The Leptin, Dopamine and Serotonin Receptors in Hypothalamic POMC-Neurons of Normal and Obese Rodents

  • Irina V. Romanova
  • Kira V. Derkach
  • Anastasiya L. Mikhrina
  • Ivan B. Sukhov
  • Elena V. Mikhailova
  • Alexander O. Shpakov
Original Paper


The pro-opiomelanocortin (POMC)-expressing neurons of the hypothalamic arcuate nucleus (ARC) are involved in the control of food intake and metabolic processes. It is assumed that, in addition to leptin, the activity of these neurons is regulated by serotonin and dopamine, but only subtype 2C serotonin receptors (5-HT2CR) was identified earlier on the POMC-neurons. The aim of this work was a comparative study of the localization and number of leptin receptors (LepR), types 1 and 2 dopamine receptors (D1R, D2R), 5-HT1BR and 5-HT2CR on the POMC-neurons and the expression of the genes encoding them in the ARC of the normal and diet-induced obese (DIO) rodents and the agouti mice (A y /a) with the melanocortin obesity. As shown by immunohistochemistry (IHC), all the studied receptors were located on the POMC-immunopositive neurons, and their IHC-content was in agreement with the expression of their genes. In DIO rats the number of D1R and D2R in the POMC-neurons and their expression in the ARC were reduced. In DIO mice the number of D1R and D2R did not change, while the number of LepR and 5-HT2CR was increased, although to a small extent. In the POMC-neurons of agouti mice the number of LepR, D2R, 5-HT1BR and 5-HT2CR was increased, and the D1R number was reduced. Thus, our data demonstrates for the first time the localization of different types of the serotonin and dopamine receptors on the POMC-neurons and a specific pattern of the changes of their number and expression in the DIO and melanocortin obesity.


Hypothalamus Serotonin Dopamine Leptin Pro-opiomelanocortin Agouti mice Obesity POMC neuron 



This work was supported by the Russian Science Foundation (Project No. 16-15-10388).

Supplementary material

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Supplementary material 1 (PDF 193 KB)
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Supplementary material 2 (PDF 120 KB)
11064_2018_2485_MOESM3_ESM.pdf (262 kb)
Supplementary material 3 (PDF 261 KB)


