Control of Energy Expenditure by AgRP Neurons of the Arcuate Nucleus: Neurocircuitry, Signaling Pathways, and Angiotensin

  • Lisa L. Morselli
  • Kristin E. Claflin
  • Huxing Cui
  • Justin L. Grobe
Hypertension and the Kidney (RM Carey, Section Editor)
  • 135 Downloads
Part of the following topical collections:
  1. Topical Collection on Hypertension and the Kidney

Abstract

Purpose of Review

Here, we review the current understanding of the functional neuroanatomy of neurons expressing Agouti-related peptide (AgRP) and the angiotensin 1A receptor (AT1A) within the arcuate nucleus (ARC) in the control of energy balance.

Recent Findings

The development and maintenance of obesity involves suppression of resting metabolic rate (RMR). RMR control is integrated via AgRP and proopiomelanocortin neurons within the ARC. Their projections to other hypothalamic and extrahypothalamic nuclei contribute to RMR control, though relatively little is known about the contributions of individual projections and the neurotransmitters involved. Recent studies highlight a role for AT1A, localized to AgRP neurons, but the specific function of AT1A within these cells remains unclear.

Summary

AT1A functions within AgRP neurons to control RMR, but additional work is required to clarify its role within subpopulations of AgRP neurons projecting to distinct second-order nuclei, and the molecular mediators of its signaling within these cells.

Keywords

Obesity Bioenergetics Metabolism Renin-angiotensin system Leptin Agouti-related peptide 

Notes

Acknowledgements

The authors were supported by grants from the National Institutes of Health (HL134850, HL084207, HL007638, HL127673, MH109920, HL007121, DK117510), the American Heart Association (14PRE20380401, 15SFRN23730000, 18EIA33890055), the American Physiological Society, and the UIHC Center for Hypertension Research.

Authors’ Contributions

LLM drafted the manuscript, and all co-authors edited and approved the final version of the manuscript.

