STAT5 ablation in AgRP neurons increases female adiposity and blunts food restriction adaptations

in Journal of Molecular Endocrinology

Correspondence should be addressed to J Donato: jdonato@icb.usp.br
Restricted access

AgRP neurons are important players in the control of energy homeostasis and are responsive to several hormones. In addition, STAT5 signalling in the brain, which is activated by metabolic hormones and growth factors, modulates food intake, body fat and glucose homeostasis. Given that, and the absence of studies that describe STAT5 function in AgRP cells, the present study investigated the metabolic effects of Stat5a/b gene ablation in these neurons. We observed that STAT5 signalling in AgRP neurons regulates body fat in female mice. However, male and female STAT5-knockout mice did not exhibit altered food intake, energy expenditure or glucose homeostasis compared to control mice. The counter-regulatory response or glucoprivic hyperphagia induced by 2-deoxy-d-glucose treatment were also not affected by AgRP-specific STAT5 ablation. However, under 60% food restriction, AgRP STAT5-knockout mice had a blunted upregulation of hypothalamic Agrp mRNA expression and corticosterone serum levels compared to control mice, suggesting a possible role for STAT5 in AgRP neurons for neuroendocrine adaptations to food restriction. Interestingly, ad libitum fed knockout male mice had reduced Pomc and Ucp-1 mRNA expression compared to control group. Taken together, these results suggest that STAT5 signalling in AgRP neurons regulates body adiposity in female mice, as well as some neuroendocrine adaptations to food restriction.

 

      Society for Endocrinology

All Time Past Year Past 30 Days
Abstract Views 45 45 37
Full Text Views 9 9 6
PDF Downloads 10 10 4
  • AlbertVCornuMHallMN 2015 mTORC1 signaling in Agrp neurons mediates circadian expression of Agrp and NPY but is dispensable for regulation of feeding behavior. Biochemical and Biophysical Research Communications 480–486. (https://doi.org/10.1016/j.bbrc.2015.06.161)

    • Search Google Scholar
    • Export Citation
  • Al-QassabHSmithMAIrvineEEGuillermet-GuibertJClaretMChoudhuryAISelmanCPiipariKClementsMLingardS, 2009 Dominant role of the p110beta isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons. Cell Metabolism 343–354. (https://doi.org/10.1016/j.cmet.2009.09.008)

    • Search Google Scholar
    • Export Citation
  • AndermannMLLowellBB 2017 Toward a wiring diagram understanding of appetite control. Neuron 757–778. (https://doi.org/10.1016/j.neuron.2017.06.014)

    • Search Google Scholar
    • Export Citation
  • AponteYAtasoyDSternsonSM 2011 AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nature Neuroscience 351–355. (https://doi.org/10.1038/nn.2739)

    • Search Google Scholar
    • Export Citation
  • AtasoyDBetleyJNSuHHSternsonSM 2012 Deconstruction of a neural circuit for hunger. Nature 172–177. (https://doi.org/10.1038/nature11270)

    • Search Google Scholar
    • Export Citation
  • BaikMNamYSPiaoMYKangHJParkSJLeeJH 2016 Liver-specific deletion of the signal transducer and activator of transcription 5 gene aggravates fatty liver in response to a high-fat diet in mice. Journal of Nutritional Biochemistry 56–63. (https://doi.org/10.1016/j.jnutbio.2015.10.018)

    • Search Google Scholar
    • Export Citation
  • BaikMLeeMSKangHJParkSJPiaoMYNguyenTHHennighausenL 2017 Muscle-specific deletion of signal transducer and activator of transcription 5 augments lipid accumulation in skeletal muscle and liver of mice in response to high-fat diet. European Journal of Nutrition 569–579. (https://doi.org/10.1007/s00394-015-1101-0)

