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New insight into GABAergic neurons in the hypothalamic feeding regulation

Abstract

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.

Introduction

Feeding is regulated by hypothalamic nuclei including the arcuate nucleus (ARC), dorsomedial hypothalamus (DMH), paraventricular nucleus (PVN), ventromedial hypothalamus (VMH), and lateral hypothalamus (LH). ARC is recognized as the first-order center that senses peripheral metabolic signals. DMH and LH are recognized as the hunger centers, VMH as the satiety center, and PVN as the integrative center. GABA (gamma-aminobutyric acid)-ergic neurons are located primarily in ARC, DMH, and LH [1] and regulate energy balance positively. Infusions of GABA and GABA receptor agonist promote food intake, whereas GABA receptor antagonist suppresses it [2]. Here, we review the progress of studies on hypothalamic GABAergic neurons in feeding regulation.

NPY/AgRP neurons in ARC

Neuropeptide Y (NPY)/Agouti-related protein (AgRP)-expressing neurons in ARC are GABAergic neurons [3, 4]. These neurons play a prominent role in promoting food intake. They are activated by peripheral orexigenic signals such as ghrelin [5, 6], while inactivated by anorexigenic signals such as leptin [4, 7], insulin [8], and glucose [9], and release NPY, AgRP, and GABA in an activity-dependent manner. Intracerebroventricular injection of NPY or AgRP promotes feeding [10, 11]. Conversely, application of their antagonists or GABA receptor antagonist to the projection site of NPY/AgRP neurons suppress feeding [12].

Optogenetics by using light-dependent channels such as channelrhodopsin, halorhodopsin, and variants, and chemogenetics by using designer receptors such as hM3Dq and hM4Di have been used to activate or inhibit the activity in selective neurons, and allow us to analyze the link between the neuronal activity and behavior. Optogenetic or chemogenetic activation of NPY/AgRP neurons promote food intake [13, 14] while chemogenetic inhibition suppresses it [14].

A study using chemogenetic activation of NPY/AgRP neurons in NPY, GABA, and/or melanocortin receptor 4 (MC4R)-deficient mice revealed that ether NPY or GABA is needed to promote food intake in the early phase whereas AgRP plays a role in prolonging feeding [15].

Optogenetics could regulate membrane potential not only in cell bodies but also in axon terminals to generate action potentials and release neurotransmitters. This allows us to identify the neurons that receive monosynaptic transmission from channelrhodopsin-expressing presynaptic neurons. Moreover, this could reveal a behavior that is mediated by the neural circuit. Using this technique, it was determined that AgRP neurons monosynaptically project to the anterior bed nucleus of the stria terminalis (aBNST), PVN, LH, the paraventricular nucleus of thalamus (PVT), the central nucleus of amygdala (CeA), the periaqueductal gray (PAG) [16], and the parabrachial nucleus (PBN) [17]. Among these projection sites, the aBNST, PVN, LH, and PVT were estimated to participate in the core forebrain feeding circuit, since presynaptic activation of AgRP neurons onto these nuclei promoted food intake [16]. Optogenetic activation of presynaptic terminals of AgRP neurons onto MC4R-expressing neurons in PVN but not in LH or aBNST-induced inhibitory postsynaptic current (IPSC) and promoted food intake, suggesting that AgRP neuron-derived hunger is mediated by MC4R neurons in PVN [18]. This study also showed that MC4R was not expressed in oxytocin neurons and that oxytocin neurons and corticotropin-releasing hormone (CRH)-expressing neurons in PVN did not mediate AgRP neuron-derived hunger [18]. This is, however, inconsistent with other reports. Atasoy et al. showed that food intake elicited by optogenetic activation of presynaptic terminal of AgRP was attenuated by additional optogenetic activation of oxytocin neurons in PVN [19]. Immunohistochemical study showed that MC4R is expressed in oxytocin neurons and CRH neurons [20] and that MC4R agonist, α-melanocyte stimulating hormone (α-MSH), and melanotan II (MTII) activates PVN oxytocin neurons [21,22,23].