Compliance with Ethical Standards

Conflict of Interest

The authors declare no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki Declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Abarca-Gómez L, Abdeen ZA, Hamid ZA, Abu-Rmeileh NM, Acosta-Cazares B, Acuin C, et al. Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults. Lancet. 2017;390(10113):2627–42.  https://doi.org/10.1016/S0140-6736(17)32129-3.CrossRefGoogle Scholar
  2. 2.
    Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL. Trends in obesity among adults in the United States, 2005 to 2014. JAMA. 2016;315(21):2284–91.  https://doi.org/10.1001/jama.2016.6458.CrossRefPubMedGoogle Scholar
  3. 3.
    •• Fothergill E, Guo J, Howard L, Kerns JC, Knuth ND, Brychta R, et al. Persistent metabolic adaptation 6 years after “the biggest loser” competition. Obesity (Silver Spring, Md). 2016;24(8):1612–9.  https://doi.org/10.1002/oby.21538. This study highlights the major role that RMR plays in weight maintenance in humans. CrossRefGoogle Scholar
  4. 4.
    Rui L. Brain regulation of energy balance and body weight. Rev Endocr Metab Disord. 2013;14(4):387–407.  https://doi.org/10.1007/s11154-013-9261-9.CrossRefPubMedGoogle Scholar
  5. 5.
    • Pandit R, Beerens S, Adan RAH. Role of leptin in energy expenditure: the hypothalamic perspective. Am J Phys Regul Integr Comp Phys. 2017;312(6):R938–R47.  https://doi.org/10.1152/ajpregu.00045.2016. A comprehensive review of the role of leptin in the regulation of energy homeostasis Google Scholar
  6. 6.
    Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science. 1997;278(5335):135–8.  https://doi.org/10.1126/science.278.5335.135.CrossRefPubMedGoogle Scholar
  7. 7.
    Shutter JR, Graham M, Kinsey AC, Scully S, Luthy R, Stark KL. Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev. 1997;11(5):593–602.  https://doi.org/10.1101/gad.11.5.593.CrossRefPubMedGoogle Scholar
  8. 8.
    Yang Z, Tao YX. Biased signaling initiated by agouti-related peptide through human melanocortin-3 and -4 receptors. Biochim Biophys Acta. 2016;1862(9):1485–94.  https://doi.org/10.1016/j.bbadis.2016.05.008.CrossRefPubMedGoogle Scholar
  9. 9.
    Andermann ML, Lowell BB. Toward a wiring diagram understanding of appetite control. Neuron. 2017;95(4):757–78.  https://doi.org/10.1016/j.neuron.2017.06.014.CrossRefPubMedGoogle Scholar
  10. 10.
    Cui H, Lopez M, Rahmouni K. The cellular and molecular bases of leptin and ghrelin resistance in obesity. Nat Rev Endocrinol. 2017;13(6):338–51.  https://doi.org/10.1038/nrendo.2016.222.CrossRefPubMedGoogle Scholar
  11. 11.
    Tong Q, Ye CP, Jones JE, Elmquist JK, Lowell BB. Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat Neurosci. 2008;11(9):998–1000.  https://doi.org/10.1038/nn.2167.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Hilzendeger AM, Morgan DA, Brooks L, Dellsperger D, Liu X, Grobe JL, et al. A brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity. Am J Physiol Heart Circ Physiol. 2012;303(2):H197–206.  https://doi.org/10.1152/ajpheart.00974.2011.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    de Kloet AD, Pati D, Wang L, Hiller H, Sumners C, Frazier CJ, et al. Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus protect against diet-induced obesity. J Neurosci. 2013;33(11):4825–33.  https://doi.org/10.1523/JNEUROSCI.3806-12.2013.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Claflin KE, Grobe JL. Control of energy balance by the brain renin-angiotensin system. Curr Hypertens Rep. 2015;17(5):38.  https://doi.org/10.1007/s11906-015-0549-x.CrossRefPubMedGoogle Scholar
  15. 15.
    •• Claflin KE, Sandgren JA, Lambertz AM, Weidemann BJ, Littlejohn NK, Burnett CM, et al. Angiotensin AT1A receptors on leptin receptor-expressing cells control resting metabolism. J Clin Invest. 2017;127(4):1414–24.  https://doi.org/10.1172/JCI88641. This study demonstrates the critical role of AT1A, localized to AgRP-expressing neurons, in RMR control CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Grobe JL, Buehrer BA, Hilzendeger AM, Liu X, Davis DR, Xu D, et al. Angiotensinergic signaling in the brain mediates metabolic effects of deoxycorticosterone (DOCA)-salt in C57 mice. Hypertension. 2011;57(3):600–7.  https://doi.org/10.1161/hypertensionaha.110.165829.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Bagnol D, Lu XY, Kaelin CB, Day HE, Ollmann M, Gantz I, et al. Anatomy of an endogenous antagonist: relationship between Agouti-related protein and proopiomelanocortin in brain. J Neurosci. 1999;19(18):RC26.CrossRefPubMedGoogle Scholar