    • Search Google Scholar
    • Export Citation
  • BarclayJLNelsonCNIshikawaMMurrayLAKerrLMMcPheeTRPowellEEWatersMJ 2011 GH-dependent STAT5 signaling plays an important role in hepatic lipid metabolism. Endocrinology 181–192. (https://doi.org/10.1210/en.2010-0537)

    • Search Google Scholar
    • Export Citation
  • BohlenTMZampieriTTFurigoICTeixeiraPDListEOKopchickJDonatoJFrazaoR 2019 Central growth hormone signaling is not required for the timing of puberty. Journal of Endocrinology 243 161–175. (https://doi.org/10.1530/JOE-19-0242)

    • Search Google Scholar
    • Export Citation
  • Bole-FeysotCGoffinVEderyMBinartNKellyPA 1998 Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocrine Reviews 225–268. (https://doi.org/10.1210/edrv.19.3.0334)

    • Search Google Scholar
    • Export Citation
  • BrobergerCJohansenJJohanssonCSchallingMHökfeltT 1998 The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. PNAS 15043–15048. (https://doi.org/10.1073/pnas.95.25.15043)

    • Search Google Scholar
    • Export Citation
  • BuonfiglioDCRamos-LoboAMSilveiraMAFurigoICHennighausenLFrazãoRDonatoJ 2015 Neuronal STAT5 signaling is required for maintaining lactation but not for postpartum maternal behaviors in mice. Hormones and Behavior 60–68. (https://doi.org/10.1016/j.yhbeh.2015.04.004)

    • Search Google Scholar
    • Export Citation
  • BurkeLKDarwishTCavanaughARVirtueSRothEMorroJLiuSMXiaJDalleyJWBurlingK, 2017 mTORC1 in AGRP neurons integrates exteroceptive and interoceptive food-related cues in the modulation of adaptive energy expenditure in mice. eLife mTORC1. (https://doi.org/10.7554/eLife.22848)

    • Search Google Scholar
    • Export Citation
  • Carter-SuCSchwartzJArgetsingerLS 2016 Growth hormone signaling pathways. Growth Hormone and IGF Research 11–15. (https://doi.org/10.1016/j.ghir.2015.09.002)

    • Search Google Scholar
    • Export Citation
  • CincottaAHTozzoEScislowskiPW 1997 Bromocriptine/SKF38393 treatment ameliorates obesity and associated metabolic dysfunctions in obese (ob/ob) mice. Life Sciences 951–956. (https://doi.org/10.1016/s0024-3205(97)00599-7)

    • Search Google Scholar
    • Export Citation
  • CincottaAHMeierAHCincottaMJr 1999 Bromocriptine improves glycaemic control and serum lipid profile in obese Type 2 diabetic subjects: a new approach in the treatment of diabetes. Expert Opinion on Investigational Drugs 1683–1707. (https://doi.org/10.1517/13543784.8.10.1683)

    • Search Google Scholar
    • Export Citation
  • ClaretMSmithMABatterhamRLSelmanCChoudhuryAIFryerLGDClementsMAl-QassabHHeffronHXuAW, 2007 AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. Journal of Clinical Investigation 2325–2336. (https://doi.org/10.1172/JCI31516)

    • Search Google Scholar
    • Export Citation
  • ConeRD 2005 Anatomy and regulation of the central melanocortin system. Nature Neuroscience 571–578. (https://doi.org/10.1038/nn1455)

  • CoppolaADianoS 2007 Hormonal regulation of the arcuate nucleus melanocortin system. Frontiers in Bioscience 3519–3530. (https://doi.org/10.2741/2331)

    • Search Google Scholar
    • Export Citation
  • CuiYRiedlingerGMiyoshiKTangWLiCDengCXRobinsonGWHennighausenL 2004 Inactivation of Stat5 in mouse mammary epithelium during pregnancy reveals distinct functions in cell proliferation, survival, and differentiation. Molecular and Cellular Biology 8037–8047. (https://doi.org/10.1128/MCB.24.18.8037-8047.2004)