  1. 1.
    Nogueiras R, Wiedmer P, Perez-Tilve D, Veyrat-Durebex C, Keogh JM, Sutton GM, Pfluger PT, Castaneda TR, Neschen S, Hofmann SM et al (2007) The central melanocortin system directly controls peripheral lipid metabolism. J Clin Invest 117(11):3475–3488. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Begriche K, Girardet C, McDonald P, Butler AA (2013) Melanocortin-3 receptors and metabolic homeostasis. Prog Mol Biol Transl Sci 114:109–146. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Girardet C, Butler AA (2014) Neural melanocortin receptors in obesity and related metabolic disorders. Biochim Biophys Acta 1842(3):482–494. CrossRefPubMedGoogle Scholar
  4. 4.
    Pandit R, Omrani A, Luijendijk MC, de Vrind VA, Van Rozen AJ, Ophuis RJ, Garner K, Kallo I, Ghanem A, Liposits Z et al (2016) Melanocortin 3 receptor signaling in midbrain dopamine neurons increases the motivation for food reward. Neuropsychopharmacology 41(9):2241–2251. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hahn TM, Breininger JF, Baskin DG, Shwartz MW (1998) Coexpression of AgRp and NPY in fasting-activated hypothalamic neurons. Nat Neurosci 1:271–272. CrossRefPubMedGoogle Scholar
  6. 6.
    Roseberry AG, Stuhrman K, Dunigan AI (2015) Regulation of the mesocorticolimbic and mesostriatal dopamine systems by α-melanocyte stimulating hormone and agouti-related protein. Neurosci Biobehav Rev 56:15–25. CrossRefPubMedGoogle Scholar
  7. 7.
    Sohn JW (2015) Network of hypothalamic neurons that control appetite. BMB Rep 48(4):229–233. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Boswell T, Dunn IC (2017) Regulation of agouti-related protein and pro-opiomelanocortin gene expression in the avian arcuate nucleus. Front Endocrinol 8:75. CrossRefGoogle Scholar
  9. 9.
    Varela L, Horvath TL (2012) Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis. EMBO Rep 13(12):1079–1086. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lima LB, Metzger M, Furigo IC, Donato J Jr (2016) Leptin receptor-positive and leptin receptor-negative proopiomelanocortin neurons innervate an identical set of brain structures. Brain Res 1646:366–376. CrossRefPubMedGoogle Scholar
  11. 11.
    Ha S, Baver S, Huo L, Gata A, Hairston J, Huntoon N, Li W, Zhang T, Benecchi EJ, Ericsson M, Hentges ST, Bjørbæk C (2013) Somato-dendritic localization and signaling by leptin receptors in hypothalamic POMC and AgRP neurons. PLoS ONE 8(10):e77622. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Derghal A, Djelloul M, Airault C, Pierre C, Dallaporta M, Troadec JD, Tillement V, Tardivel C, Bariohay B, Trouslard J, Mounien L (2015) Leptin is required for hypothalamic regulation of miRNAs targeting POMC 3′UTR. Front Cell Neurosci 9:172. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Ghamari-Langroudi M, Srisai D, Cone RD (2011) Multinodal regulation of the arcuate/paraventricular nucleus circuit by leptin. Proc Natl Acad Sci USA 108(1):355–360. CrossRefPubMedGoogle Scholar
  14. 14.
    Tecott LH (2007) Serotonin and the orchestration of energy balance. Cell Metab 6:352–361. CrossRefPubMedGoogle Scholar
  15. 15.
    Volkow ND, Wang GJ, Baler RD (2011) Reward, dopamine and the control of food intake: implications for obesity. Trends Cogn Sci 15:37–46. CrossRefPubMedGoogle Scholar
  16. 16.
    Martin-Gronert MS, Stocker CJ, Wargent ET, Cripps RL, Garfield AS, Jovanovic Z, D’Agostino G, Yeo GS, Cawthorne MA, Arch JR, Heisler LK, Ozanne SE (2016) 5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats. Dis Model Mech 9(4):401–412. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Goudreau JL, Lookingland KJ, Moore KE (1994) 5-Hydroxytryptamine2 receptor-mediated regulation of periventricular-hypophysial dopaminergic neuronal activity and the secretion of alpha-melanocyte-stimulating hormone. J Pharmacol Exp Ther 268(1):175–179PubMedGoogle Scholar
  18. 18.
    Arai T, Maejima Y, Muroya S, Yada T (2013) Rikkunshito and isoliquiritigenin counteract 5-HT-induced 2C receptor-mediated activation of pro-opiomelanocortin neurons in the hypothalamic arcuate nucleus. Neuropeptides 47(4):225–230. CrossRefPubMedGoogle Scholar
  19. 19.