Optogenetic activation of presynaptic terminals also clarified the synaptic input onto AgRP neurons from other hypothalamic feeding regulatory nucleus. Glutamatergic neurons that express thyrotropin-releasing hormone (TRH) or pituitary adenylate cyclase-activating polypeptide (PACAP) in PVN but not in VMH and DMH send an excitatory synaptic input onto ARC AgRP neurons, whereas oxytocin, arginine-vasopressin (AVP), or CRH neurons in PVN do not [24]. Chemogenetic activation of TRH or PACAP neurons in PVN promotes food intake via ARC AgRP neurons [24].

In vivo Ca2+ imaging with GRIN lens allows us to observe the activity of neurons in deep brain of free-moving mice. Food presentation without consumption acutely suppresses the neural activity of AgRP neurons of fasting mice [25, 26]. The suppression of neural activity was recovered within 10 s but not completely. Several times of food presentation weakened the neural activity, reaching the silent state. Dummy food presentation transiently suppressed and immediately recovered the neural activity. These observations indicate that the fast neurotransmission (probably mediated by GABA) from a sensory system such as vision or smell play a role in regulating AgRP neurons, as well as nutrients and hormones from peripheral organs as a result of food consumption. GABAergic neurons in DMH were reported as one of the sources of the GABA to suppress AgRP neuron activity (see the section of DMH).

POMC neurons in ARC

Approximately half of ARC POMC neurons expressed glutamic acid decarboxylase (GAD) 67, GAD 65, or vesicular GABA transporter (Vgat), the marker of GABAergic neurons, and a small potion of the neurons co-expressed vesicular glutamate transporter (Vglut)2 [27,28,29]. Additionally, GAD 67-positive POMC neurons increased while Vglut2-positive POMC neurons decreased in a postnatal developing period [30]. Acute and chronic calorie restriction reduced the expression of GAD 67 mRNA, with lesser effect on GAD 65, whereas high-fat diet feeding or stress altered them in POMC neurons [31]. However, the role of GABA release from POMC neurons still remains to be clarified.

Direct GABAergic projection from NPY/AgRP neurons to POMC neurons in ARC has been detected by electron microscopy [4]. Additionally, light-evoked IPSC was observed at POMC neurons in ARC from AgRP neuron selective channelrhodopsin-expressing mice, indicating that POMC neurons received functional synaptic connection from AgRP neurons [19, 32]. However, AgRP neuron-specific inhibition of GABA release by cell type specific deletion of Vgat or expression of botulinum toxin did not alter IPSCs onto POMC neurons [33, 34], suggesting that GABAergic input from AgRP neurons to POMC neurons depends on the states of AgRP neuron activity.

Non-NPY/AgRP, non-POMC GABAergic neurons in ARC

Although NPY/AgRP neurons and POMC neurons in ARC are established as the first-order neurons in sensing leptin, the changes in body weight and food intake in mice deficient of leptin receptor (LepR) selectively in these neurons were smaller than in conventional LepR-deleted mice or Ob/Ob mice, indicating the first-order neurons sensing leptin include new neurons other than NPY/AgRP neurons and POMC neurons. The mice deficient of LepR selectively in the neurons expressing Vgat, which is required for GABA release, showed similar increases in body weight and food intake with conventional LepR-deleted mice. In contrast, the mice deficient of LepR selectively in the Vglut-expressing neurons showed body weight and food intake comparable to wild-type littermates [1]. These results indicate that the first-order neurons other than NPY/AgRP and POMC neurons are GABAergic.

The role of non-NPY/AgRP, non-POMC GABAergic neurons in feeding regulation was investigated by using several mice lines. The mice with disrupted GABA release from LepR neurons (LepR-Cre::Vgatflox/flox) increased body weight caused by increasing food intake and decreasing energy expenditure with lowering leptin sensitivity [35]. Pancreas–duodenum homeobox 1 (Pdx-1) and Rat insulin promoter1 (RIP) are expressed in hypothalamic neurons, except for arcuate NPY/AgRP and POMC neurons [36]. The mice disrupted GABA release from hypothalamic RIP-expressing neurons (RIP-Cre::Vgatflox/flox) were obese and extremely sensitive to DIO due to dysregulation of energy expenditure but not food intake. Leptin-induced thermogenesis, but not suppression of food intake, was attenuated in the mice. Most RIP-expressing neurons in ARC are GABAergic, and half of them are LepR-positive [37]. The mice with disrupted GABA release from hypothalamic Pdx-1-expressing neurons (Pdx-1-Cre::Vgatflox/flox) showed decreased food intake and body weight in the postweaning period [38]. NPY-induced hyperphagia was attenuated in the mice [38].