    • Search Google Scholar
    • Export Citation
  • DoddGTLee-YoungRSBrüningJCTiganisT 2018 TCPTP regulates insulin signaling in AgRP neurons to coordinate glucose metabolism With feeding. Diabetes 1246–1257. (https://doi.org/10.2337/db17-1485)

    • Search Google Scholar
    • Export Citation
  • EganOKInglisMAAndersonGM 2017 Leptin signaling in AgRP neurons modulates puberty onset and adult fertility in mice. Journal of Neuroscience 3875–3886. (https://doi.org/10.1523/JNEUROSCI.3138-16.2017)

    • Search Google Scholar
    • Export Citation
  • FraleyGSDinhTTRitterS 2002 Immunotoxic catecholamine lesions attenuate 2DG-induced increase of AGRP mRNA. Peptides 1093–1099. (https://doi.org/10.1016/s0196-9781(02)00044-x)

    • Search Google Scholar
    • Export Citation
  • FranklinKPaxinosG 2008 The Mouse Brain in Stereotaxic Coordinates, Compact, 3rd ed Academic press: New York, USA.

  • FreemarkMFleenorDDriscollPBinartNKellyP 2001 Body weight and fat deposition in prolactin receptor-deficient mice. Endocrinology 532–537. (https://doi.org/10.1210/endo.142.2.7979)

    • Search Google Scholar
    • Export Citation
  • FurigoICKimKWNagaishiVSRamos-LoboAMde AlencarAPedrosoJABMetzgerMDonatoJ 2014 Prolactin-sensitive neurons express estrogen receptor-α and depend on sex hormones for normal responsiveness to prolactin. Brain Research 47–59. (https://doi.org/10.1016/j.brainres.2014.04.018)

    • Search Google Scholar
    • Export Citation
  • FurigoICMetzgerMTeixeiraPDSSoaresCRJDonatoJ 2017 Distribution of growth hormone-responsive cells in the mouse brain. Brain Structure and Function 341–363. (https://doi.org/10.1007/s00429-016-1221-1)

    • Search Google Scholar
    • Export Citation
  • FurigoICMeloHMLyra E SilvaNMRamos-LoboAMTeixeiraPDSBuonfiglioDCWasinskiFLimaERHigutiEPeroniCN, 2018 Brain STAT5 signaling modulates learning and memory formation. Brain Structure and Function 2229–2241. (https://doi.org/10.1007/s00429-018-1627-z)

    • Search Google Scholar
    • Export Citation
  • FurigoICSuzukiMFOliveiraJERamos-LoboAMTeixeiraPDSPedrosoJAde AlencarAZampieriTTBuonfiglioDCQuaresmaPGF, 2019a Suppression of prolactin secretion partially explains the antidiabetic effect of bromocriptine in ob/ob mice. Endocrinology 193–204. (https://doi.org/10.1210/en.2018-00629)

    • Search Google Scholar
    • Export Citation
  • FurigoICTeixeiraPDSde SouzaGOCoutoGCLRomeroGGPerellóMFrazãoREliasLLMetzgerMListEO, 2019b Growth hormone regulates neuroendocrine responses to weight loss via AgRP neurons. Nature Communications 662. (https://doi.org/10.1038/s41467-019-08607-1)

    • Search Google Scholar
    • Export Citation
  • FurigoICde SouzaGOTeixeiraPDSGuadagniniDFrazãoRListEOKopchickJJPradaPODonatoJ 2019c Growth hormone enhances the recovery of hypoglycemia via ventromedial hypothalamic neurons. FASEB Journal 11909–11924 (https://doi.org/10.1096/fj.201901315R)

    • Search Google Scholar
    • Export Citation
  • GongYIshida-TakahashiRVillanuevaECFingarDCMünzbergHMyersMG 2007 The long form of the leptin receptor regulates STAT5 and ribosomal protein S6 via alternate mechanisms. Journal of Biological Chemistry 31019–31027. (https://doi.org/10.1074/jbc.M702838200)

