Skip to main content
SpringerLink
Log in

Electrophysiological Analysis of Circuits Controlling Energy Homeostasis

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Since the discovery of leptin and the central melanocortin circuit, electrophysiological studies have played a major role in elucidating mechanisms underlying energy homeostasis. This review highlights the contribution of findings made by electrophysiological measurements to the current understanding of hypothalamic neuronal networks involved in energy homeostasis with a specific focus on the arcuate–paraventricular nucleus circuit.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Almli CR (1978) The ontogeny of feeding and drinking: effects of early brain damage. Neurosci Biobehav Rev 2:281–300

    Article  Google Scholar 

  2. Leibowitz SF, Hammer NJ, Chang K (1981) Hypothalamic paraventricular nucleus lesions produce overeating and obesity in the rat. Physiol Behav 27:1031–1040

    Article  PubMed  CAS  Google Scholar 

  3. Olney JW (1969) Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 164:719–721

    Article  PubMed  CAS  Google Scholar 

  4. Sims JS, Lorden JF (1986) Effect of paraventricular nucleus lesions on body weight, food intake and insulin levels. Behav Brain Res 22:265–281

    Article  PubMed  CAS  Google Scholar 

  5. Ibrahim N, Bosch MA, Smart JL, Qiu J, Rubinstein M, Ronnekleiv OK, Low MJ, Kelly MJ (2003) Hypothalamic proopiomelanocortin neurons are glucose responsive and express K(ATP) channels. Endocrinology 144:1331–1340

    Article  PubMed  CAS  Google Scholar 

  6. Roselli-Rhefus L, Mountjoy KG, Robbins LS, Mortrud MT, Low MJ, Tatro JB, Entwistle ML, Simerly RB, Cone RC (1993) Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc Natl Acad Sci U S A 90:8856–8860

    Article  Google Scholar 

  7. Ghamari-Langroudi M, Colmers WF, Cone RD (2005) PYY3–36 inhibits the action potential firing activity of POMC neurons of arcuate nucleus through postsynaptic Y2 receptors. Cell Metabol 2:191–199

    Article  CAS  Google Scholar 

  8. Jobst EE, Enriori PJ, Cowley MA (2004) The electrophysiology of feeding circuits. Trends Endocrinol Metabol 15:488–499

    Article  CAS  Google Scholar 

  9. Poulain DA, Wakerley JB (1982) Electrophysiology of hypothalamic magnocellular neurones secreting oxytocin and vasopressin. Neuroscience 7:773–808

    Article  PubMed  CAS  Google Scholar 

  10. Gasparini S, Saviane C, Voronin LL, Cherubini E (2000) Silent synapses in the developing hippocampus: lack of functional AMPA receptors or low probability of glutamate release? Proc Natl Acad Sci U S A 97:9741–9746

    Article  PubMed  CAS  Google Scholar 

  11. Banks WA, Kastin AJ, Huang W, Jaspan JB, Maness LM (1996) Leptin enters the brain by a saturable system independent of insulin. Peptides 17:305–311

    Article  PubMed  CAS  Google Scholar 

  12. Cone RD, Cowley MA, Butler AA, Fan W, Marks DL, Low MJ (2001) The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis. Int J Obes Relat Metab Disord 25(Suppl 5):S63–S67

    Article  PubMed  CAS  Google Scholar 

  13. Elmquist JK, Ahima RS, Maratos Flier E, Flier JS, Saper CB (1997) Leptin activates neurons in ventrobasal hypothalamus and brainstem. Endocrinology 138:839–842

    Article  PubMed  CAS  Google Scholar 

  14. Marks JL, Porte D Jr, Stahl WL, Baskin DG (1990) Localization of insulin receptor mRNA in rat brain by in situ hybridization. Endocrinology 127:3234–3236

    Article  PubMed  CAS  Google Scholar 

  15. Willesen M, Kristensen P, Romer J (1999) Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology 70:306–316

    Article  PubMed  CAS  Google Scholar 

  16. Gehlert DR, Beavers LS, Johnson D, Gackenheimer SL, Schober DA, Gadski RA (1996) Expression cloning of a human brain neuropeptide Y Y2 receptor. Mol Pharmacol 49:224–228

    PubMed  CAS  Google Scholar 

  17. Williams KW, Margatho LO, Lee CE, Choi M, Lee S, Scott MM, Elias CF, Elmquist JK (2010) Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. J Neurosci 30:2472–2479

    Article  PubMed  CAS  Google Scholar 

  18. Elias CF, Lee C, Kelly J, Aschkenasi C, Ahima RS, Couceyro PR, Kuhar MJ, Saper CB, Elmquist JK (1998) Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron 21:1375–1385

    Article  PubMed  CAS  Google Scholar 

  19. Hentges ST, Nishiyama M, Overstreet LS, Stenzel-Poore M, Williams JT, Low MJ (2004) GABA release from proopiomelanocortin neurons. J Neurosci 24:1578–1583