GABAergic neurons in DMH

DMH has been considered an orexigenic nucleus since its lesion decreased food intake and body weight. In DMH, however, the principal neuron that promotes food intake has not been identified, in contrast to other feeding regulatory nuclei. A subpopulation of DMH GABAergic neurons expresses leptin receptor [1], which inhibits its activity while it is activated by lowering glucose [39]. These neurons projected to ARC POMC and NPY/AgRP neurons [40] and PVN neurons [39]. Optogenetic activation of GABAergic neurons in DMH showed an increase in food consumption partly via inhibition of PVN neurons [39]. DMH GABAergic neuron projecting to NPY/AgRP neurons expressed leptin receptor while that projecting to POMC neurons did not. Leptin receptor-expressing GABAergic neurons were activated in response to food presentation, which is associated with acute inhibition of NPY/AgRP neurons [40].

GABAergic neurons in LH

Resent studies revealed that three types of GABAergic neurons in LH are associated with feeding behavior. A subpopulation of GABAergic neurons in LH is melanin-concentrating hormone (MCH)-expressing neurons, which also expresses GAD67 and LepR. MCH is an orexigenic neuropeptide that inhibits other hypothalamic neurons [41]. Local injection of MCH to PVN or DMH promotes food intake and body weight gain [42,43,44,45]. A chronic infusion of MCH or activation of MCH receptor 1 also increases food intake and body weight gain, and elevates the level of insulin and leptin [46, 47]. Conversely, the mice lacking MCH showed lean phenotype due to decreased food intake [48]. Antagonism of MCH receptor 1 leads to sustained reduction in food intake and body weight gain [47].

Optogenetic activation of axonal projection from Pdx-1-expressing neuron in LH, which also expressed MCH, to PVN promote feeding, whereas it was abolished by disruption of GABA release by deletion of Vgat [49].

Optogenetic activation of Vgat-positive GABAergic neurons in LH produces appetitive and consummatory behavior [50]. In this report, it is also shown that the Vgat-positive GABAergic neurons were distinct from MCH or orexin neurons. However, it is still not clear whether MCH neurons do not express Vgat. Additionally, in vivo Ca2+ imaging revealed that the GABAergic neurons from a distinct population that encodes appetitive behavior while others do consummatory behavior [50].

Single-cell RNA-seq analysis in hypothalamic GABAergic neurons

Single-cell RNA-seq technique is quite useful for distinguishing the hypothalamic neurons, since the hypothalamus lacks anatomical characteristics, such as distinct layering or repetitive organization observed in cortical or cerebral neurons. Romanov et al. applied this technique to neural populations of PVN, anterior hypothalamic nucleus (AHA), SCN, DMH, VMH, and ARC [51]. This analysis found 15 clusters of GABAergic neurons, which expressed Gad1, Gad2, and Slc32a1. The 15 clusters included the neurons expressing AgRP/NPY, somatostatin, corticotropin-releasing hormone (CRH), and POMC. Notably, four out of 15 GABAergic neuron clusters showed dopaminergic transcript tyrosine hydroxylase, Slc18a2 (encoding vesicular monoamine transporter 2, VMAT2) and, in some cases, Slc6a3 (encoding dopamine transporter 1, DAT), suggesting that these neuron clusters co-express dopaminergic and GABAergic phenotypes. The GABAergic (Slc17a6-positive) neurons in the ARC and the median eminence were classified into 18 clusters by using single-cell RNA-seq [37]. This analysis firstly observed two subtypes of the AgRP neurons, somatostatin (SST)-positive and -negative ones. Additionally, AgRP-negative SST neuron subpopulation showed a similar transcriptional profile as that of AgRP neurons, and chemogenetic activation of SST neurons in ARC promoted food intake, similarly to activation of AgRP neurons [37].