    • Search Google Scholar
    • Export Citation
  • GrimleyPMDongFRuiH 1999 Stat5a and Stat5b: fraternal twins of signal transduction and transcriptional activation. Cytokine and Growth Factor Reviews 131–157. (https://doi.org/10.1016/S1359-6101(99)00011-8)

    • Search Google Scholar
    • Export Citation
  • GurzovENStanleyWJPappasEGThomasHEGoughDJ 2016 The JAK/STAT pathway in obesity and diabetes. FEBS Journal 3002–3015. (https://doi.org/10.1111/febs.13709)

    • Search Google Scholar
    • Export Citation
  • HeYShuGYangYXuPXiaYWangCSaitoKHintonAYanXLiuC, 2016 A small potassium current in AgRP/NPY neurons regulates feeding behavior and energy metabolism. Cell Reports 1807–1818. (https://doi.org/10.1016/j.celrep.2016.10.044)

    • Search Google Scholar
    • Export Citation
  • HuangYHeZGaoYLieuLYaoTSunJLiuTJavadiCBoxMAfrinS, 2018 Phosphoinositide 3-kinase is integral for the acute activity of leptin and insulin in male arcuate NPY/AgRP Neurons. Journal of the Endocrine Society 518–532. (https://doi.org/10.1210/js.2018-00061)

    • Search Google Scholar
    • Export Citation
  • KamegaiJMinamiSSugiharaHHasegawaOHiguchiHWakabayashiI 1996 Growth hormone receptor gene is expressed in neuropeptide Y neurons in hypothalamic arcuate nucleus of rats. Endocrinology 2109–2112. (https://doi.org/10.1210/endo.137.5.8612554)

    • Search Google Scholar
    • Export Citation
  • KocalisHEHaganSLGeorgeLTurneyMKSiutaMALaryeaGNMorrisLCMugliaLJPrintzRLStanwoodGD, 2014 Rictor/mTORC2 facilitates central regulation of energy and glucose homeostasis. Molecular Metabolism 394–407. (https://doi.org/10.1016/j.molmet.2014.01.014)

    • Search Google Scholar
    • Export Citation
  • KongDDagonYCampbellJNGuoYYangZYiXAryalPWellensteinKKahnBBSabatiniBL, 2016 A postsynaptic AMPK→p21-activated kinase pathway drives fasting-induced synaptic plasticity in AgRP neurons. Neuron 25–33. (https://doi.org/10.1016/j.neuron.2016.05.025)

    • Search Google Scholar
    • Export Citation
  • KönnerACKlöckenerTBrüningJC 2009 Control of energy homeostasis by insulin and leptin: targeting the arcuate nucleus and beyond. Physiology and Behavior 632–638. (https://doi.org/10.1016/j.physbeh.2009.03.027)

    • Search Google Scholar
    • Export Citation
  • KrashesMJKodaSYeCRoganSCAdamsACCusherDSMaratos-FlierERothBLLowellBB 2011 Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. Journal of Clinical Investigation 1424–1428. (https://doi.org/10.1172/JCI46229)

    • Search Google Scholar
    • Export Citation
  • LadymanSRGrattanDR 2013 JAK-STAT and feeding. JAK-STAT e23675. (https://doi.org/10.4161/jkst.23675)

  • LadymanSRFieldwickDMGrattanDR 2012 Suppression of leptin-induced hypothalamic JAK/STAT signalling and feeding response during pregnancy in the mouse. Reproduction 83–90. (https://doi.org/10.1530/REP-12-0112)

    • Search Google Scholar
    • Export Citation
  • LadymanSRMacLeodMAKhant AungZKnowlesPPhillippsHRBrownRSEGrattanDR 2017 Prolactin receptors in Rip-cre cells, but not in AgRP neurones, are involved in energy homeostasis. Journal of Neuroendocrinology 29 e12474. (https://doi.org/10.1111/jne.12474)