    Article  PubMed  CAS  Google Scholar 

  20. Hentges ST, Otero-Corchon V, Pennock RL, King CM, Low MJ (2009) Proopiomelanocortin expression in both GABA and glutamate neurons. J Neurosci 29:13684–13690

    Article  PubMed  CAS  Google Scholar 

  21. Tong Q, Ye CP, Jones JE, Elmquist JK, Lowell BB (2008) Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat Neurosci 11:998–1000

    Article  PubMed  CAS  Google Scholar 

  22. Smart JL, Tolle V, Low MJ (2006) Glucocorticoids exacerbate obesity and insulin resistance in neuron-specific proopiomelanocortin-deficient mice. J Clin Invest 116:495–505

    Article  PubMed  CAS  Google Scholar 

  23. Bewick GA, Gardiner JV, Dhillo WS, Kent AS, White NE, Webster Z, Ghatei MA, Bloom SR (2005) Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J 19:1680–1682

    PubMed  CAS  Google Scholar 

  24. Sainsbury A, Schwarzer C, Couzens M, Fetissov S, Furtinger S, Jenkins A, Cox HM, Sperk G, Hokfelt T, Herzog H (2002) Important role of hypothalamic Y2 receptors in body weight regulation revealed in conditional knockout mice. Proc Natl Acad Sci U S A 99:8938–8943

    Article  PubMed  CAS  Google Scholar 

  25. Wu Q, Boyle MP, Palmiter RD (2009) Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell 137:1225–1234

    Article  PubMed  Google Scholar 

  26. Aponte Y, Atasoy D, Sternson SM (2011) AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat Neurosci 14:351–355

    Article  PubMed  CAS  Google Scholar 

  27. Krashes MJ, Koda S, Ye C, Rogan SC, Adams AC, Cusher DS, Maratos-Flier E, Roth BL, Lowell BB (2011) Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Investig 121:1424–1428

    Article  PubMed  CAS  Google Scholar 

  28. Tolle V, Low MJ (2008) In vivo evidence for inverse agonism of agouti-related peptide in the central nervous system of proopiomelanocortin-deficient mice. Diabetes 57:86–94

    Article  PubMed  CAS  Google Scholar 

  29. Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8:571–578

    Article  PubMed  CAS  Google Scholar 

  30. Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, Cone RD, Low MJ (2001) Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411:480–484

    Article  PubMed  CAS  Google Scholar 

  31. Padilla SL, Reef D, Zeltser LM (2012) Defining POMC neurons using transgenic reagents: impact of transient POMC expression in diverse immature neuronal populations. Endocrinology 153(2)

  32. Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte D Jr (1996) Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat Med 2:589–593

    Article  PubMed  CAS  Google Scholar 

  33. Elmquist JK, Bjorbaek C, Ahima RS, Flier JS, Saper CB (1998) Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol 395:535–547

    Article  PubMed  CAS  Google Scholar 

  34. Cheung CC, Clifton DK, Steiner RA (1997) Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinol 138:4489–4492

    Article  CAS  Google Scholar 

  35. Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, Morgan PJ, Trayhurn P (1996) Coexpression of leptin receptor and preproneuropeptide Y mRNA in arcuate nucleus of mouse hypothalamus. J Neuroendocrinol 8:733–735

    Article  PubMed  CAS  Google Scholar 

  36. Scott MM, Lachey JL, Sternson SM, Lee CE, Elias CF, Friedman JM, Elmquist JK (2009) Leptin targets in the mouse brain. Wiley Subscription Services, New York, pp 518–532

    Google Scholar 

  37. Vong L, Ye C, Yang Z, Choi B, Chua S Jr, Lowell Bradford B (2011) Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71:142–154

    Article  PubMed  CAS  Google Scholar 

  38. Morrison CD, Morton GJ, Niswender KD, Gelling RW, Schwartz MW (2005) Leptin inhibits hypothalamic Npy and Agrp gene expression via a mechanism that requires phosphatidylinositol 3-OH-kinase signaling. Am J Physiol Endocrinol Metab 289:E1051–E1057

    Article  PubMed  CAS  Google Scholar 

  39. Elias CF, Aschkenasi C, Lee C, Kelly J, Ahima RS, Bjorbaek C, Flier JS, Saper CB, Elmquist JK (1999) Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23:775–786

    Article  PubMed  CAS  Google Scholar 

  40. Hayes MR, Skibicka KP, Leichner TM, Guarnieri DJ, DiLeone RJ, Bence KK, Grill HJ (2010) Endogenous leptin signaling in the caudal nucleus tractus solitarius and area postrema is required for energy balance regulation. Cell Metabol 11:77–83