These studies showed the diversity of GABAergic neurons in hypothalamus, and demonstrated that the single-cell RNA-seq is a useful method for exploring new subpopulations of neurons.

Perspectives

In the past 5 years, the optogenetic approach has successfully illustrated the neural circuit of GABAergic neurons, particularly GABAergic NPY/AgRP neurons, in feeding regulation. This approach allows us to observe the functional synaptic contact among the neurons of interest and to illustrate the precise neural circuit (Fig. 1). However, the “optogenetically” functional contact is not equal to the “physiologically” functional connection, as suggested from the study of synaptic projection from NPY/AgRP neurons to POMC neurons in ARC [34]. In vivo Ca2+ imaging is an effective tool for exploring the neurons that mediate specific behaviors. These new techniques identified an orexigenic GABAergic neuron subtype that expresses neither NPY nor AgRP. Intriguingly, GABAergic neuron subtype that suppresses feeding has not been found by now. In this regard, it remains to be clarified whether or not the GABAergic neurons project to orexigenic GABAergic neurons.

Fig. 1
figure1

Schematic overview of circuit of GABAergic neurons in hypothalamus in feeding regulation. Orange indicates GABAergic and blue indicates glutamatergic neurons. The dotted lines indicate nuclei. ARC arcuate nucleus, PVN paraventricular nucleus of hypothalamus, DMH dorsomedial hypothalamus, VMH ventromedial hypothalamus, LH lateral hypothalamus, CeA central nucleus of amygdala, aBNST anterior bed nucleus of the stria terminalis, PVT paraventricular nucleus of thalamus, PAG periaqueductal gray, PBN parabrachial nucleus, NPY neuropeptide Y, AgRP agouti-related protein, POMC proopiomelanocortin, Pdx-1 pancreas–duodenum homeobox 1, RIP rat insulin promoter1, MC4R melanocortin receptor 4, PACAP pituitary adenylate cyclase-activating polypeptide, TRH thyrotropin-releasing hormone, CRH corticotropin-releasing hormone, Oxt oxytocin, LepR leptin receptor, MCH melanin-concentrating hormone (color figure online)

References

  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. https://doi.org/10.1016/j.neuron.2011.05.028

    CAS  Article  PubMed  PubMed Central  Google 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. https://doi.org/10.1016/j.physbeh.2007.05.021

    CAS  Article  PubMed  Google 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 756:283–286

    CAS  Article  Google 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. https://doi.org/10.1038/35078085

    CAS  Article  Google 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 37:649–661

    CAS  Article  Google 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 52:948–956

    CAS  Article  Google 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. https://doi.org/10.1210/en.2006-1240

    CAS  Article  PubMed  Google 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. https://doi.org/10.1016/j.cmet.2014.03.004

    CAS  Article  PubMed  PubMed Central  Google 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 449:228–232

    CAS  Article  Google 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 7:1189–1192

    CAS  Article  Google 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. https://doi.org/10.1152/ajpregu.2000.279.1.R47

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Gehlert DR (1999) Role of hypothalamic neuropeptide Y in feeding and obesity. Neuropeptides 33:329–338. https://doi.org/10.1054/npep.1999.0057

    CAS  Article  PubMed  Google 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. https://doi.org/10.1038/nn.2739

    CAS  Article  PubMed  Google 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. https://doi.org/10.1172/JCI46229

    CAS  Article  PubMed  PubMed Central  Google 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. https://doi.org/10.1016/j.cmet.2013.09.009

    CAS  Article  Google 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. https://doi.org/10.1016/j.cell.2013.11.002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Wu Q, Clark MS, Palmiter RD (2012) Deciphering a neuronal circuit that mediates appetite. Nature 483:594–597. https://doi.org/10.1038/nature10899

    CAS  Article  PubMed  PubMed Central  Google 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. https://doi.org/10.1038/nn.4011