  18. 18.
    Wang D, He X, Zhao Z, Feng Q, Lin R, Sun Y, et al. Whole-brain mapping of the direct inputs and axonal projections of POMC and AgRP neurons. Front Neuroanat. 2015;9:40.  https://doi.org/10.3389/fnana.2015.00040.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Cano G, Passerin AM, Schiltz JC, Card JP, Morrison SF, Sved AF. Anatomical substrates for the central control of sympathetic outflow to interscapular adipose tissue during cold exposure. J Comp Neurol. 2003;460(3):303–26.  https://doi.org/10.1002/cne.10643.CrossRefPubMedGoogle Scholar
  20. 20.
    Morrison SF, Cao W-H, Madden CJ. Dorsomedial hypothalamic and brainstem pathways controlling thermogenesis in brown adipose tissue. J Therm Biol. 2004;29(7):333–7.  https://doi.org/10.1016/j.jtherbio.2004.08.006.CrossRefGoogle Scholar
  21. 21.
    Yoshida K, Konishi M, Nagashima K, Saper CB, Kanosue K. Fos activation in hypothalamic neurons during cold or warm exposure: projections to periaqueductal gray matter. Neuroscience. 2005;133(4):1039–46.  https://doi.org/10.1016/j.neuroscience.2005.03.044.CrossRefPubMedGoogle Scholar
  22. 22.
    Sutton AK, Myers MG Jr, Olson DP. The role of PVH circuits in leptin action and energy balance. Annu Rev Physiol. 2016;78(1):207–21.  https://doi.org/10.1146/annurev-physiol-021115-105347.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Cao WH, Fan W, Morrison SF. Medullary pathways mediating specific sympathetic responses to activation of dorsomedial hypothalamus. Neuroscience. 2004;126(1):229–40.  https://doi.org/10.1016/j.neuroscience.2004.03.013.CrossRefPubMedGoogle Scholar
  24. 24.
    Oldfield BJ, Giles ME, Watson A, Anderson C, Colvill LM, McKinley MJ. The neurochemical characterisation of hypothalamic pathways projecting polysynaptically to brown adipose tissue in the rat. Neuroscience. 2002;110(3):515–26.  https://doi.org/10.1016/S0306-4522(01)00555-3.CrossRefPubMedGoogle Scholar
  25. 25.
    Broberger C, Johansen J, Johansson C, Schalling M, Hokfelt T. The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. Proc Natl Acad Sci U S A. 1998;95(25):15043–8.  https://doi.org/10.1073/pnas.95.25.15043.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Elias CF, Saper CB, Maratos-Flier E, Tritos NA, Lee C, Kelly J, et al. Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. J Comp Neurol. 1998;402(4):442–59.  https://doi.org/10.1002/(SICI)1096-9861(19981228)402:4<442::AID-CNE2>3.0.CO;2-R.CrossRefPubMedGoogle Scholar
  27. 27.
    Haskell-Luevano C, Chen P, Li C, Chang K, Smith MS, Cameron JL, et al. Characterization of the neuroanatomical distribution of agouti-related protein immunoreactivity in the rhesus monkey and the rat. Endocrinology. 1999;140(3):1408–15.  https://doi.org/10.1210/endo.140.3.6544.CrossRefPubMedGoogle Scholar
  28. 28.
    Betley JN, Cao ZF, Ritola KD, Sternson SM. Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell. 2013;155(6):1337–50.  https://doi.org/10.1016/j.cell.2013.11.002.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Shi Z, Madden CJ, Arcuate BVL. Neuropeptide Y inhibits sympathetic nerve activity via multiple neuropathways. J Clin Invest. 2017;127(7):2868–80.  https://doi.org/10.1172/jci92008.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Zarjevski N, Cusin I, Vettor R, Rohner-Jeanrenaud F, Jeanrenaud B. Chronic intracerebroventricular neuropeptide-Y administration to normal rats mimics hormonal and metabolic changes of obesity. Endocrinology. 1993;133(4):1753–8.  https://doi.org/10.1210/endo.133.4.8404618.CrossRefPubMedGoogle Scholar
  31. 31.
    Egawa M, Yoshimatsu H, Bray GA, Neuropeptide Y. Suppresses sympathetic activity to interscapular brown adipose tissue in rats. Am J Phys. 1991;260(2 Pt 2):R328–34.Google Scholar