    • Search Google Scholar
    • Export Citation
  • LandgrafRLandraf-LeursMMWeissmannAHörlRvon WerderKScribaPC 1977 Prolactin: a diabetogenic hormone. Diabetologia 99–104. (https://doi.org/10.1007/bf00745135)

    • Search Google Scholar
    • Export Citation
  • LanfrayDRichardD 2017 Emerging signaling pathway in arcuate feeding-related neurons: role of the Acbd7. Frontiers in Neuroscience 328. (https://doi.org/10.3389/fnins.2017.00328)

    • Search Google Scholar
    • Export Citation
  • LanningNJCarter-SuC 2006 Recent advances in growth hormone signaling. Reviews in Endocrine and Metabolic Disorders 225–235. (https://doi.org/10.1007/s11154-007-9025-5)

    • Search Google Scholar
    • Export Citation
  • LeeJYMuenzbergHGavrilovaOReedJABerrymanDVillanuevaECLouisGWLeinningerGMBertuzziSSeeleyRJ, 2008 Loss of cytokine-STAT5 signaling in the CNS and pituitary gland alters energy balance and leads to obesity. PLoS ONE e1639. (https://doi.org/10.1371/journal.pone.0001639)

    • Search Google Scholar
    • Export Citation
  • MatsumotoAAraiY 1980 Sexual dimorphism in ‘wiring pattern’ in the hypothalamic arcuate nucleus and its modification by neonatal hormonal environment. Brain Research 238–242. (https://doi.org/10.1016/0006-8993(80)91173-7)

    • Search Google Scholar
    • Export Citation
  • MeekTHNelsonJTMatsenMEDorfmanMDGuyenetSJDamianVAllisonMBScarlettJMNguyenHTThalerJP, 2016 Functional identification of a neurocircuit regulating blood glucose. PNAS E2073–E2082. (https://doi.org/10.1073/pnas.1521160113)

    • Search Google Scholar
    • Export Citation
  • MesarosAKoralovSBRotherEWunderlichFTErnstMBBarshGSRajewskyKBrüningJC 2008 Activation of Stat3 signaling in AgRP neurons promotes locomotor activity. Cell Metabolism 236–248. (https://doi.org/10.1016/j.cmet.2008.01.007)

    • Search Google Scholar
    • Export Citation
  • MøllerNJørgensenJOL 2009 Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocrine Reviews 152–177. (https://doi.org/10.1210/er.2008-0027)

    • Search Google Scholar
    • Export Citation
  • MorselliLLClaflinKECuiHGrobeJL 2018 Control of energy expenditure by AgRP neurons of the arcuate nucleus: neurocircuitry, signaling pathways, and angiotensin. Current Hypertension Reports 25. (https://doi.org/10.1007/s11906-018-0824-8)

    • Search Google Scholar
    • Export Citation
  • MortonGJSchwartzMW 2001 The NPY/AgRP neuron and energy homeostasis. International Journal of Obesity and Related Metabolic Disorders (Supplement 5) S56–S62. (https://doi.org/10.1038/sj.ijo.0801915)

    • Search Google Scholar
    • Export Citation
  • MützeJRothJGerstbergerRHübschleT 2007 Nuclear translocation of the transcription factor STAT5 in the rat brain after systemic leptin administration. Neuroscience Letters 286–291. (https://doi.org/10.1016/j.neulet.2007.02.074)

    • Search Google Scholar
    • Export Citation
  • NicollCSMayerGLRussellSM 1986 Structural features of prolactins and growth hormones that can be related to their biological properties. Endocrine Reviews 169–203. (https://doi.org/10.1210/edrv-7-2-169)