    Article  CAS  Google Scholar 

  41. Hill JW, Williams KW, Ye C, Luo J, Balthasar N, Coppari R, Cowley MA, Cantley LC, Lowell BB, Elmquist JK (2008) Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice. J Clin Investig 118:1796–1805

    Article  PubMed  CAS  Google Scholar 

  42. Qiu J, Fang Y, Ronnekleiv OK, Kelly MJ (2010) Leptin excites proopiomelanocortin neurons via activation of TRPC channels. J Neurosci 30:1560–1565

    Article  PubMed  CAS  Google Scholar 

  43. Wang JH, Wang F, Yang MJ, Yu DF, Wu WN, Liu J, Ma LQ, Cai F, Chen JG (2008) Leptin regulated calcium channels of neuropeptide Y and proopiomelanocortin neurons by activation of different signal pathways. Neuroscience 156:89–98

    Article  PubMed  CAS  Google Scholar 

  44. van den Top M, Lee K, Whyment AD, Blanks AM, Spanswick D (2004) Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus. Nat Neurosci 7:493–494

    Article  PubMed  CAS  Google Scholar 

  45. Choudhury AI, Heffron H et al (2005) The role of insulin receptor substrate 2 in hypothalamic and beta cell function. J Clin Invest 115(4):940–950

    Google Scholar 

  46. Plum L, Ma X et al (2006) Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. J Clin Invest 116(7):1886–1901

    Google Scholar 

  47. Könner AC, Janoschek R, Plum L, Jordan SD, Rother E, Ma X, Xu C, Enriori P, Hampel B, Barsh GS, Kahn CR, Cowley MA, Ashcroft FM, Brüning JC (2007) Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metabol 5:438–449

    Article  CAS  Google Scholar 

  48. Pocai A, Lam TKT, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, Aguilar-Bryan L, Rossetti L (2005) Hypothalamic KATP channels control hepatic glucose production. Nature 434:1026–1031

    Article  PubMed  CAS  Google Scholar 

  49. Al-Qassab H, Smith MA et al (2009) Dominant Role of the p110β Isoform of PI3K over p110α in Energy Homeostasis Regulation by POMC and AgRP Neurons. Cell Metabolism 10(5):343–354

    Google Scholar 

  50. Spanswick D, Smith MA, Mirshamsi S, Routh VH, Ashford ML (2000) Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat Neurosci 3:757–758

    Article  PubMed  CAS  Google Scholar 

  51. Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML, Garcia-Segura LM, Nillni EA, Mendez P, Low MJ, Sotonyi P, Friedman JM, Liu H, Pinto S, Colmers WF, Cone RD, Horvath TL (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37:649–661

    Article  PubMed  CAS  Google Scholar 

  52. Abizaid A, Liu Z-W, Andrews ZB, Shanabrough M, Borok E, Elsworth JD, Roth RH, Sleeman MW, Picciotto MR, Tschöp MH, Gao X-B, Horvath TL (2006) Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J Clin Investig 116:3229–3239

    Article  PubMed  CAS  Google Scholar 

  53. Kohno D, Gao HZ, Muroya S, Kikuyama S, Yada T (2003) Ghrelin directly interacts with neuropeptide-Y-containing neurons in the rat arcuate nucleus: Ca2+ signaling via protein kinase A and N-type channel-dependent mechanisms and cross-talk with leptin and orexin. Diabetes 52:948–956

    Article  PubMed  CAS  Google Scholar 

  54. Kohno D, Sone H, Minokoshi Y, Yada T (2008) Ghrelin raises [Ca2+]i via AMPK in hypothalamic arcuate nucleus NPY neurons. Biochem Biophys Res Commun 366:388–392

    Article  PubMed  CAS  Google Scholar 

  55. Hewson AK, Dickson SL (2000) Systemic administration of ghrelin induces Fos and Egr-1 proteins in the hypothalamic arcuate nucleus of fasted and fed rats. J Neuroendocrinol 12:1047–1049

    Article  PubMed  CAS  Google Scholar 

  56. Kamegai J, Tamura H, Shimizu T, Ishii S, Sugihara H, Wakabayashi I (2001) Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and agouti-related protein mRNA levels and body weight in rats. Diabetes 50:2438–2443

    Article  PubMed  CAS  Google Scholar 

  57. Nakazato M, Murakami N et al (2001) A role for ghrelin in the central regulation of feeding. Nature 409:194–198

    Google Scholar 

  58. Goto M, Arima H et al (2006) Ghrelin increases neuropeptide Y and agouti-related peptide gene expression in the arcuate nucleus in rat hypothalamic organotypic cultures. Endocrinology 147(11):5102–9

    Google Scholar 

  59. Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA, Dakin CL, Wren AM, Brynes AE, Low MJ, Ghatei MA, Cone RD, Bloom SR (2002) Gut hormone PYY(3–36) physiologically inhibits food intake. Nature 418:650–654

