The Journal of Physiological Sciences

, Volume 68, Issue 6, pp 717–722 | Cite as

New insight into GABAergic neurons in the hypothalamic feeding regulation

  • Shigetomo SuyamaEmail author
  • Toshihiko YadaEmail author


Several lines of study have suggested that GABA in the hypothalamic feeding center plays a role in promoting food intake. Recent studies revealed that not only NPY/AgRP neurons in the hypothalamic arcuate nucleus (ARC) that co-express GABA but also other GABAergic neurons act as an orexigenic. Here, we review the progress of studies on hypothalamic GABAergic neurons distributed in ARC, dorsomedial hypothalamus (DMH), and lateral hypothalamus (LH). Three advanced technologies have been applied and greatly contributed to the recent progress. Optogenetic (and chemogenetic) approaches map input and output pathways of particular subpopulations of GABAergic neurons. In vivo Ca2+ imaging using GRIN lens and GCaMP can correlate the activity of GABAergic neuron subpopulations with feeding behavior. Single-cell RNA-seq approach clarifies precise transcriptional profiles of GABAergic neuron subpopulations. These approaches have shown diversity of GABAergic neurons and the subpopulation-dependent role in feeding regulation.


Hypothalamus Food intake GABAergic neurons NPY/AgRP neruons 



This study was supported in part by the Grant-in-Aid for Innovative Areas (26670453 to T.Y.) from Japan Society of the Promotion of Science, and grants from Japan Diabetes Foundation to Toshihiko Yada. T.Y. is supported by Programs for Strategic Research Foundation at Private Universities 2011–2015 and 2013–2017 supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), and the Advanced Research and Development Programs for Medical Innovation (AMED-CREST) from Japan Agency for Medical Research and development (AMED).