  32. 32.
    Luo N, Marcelin G, Liu SM, Schwartz G, Chua S Jr. Neuropeptide Y and agouti-related peptide mediate complementary functions of hyperphagia and reduced energy expenditure in leptin receptor deficiency. Endocrinology. 2011;152(3):883–9.  https://doi.org/10.1210/en.2010-1135.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Shi YC, Lau J, Lin Z, Zhang H, Zhai L, Sperk G, et al. Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN. Cell Metab. 2013;17(2):236–48.  https://doi.org/10.1016/j.cmet.2013.01.006.CrossRefPubMedGoogle Scholar
  34. 34.
    Madden CJ, Morrison SF. Neurons in the paraventricular nucleus of the hypothalamus inhibit sympathetic outflow to brown adipose tissue. Am J Phys Regul Integr Comp Phys. 2009;296(3):R831–43.  https://doi.org/10.1152/ajpregu.91007.2008.Google Scholar
  35. 35.
    Xu Y, O'Brien WG 3rd, Lee CC, Myers MG Jr, Tong Q. Role of GABA release from leptin receptor-expressing neurons in body weight regulation. Endocrinology. 2012;153(5):2223–33.  https://doi.org/10.1210/en.2011-2071.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Cowley MA, Pronchuk N, Fan W, Dinulescu DM, Colmers WF, Cone RD. Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron. 1999;24(1):155–63.  https://doi.org/10.1016/S0896-6273(00)80829-6.CrossRefPubMedGoogle Scholar
  37. 37.
    Balthasar N, Dalgaard LT, Lee CE, Yu J, Funahashi H, Williams T, et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell. 2005;123(3):493–505.  https://doi.org/10.1016/j.cell.2005.08.035.CrossRefPubMedGoogle Scholar
  38. 38.
    Garfield AS, Li C, Madara JC, Shah BP, Webber E, Steger JS, et al. A neural basis for melanocortin-4 receptor-regulated appetite. Nat Neurosci. 2015;18(6):863–71.  https://doi.org/10.1038/nn.4011.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Chitravanshi VC, Kawabe K, Sapru HN. Stimulation of the hypothalamic arcuate nucleus increases brown adipose tissue nerve activity via hypothalamic paraventricular and dorsomedial nuclei. Am J Physiol Heart Circ Physiol. 2016;311(2):H433–44.  https://doi.org/10.1152/ajpheart.00176.2016.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Morrison SF, Nakamura K. Central neural pathways for thermoregulation. Front Biosci (Landmark Ed). 2011;16(1):74–104.  https://doi.org/10.2741/3677.CrossRefGoogle Scholar
  41. 41.
    • Contreras C, Nogueiras R, Dieguez C, Rahmouni K, Lopez M. Traveling from the hypothalamus to the adipose tissue: the thermogenic pathway. Redox Biol. 2017;12:854–63.  https://doi.org/10.1016/j.redox.2017.04.019. A comprehensive review of the neurocircuitry of non-shivering thermogenesis. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Enriori PJ, Sinnayah P, Simonds SE, Garcia Rudaz C, Cowley MA. Leptin action in the dorsomedial hypothalamus increases sympathetic tone to brown adipose tissue in spite of systemic leptin resistance. J Neurosci. 2011;31(34):12189–97.  https://doi.org/10.1523/JNEUROSCI.2336-11.2011.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Kishi T, Aschkenasi CJ, Choi BJ, Lopez ME, Lee CE, Liu H, et al. Neuropeptide Y Y1 receptor mRNA in rodent brain: distribution and colocalization with melanocortin-4 receptor. J Comp Neurol. 2005;482(3):217–43.  https://doi.org/10.1002/cne.20432.CrossRefPubMedGoogle Scholar
  44. 44.
    Liu T, Kong D, Shah BP, Ye C, Koda S, Saunders A, et al. Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone. Neuron. 2012;73(3):511–22.  https://doi.org/10.1016/j.neuron.2011.11.027.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Berthoud HR, Munzberg H. The lateral hypothalamus as integrator of metabolic and environmental needs: from electrical self-stimulation to opto-genetics. Physiol Behav. 2011;104(1):29–39.  https://doi.org/10.1016/j.physbeh.2011.04.051.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Lammers GJ, Pijl H, Iestra J, Langius JA, Buunk G, Meinders AE. Spontaneous food choice in narcolepsy. Sleep. 1996;19(1):75–6.  https://doi.org/10.1093/sleep/19.1.75.CrossRefPubMedGoogle Scholar
  47. 47.
    Dahmen N, Bierbrauer J, Kasten M. Increased prevalence of obesity in narcoleptic patients and relatives. Eur Arch Psychiatry Clin Neurosci. 2001;251(2):85–9.  https://doi.org/10.1007/s004060170057.CrossRefPubMedGoogle Scholar