    Berglund ED, Liu C, Sohn JW, Liu T, Kim MH, Lee CE, Vianna CR, Williams KW, Xu Y, Elmquist JK (2013) Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis. J Clin Invest 123(12):5061–5070. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Doslikova B, Garfield AS, Shaw J, Evans ML, Burdakov D, Billups B, Heisler LK (2013) 5-HT2C receptor agonist anorectic efficacy potentiated by 5-HT1B receptor agonist coapplication: an effect mediated via increased proportion of pro-opiomelanocortin neurons activated. J Neurosci 33(23):9800–9804. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Burke LK, Doslikova B, D’Agostino G, Garfield AS, Farooq G, Burdakov D, Low MJ, Rubinstein M, Evans ML, Billups B, Heisler LK (2014) 5-HT obesity medication efficacy via POMC activation is maintained during aging. Endocrinology 155(10):3732–3738. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, Luther M, Chen W, Woychik RP, Wilkison WO et al (1994) Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 371(6500):799–802. CrossRefPubMedGoogle Scholar
  23. 23.
    Makarova EN, Yakovleva TV, Shevchenko AY, Bazhan NM (2010) Pregnancy and lactation have anti-obesity and anti-diabetic effects in A(y)/a mice. Acta Physiol 198(2):169–177. CrossRefGoogle Scholar
  24. 24.
    Derkach KV, Bondareva VM, Chistyakova OV, Berstein LM, Shpakov AO (2015) The effect of long-term intranasal serotonin treatment on metabolic parameters and hormonal signaling in rats with high-fat diet/low-dose streptozotocin-induced type 2 diabetes. Int J Endocrinol. PubMedPubMedCentralGoogle Scholar
  25. 25.
    Ebihara K, Ogawa Y, Katsuura G, Numata Y, Masuzaki H, Satoh N, Tamaki M, Yoshioka T, Hayase M, Matsuoka N, Aizawa-Abe M, Yoshimasa Y, Nakao K (1999) Involvement of agouti-related protein, an endogenous antagonist of hypothalamic melanocortin receptor, in leptin action. Diabetes 48:2028–2033CrossRefPubMedGoogle Scholar
  26. 26.
    Mikhrina AL, Romanova IV (2015) The role of Agrp in regulating dopaminergic neurons in the brain. Neurosci Behav Physiol 45(5):536–541. CrossRefGoogle Scholar
  27. 27.
    Füzesi T, Wittmann G, Liposits Z, Lechan RM, Fekete C (2007) Contribution of noradrenergic and adrenergic cell groups of the brainstem and agouti-related protein-synthesizing neurons of the arcuate nucleus to neuropeptide-y innervation of corticotropin-releasing hormone neurons in hypothalamic paraventricular nucleus of the rat. Endocrinology 148(11):5442–5450. CrossRefPubMedGoogle Scholar
  28. 28.
    Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3(6):1101–1108CrossRefPubMedGoogle Scholar
  29. 29.
    Xu Y, Jones JE, Kohno D, Williams KW, Lee CE, Choi MJ, Anderson JG, Heisler LK, Zigman JM, Lowell BB, Elmquist JK (2008) 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate energy homeostasis. Neuron 60:582–589. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Xu Y, Jones JE, Lauzon DA, Anderson JG, Balthasar N, Heisler LK, Zinn AR, Lowell BB, Elmquist JK (2010) A serotonin and melanocortin circuit mediates d-fenfluramine anorexia. J Neurosci 30:14630–14634. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Heisler LK, Jobst EE, Sutton GM, Zhou L, Borok E, Thornton-Jones Z, Liu HY, Zigman JM, Balthasar N, Kishi T et al (2006) Serotonin reciprocally regulates melanocortin neurons to modulate food intake. Neuron 51:239–249. CrossRefPubMedGoogle Scholar
  32. 32.
    Sohn JW, Xu Y, Jones JE, Wickman K, Williams KW, Elmquist JK (2011) Serotonin 2C receptor activates a distinct population of arcuate pro-opiomelanocortin neurons via TRPC channels. Neuron 71:488–497. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kim MO, Lee YK, Choi WS, Kim JH, Hwang SK, Lee BJ, Kang SG, Kim K, Baik SH (1997) Prolonged ethanol intake increases D2 dopamine receptor expression in the rat brain. Mol Cells 7(5):682–687PubMedGoogle Scholar
  34. 34.
    Doron R, Fridman L, Yadid G (2006) Dopamine-2 receptors in the arcuate nucleus modulate cocaine-seeking behavior. Neuroreport 17(15):1633–1636. CrossRefPubMedGoogle Scholar
  35. 35.
    Yoon YR, Baik JH (2015) Melanocortin 4 receptor and dopamine D2 receptor expression in brain areas involved in food intake. Endocrinol Metab (Seoul) 30(4):576–583. CrossRefGoogle Scholar
  36. 36.
    Dubois A, Savasta M, Curet O, Scatton B (1986) Autoradiographic distribution of the D1 agonist [3H]SKF 38393, in the rat brain and spinal cord. Comparison with the distribution of D2 dopamine receptors. Neuroscience 19(1):125–137CrossRefPubMedGoogle Scholar
  37. 37.
    Perreault ML, Shen MY, Fan T, George SR (2015) Regulation of c-fos expression by the dopamine D1-D2 receptor heteromer. Neuroscience 285:194–203. CrossRefPubMedGoogle Scholar
  38. 38.
    Franco R, Martínez-Pinilla E, Lanciego JL, Navarro G (2016) Basic pharmacological and structural evidence for class A G-protein-coupled receptor heteromerization. Front Pharmacol 7:76. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Miyazaki M, Sampath H, Liu X, Flowers MT, Chu K, Dobrzyn A, Ntambi JM (2009) Stearoyl-CoA desaturase-1 deficiency attenuates obesity and insulin resistance in leptin-resistant obese mice. Biochem Biophys Res Commun 380(4):818–822. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Madsen AN, Hansen G, Paulsen SJ, Lykkegaard K, Tang-Christensen M, Hansen HS, Levin BE, Larsen PJ, Knudsen LB, Fosgerau K, Vrang N (2010) Long-term characterization of the diet-induced obese and diet-resistant rat model: a polygenetic rat model mimicking the human obesity syndrome. J Endocrinol 206(3):287–296. CrossRefPubMedGoogle Scholar