    Article  PubMed  CAS  Google Scholar 

  60. Acuna-Goycolea C, van den Pol AN (2005) Peptide YY(3–36) inhibits both anorexigenic proopiomelanocortin and orexigenic neuropeptide Y neurons: implications for hypothalamic regulation of energy homeostasis. J Neurosci 25:10510–10519

    Article  PubMed  CAS  Google Scholar 

  61. Ma X, Zubcevic L, Bruning JC, Ashcroft FM, Burdakov D (2007) Electrical inhibition of identified anorexigenic POMC neurons by orexin/hypocretin. J Neurosci 27:1529–1533

    Article  PubMed  CAS  Google Scholar 

  62. Muroya S, Funahashi H, Yamanaka A, Kohno D, Uramura K, Nambu T, Shibahara M, Kuramochi M, Takigawa M, Yanagisawa M, Sakurai T, Shioda S, Yada T (2004) Orexins (hypocretins) directly interact with neuropeptide Y, POMC and glucose-responsive neurons to regulate Ca 2+ signaling in a reciprocal manner to leptin: orexigenic neuronal pathways in the mediobasal hypothalamus. Eur J Neurosci 19:1524–1534

    Article  PubMed  Google Scholar 

  63. Acuna-Goycolea C, van den Pol AN (2009) Neuroendocrine proopiomelanocortin neurons are excited by hypocretin/orexin. J Neurosci 29:1503–1513

    Article  PubMed  CAS  Google Scholar 

  64. Guan JL, Saotome T, Wang QP, Funahashi H, Hori T, Tanaka S, Shioda S (2001) Orexinergic innervation of POMC-containing neurons in the rat arcuate nucleus. Neuroreport 12:547–551

    Article  PubMed  CAS  Google Scholar 

  65. Burdakov D, Liss B, Ashcroft FM (2003) Orexin excites GABAergic neurons of the arcuate nucleus by activating the sodium–calcium exchanger. J Neurosci 23:4951–4957

    PubMed  CAS  Google Scholar 

  66. Myers MG, Cowley MA, Münzberg H (2008) Mechanisms of leptin action and leptin resistance. Annu Rev Physiol 70:537–556

    Article  PubMed  CAS  Google Scholar 

  67. Balthasar N, Coppari R, McMinn J, Liu SM, Lee CE, Tang V, Kenny CD, McGovern RA, Chua SC Jr, Elmquist JK, Lowell BB (2004) Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42:983–991

    Article  PubMed  CAS  Google Scholar 

  68. van de Wall E, Leshan R, Xu AW, Balthasar N, Coppari R, Liu SM, Jo YH, MacKenzie RG, Allison DB, Dun NJ, Elmquist J, Lowell BB, Barsh GS, de Luca C, Myers MG Jr, Schwartz GJ, Chua SC Jr (2008) Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion. Endocrinology 149:1773–1785

    Article  PubMed  CAS  Google Scholar 

  69. Dhillon H, Zigman JM, Ye C, Lee CE, McGovern RA, Tang V, Kenny CD, Christiansen LM, White RD, Edelstein EA, Coppari R, Balthasar N, Cowley MA, Chua S, Elmquist JK, Lowell BB (2006) Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 49:191–203

    Article  PubMed  CAS  Google Scholar 

  70. Ghamari-Langroudi M, Srisai D, Cone RD (2011) Multinodal regulation of the arcuate/paraventricular nucleus circuit by leptin. Proc Natl Acad Sci 108:355–360

    Article  PubMed  CAS  Google Scholar 

  71. Ghamari-Langroudi M, Vella KR, Srisai D, Sugrue ML, Hollenberg AN, Cone RD (2010) Regulation of thyrotropin-releasing hormone-expressing neurons in paraventricular nucleus of the hypothalamus by signals of adiposity. Mol Endocrinol 24:2366–2381

    Article  PubMed  CAS  Google Scholar 

  72. Brief DJ, Davis JD (1984) Reduction of food intake and body weight by chronic intraventricular insulin infusion. Brain Res Bull 12:571–575

    Article  PubMed  CAS  Google Scholar 

  73. Woods SC, Lotter EC, McKay LD, Porte D Jr (1979) Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282:503–505

    Article  PubMed  CAS  Google Scholar 

  74. Baura GD, Foster DM, Porte D Jr, Kahn SE, Bergman RN, Cobelli C, Schwartz MW (1993) Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain. J Clin Invest 92:1824–1830

    Article  PubMed  CAS  Google Scholar 

  75. Havrankova J, Fau-Roth J, Roth J, Fau-Brownstein M, Brownstein M (1978) Insulin receptors are widely distributed in the central nervous system of the rat. Nature 272:827–829

