HT
pubmed: 30146485
pmcid: 6371983
doi: 10.1016/j.cmet.2018.07.017