    • Search Google Scholar
    • Export Citation
  • PadillaSLQiuJNestorCCZhangCSmithAWWhiddonBBRønnekleivOKKellyMJPalmiterRD 2017 AgRP to Kiss1 neuron signaling links nutritional state and fertility. PNAS 2413–2418. (https://doi.org/10.1073/pnas.1621065114)

    • Search Google Scholar
    • Export Citation
  • PanWAllisonMBSabatiniPRuppAAdamsJPattersonCJonesJCOlsonDPMyersMG 2019 Transcriptional and physiological roles for STAT proteins in leptin action. Molecular Metabolism 121–131. (https://doi.org/10.1016/j.molmet.2019.01.007)

    • Search Google Scholar
    • Export Citation
  • PattersonCMVillanuevaECGreenwald-YarnellMRajalaMGonzalezIESainiNJonesJMyersMG 2012 Leptin action via LepR-b Tyr1077 contributes to the control of energy balance and female reproduction. Molecular Metabolism 61–69. (https://doi.org/10.1016/j.molmet.2012.05.001)

    • Search Google Scholar
    • Export Citation
  • QuaresmaPGFTeixeiraPDSFurigoICWasinskiFCoutoGCFrazãoRListEOKopchickJJDonatoJ 2019 Growth hormone/STAT5 signaling in proopiomelanocortin neurons regulates glucoprivic hyperphagia. Molecular and Cellular Endocrinology 110574. (https://doi.org/10.1016/j.mce.2019.110574)

    • Search Google Scholar
    • Export Citation
  • RauARHentgesST 2017 The relevance of AgRP neuron-derived GABA inputs to POMC neurons differs for spontaneous and evoked release. Journal of Neuroscience 7362–7372. (https://doi.org/10.1523/JNEUROSCI.0647-17.2017)

    • Search Google Scholar
    • Export Citation
  • RomanovRAZeiselABakkerJGirachFHellysazATomerRAlpárAMulderJClotmanFKeimpemaE, 2017 Molecular interrogation of hypothalamic organization reveals distinct dopamine neuronal subtypes. Nature Neuroscience 176–188. (https://doi.org/10.1038/nn.4462)

    • Search Google Scholar
    • Export Citation
  • SilveiraMAFurigoICZampieriTTBohlenTMde PaulaDGFranciCRDonatoJFrazaoR 2017 STAT5 signaling in kisspeptin cells regulates the timing of puberty. Molecular and Cellular Endocrinology 55–65. (https://doi.org/10.1016/j.mce.2017.03.024)

    • Search Google Scholar
    • Export Citation
  • SmithMAKatsouriLIrvineEEHankirMKPedroniSMAVosholPJGordonMWChoudhuryAIWoodsAVidal-PuigA, 2015 Ribosomal S6K1 in POMC and AgRP neurons regulates glucose homeostasis but not feeding behavior in mice. Cell Reports 335–343. (https://doi.org/10.1016/j.celrep.2015.03.029)

    • Search Google Scholar
    • Export Citation
  • TuzcuAYalakiSArikanSGokalpDBahcecMTuzcuS 2009 Evaluation of insulin sensitivity in hyperprolactinemic subjects by euglycemic hyperinsulinemic clamp technique. Pituitary 330–334. (https://doi.org/10.1007/s11102-009-0183-1)

    • Search Google Scholar
    • Export Citation
  • van de WallELeshanRXuAWBalthasarNCoppariRLiuSMJoYHMacKenzieRGAllisonDBDunNJ, 2008 Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion. Endocrinology 1773–1785. (https://doi.org/10.1210/en.2007-1132)

    • Search Google Scholar
    • Export Citation
  • ZagmuttSMeraPSoler-VázquezMCHerreroLSerraD 2018 Targeting AgRP neurons to maintain energy balance: lessons from animal models. Biochemical Pharmacology 224–232. (https://doi.org/10.1016/j.bcp.2018.07.008)

    • Search Google Scholar
    • Export Citation