    Article  PubMed  CAS  Google Scholar 

  76. Koch L, Wunderlich FT, Seibler J, Könner AC, Hampel B, Irlenbusch S, Brabant G, Kahn CR, Schwenk F, Brüning JC (2008) Central insulin action regulates peripheral glucose and fat metabolism in mice. J Clin Investig 118:2132–2147

    PubMed  CAS  Google Scholar 

  77. Obici S, Zhang BB, Karkanias G, Rossetti L (2002) Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8:1376–1382

    Article  PubMed  CAS  Google Scholar 

  78. Obici S, Feng Z, Karkanias G, Baskin DG, Rossetti L (2002) Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci 5:566–572

    Article  PubMed  CAS  Google Scholar 

  79. Gelling RW, Morton GJ, Morrison CD, Niswender KD, Myers MG Jr, Rhodes CJ, Schwartz MW (2006) Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes. Cell Metabol 3:67–73

    Article  CAS  Google Scholar 

  80. Lin HV, Plum L, Ono H, Gutiérrez-Juárez R, Shanabrough M, Borok E, Horvath TL, Rossetti L, Accili D (2010) Divergent regulation of energy expenditure and hepatic glucose production by insulin receptor in agouti-related protein and POMC neurons. Diabetes 59:337–346

    Article  PubMed  CAS  Google Scholar 

  81. van den Hoek AM, van Heijningen C, Schrö-van der Elst JP, Ouwens DM, Havekes LM, Romijn JA, Kalsbeek A, Pijl H (2008) Intracerebroventricular administration of neuropeptide Y induces hepatic insulin resistance via sympathetic innervation. Diabetes 57:2304–2310

    Article  PubMed  CAS  Google Scholar 

  82. Carvalheira JB, Torsoni MA, Ueno M, Amaral ME, Araujo EP, Velloso LA, Gontijo JA, Saad MJ (2005) Cross-talk between the insulin and leptin signaling systems in rat hypothalamus. Obes Res 13:48–57

    Article  PubMed  CAS  Google Scholar 

  83. Morton GJ, Gelling RW, Niswender KD, Morrison CD, Rhodes CJ, Schwartz MW (2005) Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell Metabol 2:411–420

    Article  CAS  Google Scholar 

  84. Niswender KD, Morrison CD, Clegg DJ, Olson R, Baskin DG, Myers MG Jr, Seeley RJ, Schwartz MW (2003) Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes 52:227–231

    Article  PubMed  CAS  Google Scholar 

  85. Niswender K, Morton G, Stearns W, Rhodes C, Myers M, Schwartz M (2001) Intracellular signaling: key enzyme in leptin-induced anorexia. Nature 413:794–795

    Article  PubMed  CAS  Google Scholar 

  86. Castañeda TR, Tong J, Datta R, Culler M, Tschöp MH (2010) Ghrelin in the regulation of body weight and metabolism. Front Neuroendocrinol 31:44–60

    Article  PubMed  CAS  Google Scholar 

  87. Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M, Sirinathsinghji DJ, Dean DC, Melillo DG, Van der Ploeg LH et al (1996) A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273:974–977

    Article  PubMed  CAS  Google Scholar 

  88. Bednarek MA, Feighner SD, Pong SS, McKee KK, Hreniuk DL, Silva MV, Warren VA, Howard AD, Van Der Ploeg LH, Heck JV (2000) Structure–function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a. J Med Chem 43:4370–4376

    Article  PubMed  CAS  Google Scholar 

  89. Cummings DE (2006) Ghrelin and the short- and long-term regulation of appetite and body weight. Physiol Behav 89:71–84

    Article  PubMed  CAS  Google Scholar 

  90. Tschop M, Wawarta R, Riepl RL, Friedrich S, Bidlingmaier M, Landgraf R, Folwaczny C (2001) Post-prandial decrease of circulating human ghrelin levels. J Endocrinol Investig 24:RC19–RC21

    CAS  Google Scholar 

  91. Sakata I, Yamazaki M, Inoue K, Hayashi Y, Kangawa K, Sakai T (2003) Growth hormone secretagogue receptor expression in the cells of the stomach-projected afferent nerve in the rat nodose ganglion. Neurosci Lett 342:183–186

    Article  PubMed  CAS  Google Scholar 

  92. Zigman JM, Jones JE, Lee CE, Saper CB, Elmquist JK (2006) Expression of ghrelin receptor mRNA in the rat and the mouse brain. J Comp Neurol 494:528–548

    Article  PubMed  CAS  Google Scholar 

  93. Date Y, Nakazato M, Murakami N, Kojima M, Kangawa K, Matsukura S (2001) Ghrelin acts in the central nervous system to stimulate gastric acid secretion. Biochem Biophys Res Commun 280:904–907

    Article  PubMed  CAS  Google Scholar 

  94. Faulconbridge LF, Cummings DE, Kaplan JM, Grill HJ (2003) Hyperphagic effects of brainstem ghrelin administration. Diabetes 52:2260–2265