  48. 48.
    Sellayah D, Bharaj P, Sikder D. Orexin is required for brown adipose tissue development, differentiation, and function. Cell Metab. 2011;14(4):478–90.  https://doi.org/10.1016/j.cmet.2011.08.010.CrossRefPubMedGoogle Scholar
  49. 49.
    Berthoud HR, Patterson LM, Sutton GM, Morrison C, Zheng H. Orexin inputs to caudal raphe neurons involved in thermal, cardiovascular, and gastrointestinal regulation. Histochem Cell Biol. 2005;123(2):147–56.  https://doi.org/10.1007/s00418-005-0761-x.CrossRefPubMedGoogle Scholar
  50. 50.
    Tupone D, Madden CJ, Cano G, Morrison SF. An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis. J Neurosci. 2011;31(44):15944–55.  https://doi.org/10.1523/JNEUROSCI.3909-11.2011.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Fu LY, Acuna-Goycolea C, van den Pol AN. Neuropeptide Y inhibits hypocretin/orexin neurons by multiple presynaptic and postsynaptic mechanisms: tonic depression of the hypothalamic arousal system. J Neurosci. 2004;24(40):8741–51.  https://doi.org/10.1523/JNEUROSCI.2268-04.2004.CrossRefPubMedGoogle Scholar
  52. 52.
    Eggermann E, Bayer L, Serafin M, Saint-Mleux B, Bernheim L, Machard D, et al. The wake-promoting hypocretin-orexin neurons are in an intrinsic state of membrane depolarization. J Neurosci. 2003;23(5):1557–62.CrossRefPubMedGoogle Scholar
  53. 53.
    Xie X, Crowder TL, Yamanaka A, Morairty SR, Lewinter RD, Sakurai T, et al. GABA(B) receptor-mediated modulation of hypocretin/orexin neurones in mouse hypothalamus. J Physiol. 2006;574(Pt 2):399–414.  https://doi.org/10.1113/jphysiol.2006.108266.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Guyon A, Conductier G, Rovere C, Enfissi A, Nahon JL. Melanin-concentrating hormone producing neurons: activities and modulations. Peptides. 2009;30(11):2031–9.  https://doi.org/10.1016/j.peptides.2009.05.028.CrossRefPubMedGoogle Scholar
  55. 55.
    Parks GS, Wang L, Wang Z, Civelli O. Identification of neuropeptide receptors expressed by melanin-concentrating hormone neurons. J Comp Neurol. 2014;522(17):3817–33.  https://doi.org/10.1002/cne.23642.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Cui H, Sohn JW, Gautron L, Funahashi H, Williams KW, Elmquist JK, et al. Neuroanatomy of melanocortin-4 receptor pathway in the lateral hypothalamic area. J Comp Neurol. 2012;520(18):4168–83.  https://doi.org/10.1002/cne.23145.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Morrison SF, Madden CJ, Tupone D. Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell Metab. 2014;19(5):741–56.  https://doi.org/10.1016/j.cmet.2014.02.007.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Gavini CK, Jones WC 2nd, Novak CM. Ventromedial hypothalamic melanocortin receptor activation: regulation of activity energy expenditure and skeletal muscle thermogenesis. J Physiol. 2016;594(18):5285–301.  https://doi.org/10.1113/JP272352.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Contreras C, Gonzalez F, Ferno J, Dieguez C, Rahmouni K, Nogueiras R, et al. The brain and brown fat. Ann Med. 2015;47(2):150–68.  https://doi.org/10.3109/07853890.2014.919727.CrossRefPubMedGoogle Scholar
  60. 60.
    Song CK, Vaughan CH, Keen-Rhinehart E, Harris RB, Richard D, Bartness TJ. Melanocortin-4 receptor mRNA expressed in sympathetic outflow neurons to brown adipose tissue: neuroanatomical and functional evidence. Am J Phys Regul Integr Comp Phys. 2008;295(2):R417–28.  https://doi.org/10.1152/ajpregu.00174.2008.Google Scholar
  61. 61.
    Monge-Roffarello B, Labbe SM, Lenglos C, Caron A, Lanfray D, Samson P, et al. The medial preoptic nucleus as a site of the thermogenic and metabolic actions of melanotan II in male rats. Am J Phys Regul Integr Comp Phys. 2014;307(2):R158–66.  https://doi.org/10.1152/ajpregu.00059.2014.Google Scholar
  62. 62.