  1. 1.
    Vong L, Ye C, Yang Z et al (2011) Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71:142–154. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Meister B (2007) Neurotransmitters in key neurons of the hypothalamus that regulate feeding behavior and body weight. Physiol Behav 92:263–271. CrossRefPubMedGoogle Scholar
  3. 3.
    Horvath TL, Bechmann I, Naftolin F et al (1997) Heterogeneity in the neuropeptide Y-containing neurons of the rat arcuate nucleus: GABAergic and non-GABAergic subpopulations. Brain Res 756:283–286CrossRefGoogle Scholar
  4. 4.
    Cowley MA, Smart JL, Rubinstein M et al (2001) Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus: abstract. Nature 411:480–484. CrossRefGoogle Scholar
  5. 5.
    Cowley MA, Smith RG, Diano S et al (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37:649–661CrossRefGoogle Scholar
  6. 6.
    Kohno D, Gao HZ, Muroya S et al (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 52:948–956CrossRefGoogle Scholar
  7. 7.
    Kohno D, Nakata M, Maekawa F et al (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. CrossRefPubMedGoogle Scholar
  8. 8.
    Qiu J, Zhang C, Borgquist A et al (2014) Insulin excites anorexigenic proopiomelanocortin neurons via activation of canonical transient receptor potential channels. Cell Metab 19:682–693. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Parton L, Ye C, Coppari R et al (2007) Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449:228–232CrossRefGoogle Scholar
  10. 10.
    Stanley BG, Kyrkouli SE, Lampert S, Leibowitz SF (1986) Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity. Peptides 7:1189–1192CrossRefGoogle Scholar
  11. 11.
    Hagan MM, Rushing PA, Pritchard LM et al (2000) Long-term orexigenic effects of AgRP-(83—132) involve mechanisms other than melanocortin receptor blockade. Am J Physiol Regul Integr Comp Physiol 279:R47–R52. CrossRefPubMedGoogle Scholar
  12. 12.
    Gehlert DR (1999) Role of hypothalamic neuropeptide Y in feeding and obesity. Neuropeptides 33:329–338. CrossRefPubMedGoogle Scholar
  13. 13.
    Aponte Y, Atasoy D, Sternson SM (2011) AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat Neurosci 14:351–355. CrossRefPubMedGoogle Scholar
  14. 14.
    Krashes MJ, Koda S, Ye C et al (2011) Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Invest 121:1424–1428. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Krashes MJ, Shah BP, Koda S, Lowell BB (2013) Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Cell Metab 18:588–595. CrossRefGoogle Scholar
  16. 16.
    Betley JN, Cao ZFH, Ritola KD, Sternson SM (2013) Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell 155:1337–1350. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Wu Q, Clark MS, Palmiter RD (2012) Deciphering a neuronal circuit that mediates appetite. Nature 483:594–597. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Garfield AS, Li C, Madara JC et al (2015) A neural basis for melanocortin-4 receptor-regulated appetite. Nat Neurosci 18:863–871. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Atasoy D, Betley JN, Su HH, Sternson SM (2012) Deconstruction of a neural circuit for hunger. Nature 488:172–177. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Liu H, Kishi T, Roseberry AG et al (2003) Transgenic mice expressing green fluorescent protein under the control of the melanocortin-4 receptor promoter. J Neurosci 23:7143–7154CrossRefGoogle Scholar
  21. 21.
    Olszewski PK, Wirth MM, Shaw TJ et al (2001) Role of alpha-MSH in the regulation of consummatory behavior: immunohistochemical evidence. Am J Physiol Regul Integr Comp Physiol 281:R673–R680. CrossRefPubMedGoogle Scholar
  22. 22.
    Sabatier N, Caquineau C, Dayanithi G et al (2003) α-Melanocyte-stimulating hormone stimulates oxytocin release from the dendrites of hypothalamic neurons while inhibiting oxytocin release from their terminals in the neurohypophysis. J Neurosci 23:10351CrossRefGoogle Scholar
  23. 23.
    Modi ME, Inoue K, Barrett CE et al (2015) Melanocortin receptor agonists facilitate oxytocin-dependent partner preference formation in the prairie vole. Neuropsychopharmacology 40:1856–1865. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Krashes MJ, Shah BP, Madara JC et al (2014) An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Chen Y, Lin YC, Kuo TW, Knight ZA (2015) Sensory detection of food rapidly modulates arcuate feeding circuits. Cell 160:829–841. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Betley JN, Xu S, Cao ZFH et al (2015) Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature 521:180–185. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Hentges ST, Otero-Corchon V, Pennock RL et al (2009) Proopiomelanocortin expression in both GABA and glutamate neurons. J Neurosci 29:13684–13690. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Jarvie BC, Hentges ST (2012) Expression of GABAergic and glutamatergic phenotypic markers in hypothalamic proopiomelanocortin neurons. J Comp Neurol 520:3863–3876. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Wittmann G, Hrabovszky E, Lechan RM (2013) 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. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Dennison CS, King CM, Dicken MS, Hentges ST (2016) Age-dependent changes in amino acid phenotype and the role of glutamate release from hypothalamic proopiomelanocortin neurons. J Comp Neurol 524:1222–1235. CrossRefPubMedGoogle Scholar
  31. 31.
    Jarvie BC, King CM, Hughes AR et al (2016) Caloric restriction selectively reduces the GABAergic phenotype of mouse hypothalamic proopiomelanocortin neurons. J Physiol. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Dicken MS, Hughes AR, Hentges ST (2015) Gad1 mRNA as a reliable indicator of altered GABA release from orexigenic neurons in the hypothalamus. Eur J Neurosci 42:2644–2653. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Tong Q, Ye CP, Jones JE et al (2008) Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat Neurosci 11:998–1000. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Rau AR, Hentges ST (2017) The relevance of AgRP neuron-derived GABA inputs to POMC neurons differs for spontaneous and evoked release. J Neurosci 37:7362–7372. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Xu Y, O’Brien WG, Lee CC et al (2012) Role of GABA release from leptin receptor-expressing neurons in body weight regulation. Endocrinology 153:2223–2233. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Song J, Xu Y, Hu X et al (2010) Brain expression of cre recombinase driven by pancreas-specific promoters. Genesis 48:628–634. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Campbell JN, Macosko EZ, Fenselau H et al (2017) A molecular census of arcuate hypothalamus and median eminence cell types. Nat Neurosci 20:484–496. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Kim ER, Wu Z, Sun H et al (2015) Hypothalamic non-AgRP, non-POMC GABAergic neurons are required for postweaning feeding and NPY hyperphagia. J Neurosci 35:10440–10450. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Otgon-Uul Z, Suyama S, Onodera H, Yada T (2016) Optogenetic activation of leptin-and glucose-regulated GABAergic neurons in dorsomedial hypothalamus promotes food intake via inhibitory transmission to paraventricular nucleus of hypothalamus. Mol Metab 5(8):709–715CrossRefGoogle Scholar
  40. 40.
    Garfield AS, Shah BP, Burgess CR et al (2016) Dynamic GABAergic afferent modulation of AgRP neurons. Nat Neurosci. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Gao XB (2009) Electrophysiological effects of MCH on neurons in the hypothalamus. Peptides 30:2025–2030. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Abbott CR, Kennedy AR, Wren AM et al (2003) Identification of hypothalamic nuclei involved in the orexigenic effect of melanin-concentrating hormone. Endocrinology 144:3943–3949. CrossRefPubMedGoogle Scholar
  43. 43.
    Clegg DJ, Air EL, Benoit SC et al (2003) Intraventricular melanin-concentrating hormone stimulates water intake independent of food intake. Am J Physiol Regul Integr Comp Physiol 284:R494–R499. CrossRefPubMedGoogle Scholar
  44. 44.
    Qu D, Ludwig DS, Gammeltoft S et al (1996) A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 380:243–247. CrossRefPubMedGoogle Scholar
  45. 45.
    Rossi M, Beak SA, Choi SJ et al (1999) Investigation of the feeding effects of melanin concentrating hormone on food intake—action independent of galanin and the melanocortin receptors. Brain Res 846:164–170CrossRefGoogle Scholar
  46. 46.
    Ito M, Gomori A, Ishihara A et al (2003) Characterization of MCH-mediated obesity in mice. Am J Physiol Endocrinol Metab 284:E940–E945. CrossRefPubMedGoogle Scholar
  47. 47.
    Shearman LP, Camacho RE, Sloan Stribling D et al (2003) Chronic MCH-1 receptor modulation alters appetite, body weight and adiposity in rats. Eur J Pharmacol 475:37–47CrossRefGoogle Scholar
  48. 48.
    Shimada M, Tritos NA, Lowell BB et al (1998) Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 396:670–674. CrossRefPubMedGoogle Scholar
  49. 49.
    Wu Z, Kim ER, Sun H et al (2015) GABAergic projections from lateral hypothalamus to paraventricular hypothalamic nucleus promote feeding. J Neurosci 35:3312–3318. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Jennings JH, Ung RL, Resendez SL et al (2015) Visualizing hypothalamic network dynamics for appetitive and consummatory behaviors. Cell 160:516–527. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Romanov RA, Zeisel A, Bakker J et al (2016) Molecular interrogation of hypothalamic organization reveals distinct dopamine neuronal subtypes. Nat Neurosci 20:176–188. CrossRefPubMedGoogle Scholar

Copyright information

© The Physiological Society of Japan and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Integrative Physiology, Department of PhysiologyJichi Medical University School of MedicineShimotsukeJapan
  2. 2.Kansai Electric Power Medical Research InstituteKobeJapan

Personalised recommendations