    Article  PubMed  CAS  Google Scholar 

  95. Date Y, Murakami N, Toshinai K, Matsukura S, Niijima A, Matsuo H, Kangawa K, Nakazato M (2002) The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 123:1120–1128

    Article  PubMed  CAS  Google Scholar 

  96. Date Y, Shimbara T, Koda S, Toshinai K, Ida T, Murakami N, Miyazato M, Kokame K, Ishizuka Y, Ishida Y, Kageyama H, Shioda S, Kangawa K, Nakazato M (2006) Peripheral ghrelin transmits orexigenic signals through the noradrenergic pathway from the hindbrain to the hypothalamus. Cell Metabol 4:323–331

    Article  CAS  Google Scholar 

  97. Arnold M, Mura A, Langhans W, Geary N (2006) Gut vagal afferents are not necessary for the eating-stimulatory effect of intraperitoneally injected ghrelin in the rat. J Neurosci 26:11052–11060

    Article  PubMed  CAS  Google Scholar 

  98. Shintani M, Ogawa Y, Ebihara K, Aizawa-Abe M, Miyanaga F, Takaya K, Hayashi T, Inoue G, Hosoda K, Kojima M, Kangawa K, Nakao K (2001) Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes 50:227–232

    Article  PubMed  CAS  Google Scholar 

  99. Shaw AM, Irani BG, Moore MC, Haskell-Luevano C, Millard WJ (2005) Ghrelin-induced food intake and growth hormone secretion are altered in melanocortin 3 and 4 receptor knockout mice. Peptides 26:1720–1727

    Article  PubMed  CAS  Google Scholar 

  100. Kola B, Farkas I, Christ-Crain M, Wittmann G, Lolli F, Amin F, Harvey-White J, Liposits Z, Kunos G, Grossman AB, Fekete C, Korbonits M (2008) The orexigenic effect of ghrelin is mediated through central activation of the endogenous cannabinoid system. PLoS One 3:e1797

    Article  PubMed  CAS  Google Scholar 

  101. Kohno D, Nakata M, Maekawa F, Fujiwara K, Maejima Y, Kuramochi M, Shimazaki T, Okano H, Onaka T, Yada T (2007) Leptin suppresses ghrelin-induced activation of neuropeptide Y neurons in the arcuate nucleus via phosphatidylinositol 3-kinase- and phosphodiesterase 3-mediated pathway. Endocrinology 148:2251–2263

    Article  PubMed  CAS  Google Scholar 

  102. Horvath TL (2006) Synaptic plasticity in energy balance regulation. Obesity 14:228S–233S

    Article  PubMed  CAS  Google Scholar 

  103. Cui RJ, Li X, Appleyard SM (2011) Ghrelin inhibits visceral afferent activation of catecholamine neurons in the solitary tract nucleus. J Neurosci 31:3484–3492

    Article  PubMed  CAS  Google Scholar 

  104. Fry M, Ferguson AV (2009) Ghrelin modulates electrical activity of area postrema neurons. Am J Physiol Regul Integr Comp Physiol 296:R485–R492

    Article  PubMed  CAS  Google Scholar 

  105. Gilg S, Lutz TA (2006) The orexigenic effect of peripheral ghrelin differs between rats of different age and with different baseline food intake, and it may in part be mediated by the area postrema. Physiol Behav 87:353–359

    Article  PubMed  CAS  Google Scholar 

  106. Adrian TE, Ferri GL, Bacarese-Hamilton AJ, Fuessl HS, Polak JM, Bloom SR (1985) Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 89:1070–1077

    PubMed  CAS  Google Scholar 

  107. Hagan MM (2002) Peptide YY: a key mediator of orexigenic behavior. Peptides 23:377–382

    Article  PubMed  CAS  Google Scholar 

  108. Morley JE, Levine AS, Grace M, Kneip J (1985) Peptide YY (PYY), a potent orexigenic agent. Brain Res 341:200–203

    Article  PubMed  CAS  Google Scholar 

  109. Broberger C, Landry M, Wong H, Walsh JN, Hokfelt T (1997) Subtypes Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in pro-opiomelanocortin- and neuropeptide Y-containing neurons of the rat hypothalamic arcuate nucleus. Neuroendocrinology 66:393–408

    Article  PubMed  CAS  Google Scholar 

  110. Halatchev IG, Ellacott KL, Fan W, Cone RD (2004) Peptide YY3–36 inhibits food intake in mice through a melanocortin-4 receptor-independent mechanism. Endocrinology 145:2585–2590

    Article  PubMed  CAS  Google Scholar 

  111. Challis BG, Coll AP, Yeo GS, Pinnock SB, Dickson SL, Thresher RR, Dixon J, Zahn D, Rochford JJ, White A, Oliver RL, Millington G, Aparicio SA, Colledge WH, Russ AP, Carlton MB, O'Rahilly S (2004) Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3–36). Proc Natl Acad Sci U S A 101:4695–4700