    Krashes MJ, Shah BP, Madara JC, Olson DP, Strochlic DE, Garfield AS, et al. An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature. 2014;507(7491):238–42.  https://doi.org/10.1038/nature12956.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Garfield AS, Shah BP, Burgess CR, Li MM, Li C, Steger JS, et al. Dynamic GABAergic afferent modulation of AgRP neurons. Nat Neurosci. 2016;19(12):1628–35.  https://doi.org/10.1038/nn.4392.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Samuels ER, Szabadi E. Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part II: physiological and pharmacological manipulations and pathological alterations of locus coeruleus activity in humans. Curr Neuropharmacol. 2008;6(3):254–85.  https://doi.org/10.2174/157015908785777193.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Hermann DM, Luppi PH, Peyron C, Hinckel P, Jouvet M. Afferent projections to the rat nuclei raphe magnus, raphe pallidus and reticularis gigantocellularis pars alpha demonstrated by iontophoretic application of choleratoxin (subunit b). J Chem Neuroanat. 1997;13(1):1–21.  https://doi.org/10.1016/S0891-0618(97)00019-7.CrossRefPubMedGoogle Scholar
  66. 66.
    Kopp J, Xu ZQ, Zhang X, Pedrazzini T, Herzog H, Kresse A, et al. Expression of the neuropeptide Y Y1 receptor in the CNS of rat and of wild-type and Y1 receptor knock-out mice. Focus on immunohistochemical localization. Neuroscience. 2002;111(3):443–532.  https://doi.org/10.1016/S0306-4522(01)00463-8.CrossRefPubMedGoogle Scholar
  67. 67.
    Rathner JA, Morrison SF. Rostral ventromedial periaqueductal gray: a source of inhibition of the sympathetic outflow to brown adipose tissue. Brain Res. 2006;1077(1):99–107.  https://doi.org/10.1016/j.brainres.2006.01.035.CrossRefPubMedGoogle Scholar
  68. 68.
    Gelez H, Poirier S, Facchinetti P, Allers KA, Wayman C, Bernabe J, et al. Neuroanatomical distribution of the melanocortin-4 receptors in male and female rodent brain. J Chem Neuroanat. 2010;40(4):310–24.  https://doi.org/10.1016/j.jchemneu.2010.09.002.CrossRefPubMedGoogle Scholar
  69. 69.
    Wu Q, Boyle MP, Palmiter RD. Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell. 2009;137(7):1225–34.  https://doi.org/10.1016/j.cell.2009.04.022.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Atasoy D, Betley JN, Su HH, Sternson SM. Deconstruction of a neural circuit for hunger. Nature. 2012;488(7410):172–7.  https://doi.org/10.1038/nature11270.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Alhadeff AL, Golub D, Hayes MR, Grill HJ. Peptide YY signaling in the lateral parabrachial nucleus increases food intake through the Y1 receptor. Am J Physiol Endocrinol Metab. 2015;309(8):E759–66.  https://doi.org/10.1152/ajpendo.00346.2015.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    •• Romanov RA, Zeisel A, Bakker J, Girach F, Hellysaz A, Tomer R, et al. Molecular interrogation of hypothalamic organization reveals distinct dopamine neuronal subtypes. Nat Neurosci. 2017;20(2):176–88.  https://doi.org/10.1038/nn.4462. This study utilized single-cell RNAsequencing to map transcriptomes of individual neurons of the hypothalamus, enabling dissection of traditional classes of neurons (such as ‘AgRP’ neurons) into distinct subsets such as those that do, versus do not, express AT1A CrossRefPubMedGoogle Scholar
  73. 73.
    Sapouckey SA, Deng G, Sigmund CD, Grobe JL. Potential mechanisms of hypothalamic renin-angiotensin system activation by leptin and DOCA-salt for the control of resting metabolism. Physiol Genomics. 2017;  https://doi.org/10.1152/physiolgenomics.00087.2017.

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Lisa L. Morselli
    • 1
    • 2
  • Kristin E. Claflin
    • 1
  • Huxing Cui
    • 1
    • 3
    • 4
    • 5
    • 6
    • 7
  • Justin L. Grobe
    • 1
    • 3
    • 4
    • 5
    • 6
    • 7
  1. 1.Department of PharmacologyUniversity of IowaIowa CityUSA
  2. 2.Department of Internal Medicine, Division of EndocrinologyUniversity of IowaIowa CityUSA
  3. 3.Center for Hypertension ResearchUniversity of IowaIowa CityUSA
  4. 4.Obesity Research & Education InitiativeUniversity of IowaIowa CityUSA
  5. 5.Fraternal Order of Eagles Diabetes Research CenterUniversity of IowaIowa CityUSA
  6. 6.Iowa Neuroscience InstituteUniversity of IowaIowa CityUSA
  7. 7.Abboud Cardiovascular Research CenterUniversity of IowaIowa CityUSA

Personalised recommendations