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Atasoy D, Betley JN, Su HH, Sternson SM (2012) Deconstruction of a neural circuit for hunger. Nature 488:172–177. https://doi.org/10.1038/nature11270

    CAS  Article  PubMed  PubMed Central  Google 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 23:7143–7154

    CAS  Article  Google 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. https://doi.org/10.1152/ajpregu.2001.281.2.R673

    CAS  Article  PubMed  Google 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 23:10351

    CAS  Article  Google 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. https://doi.org/10.1038/npp.2015.35

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Krashes MJ, Shah BP, Madara JC et al (2014) An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature. https://doi.org/10.1038/nature12956

    Article  PubMed  PubMed Central  Google 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. https://doi.org/10.1016/j.cell.2015.01.033

    CAS  Article  PubMed  PubMed Central  Google 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. https://doi.org/10.1038/nature14416

    CAS  Article  PubMed  PubMed Central  Google 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. https://doi.org/10.1523/jneurosci.3770-09.2009

    CAS  Article  PubMed  PubMed Central  Google 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. https://doi.org/10.1002/cne.23127

    CAS  Article  PubMed  PubMed Central  Google 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. https://doi.org/10.1002/cne.23350

    CAS  Article  PubMed  PubMed Central  Google 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. https://doi.org/10.1002/cne.23900

    CAS  Article  PubMed  Google 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. https://doi.org/10.1113/JP273020

    Article  PubMed  PubMed Central  Google 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. https://doi.org/10.1111/ejn.13076

    Article  PubMed  PubMed Central  Google 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. https://doi.org/10.1038/nn.2167

    CAS  Article  PubMed  PubMed Central  Google 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. https://doi.org/10.1523/JNEUROSCI.0647-17.2017

    CAS  Article  PubMed  PubMed Central  Google 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. https://doi.org/10.1210/en.2011-2071

    CAS  Article  PubMed  PubMed Central  Google 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. https://doi.org/10.1002/dvg.20672

    CAS  Article  PubMed  PubMed Central  Google 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. https://doi.org/10.1038/nn.4495

    CAS  Article  PubMed  PubMed Central  Google 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. https://doi.org/10.1523/JNEUROSCI.1110-15.2015

    CAS  Article  PubMed  PubMed Central  Google 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):709–715

    CAS  Article  Google Scholar 

  40. 40.

    Garfield AS, Shah BP, Burgess CR et al (2016) Dynamic GABAergic afferent modulation of AgRP neurons. Nat Neurosci. https://doi.org/10.1038/nn.4392

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Gao XB (2009) Electrophysiological effects of MCH on neurons in the hypothalamus. Peptides 30:2025–2030. https://doi.org/10.1016/j.peptides.2009.05.006

    CAS  Article  PubMed  PubMed Central  Google 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. https://doi.org/10.1210/en.2003-0149

    CAS  Article  PubMed  Google 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. https://doi.org/10.1152/ajpregu.00399.2002

    CAS  Article  PubMed  Google 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. https://doi.org/10.1038/380243a0

    CAS  Article  PubMed  Google 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 846:164–170

    CAS  Article  Google 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. https://doi.org/10.1152/ajpendo.00529.2002

    CAS  Article  PubMed  Google 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 475:37–47

    CAS  Article  Google 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. https://doi.org/10.1038/25341

    CAS  Article  PubMed  Google 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. https://doi.org/10.1523/JNEUROSCI.3720-14.2015

    CAS  Article  PubMed  PubMed Central  Google 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. https://doi.org/10.1016/j.cell.2014.12.026

    CAS  Article  PubMed  PubMed Central  Google 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. https://doi.org/10.1038/nn.4462

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

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).

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Correspondence to Shigetomo Suyama or Toshihiko Yada.

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Suyama, S., Yada, T. New insight into GABAergic neurons in the hypothalamic feeding regulation. J Physiol Sci 68, 717–722 (2018). https://doi.org/10.1007/s12576-018-0622-8

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Keywords

  • Hypothalamus
  • Food intake
  • GABAergic neurons
  • NPY/AgRP neruons