    Article  PubMed  CAS  Google Scholar 

  112. Martin NM, Small CJ, Sajedi A, Patterson M, Ghatei MA, Bloom SR (2004) Pre-obese and obese agouti mice are sensitive to the anorectic effects of peptide YY(3–36) but resistant to ghrelin. Int J Obes Relat Metab Disord 28:886–893

    Article  PubMed  CAS  Google Scholar 

  113. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585

    Article  PubMed  CAS  Google Scholar 

  114. Horvath TL, Diano S, van den Pol AN (1999) Synaptic interaction between hypocretin (orexin) and neuropeptide Y cells in the rodent and primate hypothalamus: a novel circuit implicated in metabolic and endocrine regulations. J Neurosci 19:1072–1087

    PubMed  CAS  Google Scholar 

  115. Backberg M, Hervieu G, Wilson S, Meister B (2002) Orexin receptor-1 (OX-R1) immunoreactivity in chemically identified neurons of the hypothalamus: focus on orexin targets involved in control of food and water intake. Eur J Neurosci 15:315–328

    Article  PubMed  Google Scholar 

  116. Guan JL, Suzuki R, Funahashi H, Wang QP, Kageyama H, Uehara K, Yamada S, Tsurugano S, Shioda S (2002) Ultrastructural localization of orexin-1 receptor in pre- and post-synaptic neurons in the rat arcuate nucleus. Neurosci Lett 329:209–212

    Article  PubMed  CAS  Google Scholar 

  117. Rauch M, Riediger T, Schmid HA, Simon E (2000) Orexin A activates leptin-responsive neurons in the arcuate nucleus. Pflugers Archiv 440:699–703

    Article  PubMed  CAS  Google Scholar 

  118. Brown CH, Bourque CW (2004) Autocrine feedback inhibition of plateau potentials terminates phasic bursts in magnocellular neurosecretory cells of the rat supraoptic nucleus. J Physiol 557:949–960

    Article  PubMed  CAS  Google Scholar 

  119. Jegou S, Boutelet I, Vaudry H (2000) Melanocortin-3 receptor mRNA expression in pro-opiomelanocortin neurones of the rat arcuate nucleus. J Neuroendocrinol 12:501–505

    Article  PubMed  CAS  Google Scholar 

  120. Grieco P, Balse PM, Weinberg D, MacNeil T, Hruby VJ (2000) D-Amino acid scan of gamma-melanocyte-stimulating hormone: importance of Trp(8) on human MC3 receptor selectivity. J Med Chem 43:4998–5002

    Article  PubMed  CAS  Google Scholar 

  121. Marks DL, Hruby V, Brookhart G, Cone RD (2006) The regulation of food intake by selective stimulation of the type 3 melanocortin receptor (MC3R). Peptides 27:259–264

    Article  PubMed  CAS  Google Scholar 

  122. Smith MA, Hisadome K, Al-Qassab H, Heffron H, Withers DJ, Ashford ML (2007) Melanocortins and agouti-related protein modulate the excitability of two arcuate nucleus neuron populations by alteration of resting potassium conductances. J Physiol 578:425–438

    Article  PubMed  CAS  Google Scholar 

  123. Renquist BJ, Lippert RN, Sebag JA, Ellacott KLJ, Cone RD (2011) Physiological roles of the melanocortin MC3 receptor. Eur J Pharmacol 660:13–20

    Article  PubMed  CAS  Google Scholar 

  124. Markowitz CE, Berkowitz KM, Jaffe SB, Wardlaw SL (1992) Effect of opioid receptor antagonism on proopiomelanocortin peptide levels and gene expression in the hypothalamus. Mol Cell Neurosci 3:184–190

    Article  PubMed  CAS  Google Scholar 

  125. Jaffe SB, Sobieszczyk S, Wardlaw SL (1994) Effect of opioid antagonism on [beta]-endorphin processing and proopiomelanocortin-peptide release in the hypothalamus. Brain Res 648:24–31

    Article  PubMed  CAS  Google Scholar 

  126. Kelly MJ, Loose MD, Ronnekleiv OK (1990) Opioids hyperpolarize beta-endorphin neurons via mu-receptor activation of a potassium conductance. Neuroendocrinology 52:268–275

    Article  PubMed  CAS  Google Scholar 

  127. Bouret S, Prevot V, Croix D, Jégou S, Vaudry H, Stefano GB, Beauvillain J-C, Mitchell V (1999) [mu]-Opioid receptor mRNA expression in proopiomelanocortin neurons of the rat arcuate nucleus. Mol Brain Res 70:155–158