  41. 41.
    Paulsen SJ, Jelsing J, Madsen AN, Hansen G, Lykkegaard K, Larsen LK, Larsen PJ, Levin BE, Vrang N (2010) Characterization of beta-cell mass and insulin resistance in diet-induced obese and diet-resistant rats. Obesity 18(2):266–273. CrossRefPubMedGoogle Scholar
  42. 42.
    Derkach KV, Kuznetsova LA, Chistyakova OV, Ignatieva PA, Shpakov AO (2015) The effect of four-week levothyroxine treatment on hormonal regulation of adenylyl cyclase in the brain and peripheral tissues of obese rats. Biochem Suppl Ser A 9(4):236–245. CrossRefGoogle Scholar
  43. 43.
    El-Haschimi K, Pierroz DD, Hileman SM, Bjorbaek C, Flier JS (2000) Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest 105:1827–1832. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Banks WA, Farrell CL (2003) Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible. Am J Physiol Endocrinol Metab 285(1):E10–E15. CrossRefPubMedGoogle Scholar
  45. 45.
    Zhou Y, Rui L (2013) Leptin signaling and leptin resistance. Front Med 7(2):207–222. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Rowland NE, Schaub JW, Robertson KL, Andreasen A, Haskell-Luevano C (2010) Effect of MTII on food intake and brain c-Fos in melanocortin-3, melanocortin-4, and double MC3 and MC4 receptor knockout mice. Peptides 31(12):2314–2317. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Cakir I, Cyr NE, Perello M, Litvinov BP, Romero A, Stuart RC, Nillni EA (2013) Obesity induces hypothalamic endoplasmic reticulum stress and impairs proopiomelanocortin (POMC) post-translational processing. J Biol Chem 288(24):17675–17688. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Lu XY, Nicholson JR, Akil H, Watson SJ (2001) Time course of short-term and long-term orexigenic effects of Agouti-related protein (86-132). Neuroreport 12:1281–1284CrossRefPubMedGoogle Scholar
  49. 49.
    McMinn JE, Wilkinson CW, Havel PJ, Woods SC, Schwartz MW (2000) Effect of intracerebroventricular alpha-MSH on food intake, adiposity, c-Fos induction, and neuropeptide expression. Am J Physiol Regul Integr Comp Physiol 279(2):R695–R703CrossRefPubMedGoogle Scholar
  50. 50.
    Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404(6778):661–671. CrossRefPubMedGoogle Scholar
  51. 51.
    Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8(5):571–578. CrossRefPubMedGoogle Scholar
  52. 52.
    Sindelar DK, Mystkowski P, Marsh DJ, Palmiter RD, Schwartz MW (2002) Attenuation of diabetic hyperphagia in neuropeptide Y-deficient mice. Diabetes 51(3):778–783CrossRefPubMedGoogle Scholar
  53. 53.
    Kim JD, Leyva S, Diano S (2014) Hormonal regulation of the hypothalamic melanocortin system. Front Physiol 5:480. PubMedPubMedCentralGoogle Scholar
  54. 54.
    Albarado DC, McClaine J, Stephens JM, Mynatt RL, Ye J, Bannon AW, Richards WG, Butler AA (2004) Impaired coordination of nutrient intake and substrate oxidation in melanocortin-4 receptor knockout mice. Endocrinology 145(1):243–252. CrossRefPubMedGoogle Scholar
  55. 55.
    Zhou L, Sutton GM, Rochford JJ, Semple RK, Lam DD, Oksanen LJ, Thornton-Jones ZD, Clifton PG, Yueh CY, Evans ML et al (2007) Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways. Cell Metab 6:398–405. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Scranton R, Cincotta A (2010) Bromocriptine–unique formulation of a dopamine agonist for the treatment of type 2 diabetes. Expert Opin Pharmacother 11:269–279. CrossRefPubMedGoogle Scholar
  57. 57.
    Derkach KV, Ivantsov AO, Sukhov IB, Shpakov AO (2017) Restoration of hypothalamic signaling systems as a cause of improved metabolic parameters in rats with neonatal diabetes model during treatment with bromocryptine mesylate. Cell Tissue Biol 11(3):234–241. CrossRefGoogle Scholar
  58. 58.
    Shpakov AO, Derkach KV, Berstein LM (2015) Brain signaling systems in the type 2 diabetes and metabolic syndrome: promising target to treat and prevent these diseases. Future Sci OA. PubMedPubMedCentralGoogle Scholar

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Authors and Affiliations

  1. 1.I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry of Russian Academy of SciencesSaint PetersburgRussia

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