    Article  PubMed  CAS  Google Scholar 

  128. Horvath T, Naftolin F, Kalra S, Leranth C (1992) Neuropeptide Y innervation of b-endorphin-containing cells in the rat mediobasal hypothalamus. A light and electron microscopic double-immunostaining study. Endo 131:2461–2467

    CAS  Google Scholar 

  129. Coppola A, Liu ZW, Andrews ZB, Paradis E, Roy MC, Friedman JM, Ricquier D, Richard D, Horvath TL, Gao XB, Diano S (2007) A central thermogenic-like mechanism in feeding regulation: an interplay between arcuate nucleus T3 and UCP2. Cell Metabol 5:21–33

    Article  CAS  Google Scholar 

  130. Bagnol T, Lu XY, Kaelin CB, Day HE, Ollmann M, Gantz I, Akil H, Barsh GS, Watson SJ (1999) The anatomy of an endogenous antagonist: relationship between agouti-related protein and proopiomelanocortin in brain. J Neurosci 19:RC26

    PubMed  CAS  Google Scholar 

  131. Singru PS, Sanchez E, Fekete C, Lechan RM (2007) Importance of melanocortin signaling in refeeding-induced neuronal activation and satiety. Endocrinology 148:638–646

    Article  PubMed  CAS  Google Scholar 

  132. Menyhert J, Wittmann G, Hrabovszky E, Keller E, Liposits Z, Fekete C (2006) Interconnection between orexigenic neuropeptide Y- and anorexigenic alpha-melanocyte stimulating hormone-synthesizing neuronal systems of the human hypothalamus. Brain Res 1076:101–105

    Article  PubMed  CAS  Google Scholar 

  133. Berthoud H-R (2002) Multiple neural systems controlling food intake and body weight. Neurosci Biobehav Rev 26:393–428

    Article  PubMed  Google Scholar 

  134. Sternson SM, Shepherd GMG, Friedman JM (2005) Topographic mapping of VMH [rarr] arcuate nucleus microcircuits and their reorganization by fasting. Nat Neurosci 8:1356–1363

    Article  PubMed  CAS  Google Scholar 

  135. Louis GW, Greenwald-Yarnell M, Phillips R, Coolen LM, Lehman MN, Myers MG (2011) Molecular mapping of the neural pathways linking leptin to the neuroendocrine reproductive axis. Endocrinology 152:2302–2310

    Article  PubMed  CAS  Google Scholar 

  136. Myers MG (2010) Outstanding scientific achievement award lecture 2010: deconstructing leptin: from signals to circuits. Diabetes 59:2708–2714

    Article  PubMed  CAS  Google Scholar 

  137. Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS (1999) Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev 20:68–100

    Article  PubMed  CAS  Google Scholar 

  138. Gao Q, Mezei G, Nie Y, Rao Y, Choi CS, Bechmann I, Leranth C, Toran-Allerand D, Priest CA, Roberts JL, Gao X-B, Mobbs C, Shulman GI, Diano S, Horvath TL (2007) Anorectic estrogen mimics leptin’s effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. Nat Med 13:89–94

    Article  PubMed  CAS  Google Scholar 

  139. Gyengesi E, Liu Z-W, D'Agostino G, Gan G, Horvath TL, Gao X-B, Diano S (2010) Corticosterone regulates synaptic input organization of POMC and NPY/AgRP neurons in adult mice. Endocrinology 151:5395–5402

    Article  PubMed  CAS  Google Scholar 

  140. Pinto S, Roseberry AG, Liu H, Diano S, Shanabrough M, Cai X, Friedman JM, Horvath TL (2004) Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304:110–115

    Article  PubMed  CAS  Google Scholar 

  141. Takahashi KA, Cone RD (2005) Fasting induces a large, leptin-dependent increase in the intrinsic action potential frequency of orexigenic arcuate nucleus neuropeptide Y/agouti-related protein neurons. Endocrinology 146:1043–1047

    Article  PubMed  CAS  Google Scholar 

  142. Perello M, Stuart RC, Nillni EA (2006) The role of intracerebroventricular administration of leptin in the stimulation of prothyrotropin releasing hormone neurons in the hypothalamic paraventricular nucleus. Endocrinology 147:3296–3306

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

I am greatly thankful to Drs. Amanda Vanhoose, Roger D Cone, Benjamin Renquist, and David Jacobson for their assistance in preparation of this manuscript.

Author information

Authors and Affiliations

  1. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA

    Masoud Ghamari-Langroudi

Authors
  1. Masoud Ghamari-Langroudi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masoud Ghamari-Langroudi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ghamari-Langroudi, M. Electrophysiological Analysis of Circuits Controlling Energy Homeostasis. Mol Neurobiol 45, 258–278 (2012). https://doi.org/10.1007/s12035-012-8241-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-012-8241-5

Keywords

Search

Navigation