Neuroendocrine integration of nutritional signals on reproduction

Journal of Molecular Endocrinology

Volumn 58, Issue 2, 2017, Pages R107-R128

  Evans, Maggie C ^a   Anderson, Greg M ^a  

^a UNIVERSITY OF OTAGO   (New Zealand)

Author keywords

Fertility; Ghrelin; GNRH; Insulin; Leptin

Indexed keywords

4 AMINOBUTYRIC ACID; AGOUTI RELATED PROTEIN; COCAINE AND AMPHETAMINE REGULATED TRANSCRIPT PEPTIDE; GALANIN LIKE PEPTIDE; GHRELIN; GLUTAMIC ACID; GONADORELIN; INSULIN; KISSPEPTIN; LEPTIN; NEUROPEPTIDE Y; NITRIC OXIDE SYNTHASE; PROOPIOMELANOCORTIN; STEROIDOGENIC FACTOR 1; TYROSINE 3 MONOOXYGENASE;

ASTROCYTE; CELL ENERGY; CELL POPULATION; HUMAN; HYPOTHALAMUS HYPOPHYSIS GONAD SYSTEM; INTRACELLULAR SIGNALING; METABOLIC REGULATION; NERVE CELL; NERVE CELL NETWORK; NEUROENDOCRINE SYSTEM; NONHUMAN; NUTRITION; PRIORITY JOURNAL; PROTEIN EXPRESSION; REPRODUCTION; REVIEW; SENSOR; SIGNAL TRANSDUCTION; STRESS; ANIMAL; ENDOCRINE SYSTEM; GONAD; HYPOTHALAMUS HYPOPHYSIS SYSTEM; METABOLISM; NERVOUS SYSTEM FUNCTION; PHYSIOLOGY;

ANIMALS; ENDOCRINE SYSTEM; GHRELIN; GONADOTROPIN-RELEASING HORMONE; GONADS; HUMANS; HYPOTHALAMO-HYPOPHYSEAL SYSTEM; LEPTIN; NERVOUS SYSTEM PHYSIOLOGICAL PHENOMENA; NEURONS; NUTRITIONAL PHYSIOLOGICAL PHENOMENA; REPRODUCTION; SIGNAL TRANSDUCTION;

EID: 85012195855     PISSN: 09525041     EISSN: 14796813     Source Type: Journal    
DOI: 10.1530/JME-16-0212     Document Type: Review

References (236)

1. Abe M, Saito M, Ikeda H & Shimazu T 1991 Increased neuropeptide Y content in the arcuato-paraventricular hypothalamic neuronal system in both insulin-dependent and non-insulin-dependent diabetic rats. Brain Research 539 223–227. (doi:10.1016/0006-8993(91)91624-A)
2. Abizaid A 2009 Ghrelin and dopamine: new insights on the peripheral regulation of appetite. Journal of Neuroendocrinology 21 787–793. (doi:10.1111/j.1365-2826.2009.01896.x)
3. Acosta-Martinez M 2011 PI3K: an attractive candidate for the central integration of metabolism and reproduction. Frontiers in Endocrinology 2 110. (doi:10.3389/fendo.2011.00110)
4. Adler BA & Crowley WR 1986 Evidence for gamma-aminobutyric acid modulation of ovarian hormonal effects on luteinizing hormone secretion and hypothalamic catecholamine activity in the female rat. Endocrinology 118 91–97. (doi:10.1210/endo-118-1-91)
5. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E & Flier JS 1996 Role of leptin in the neuroendocrine response to fasting. Nature 382 250–252. (doi:10.1038/382250a0)
6. Alsio J, Nordenankar K, Arvidsson E, Birgner C, Mahmoudi S, Halbout B, Smith C, Fortin GM, Olson L, Descarries L, et al. 2011 Enhanced sucrose and cocaine self-administration and cue-induced drug seeking after loss of VGLUT2 in midbrain dopamine neurons in mice. Journal of Neuroscience 31 12593–12603. (doi:10.1523/JNEUROSCI.2397-11.2011)
7. Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Ueno N, Makino S, Fujimiya M, Niijima A, Fujino MA, et al. 2001 Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology 120 337–345. (doi:10.1053/gast.2001.22158)
8. Backholer K, Smith J & Clarke IJ 2009 Melanocortins may stimulate reproduction by activating orexin neurons in the dorsomedial hypothalamus and kisspeptin neurons in the preoptic area of the ewe. Endocrinology 150 5488–5497. (doi:10.1210/en.2009-0604)
9. Balthasar N, Coppari R, McMinn J, Liu SM, Lee CE, Tang V, Kenny CD, McGovern RA, Chua SC Jr, Elmquist JK, et al. 2004 Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42 983–991. (doi:10.1016/j.neuron.2004.06.004)
10. Barash IA, Cheung CC, Weigle DS, Ren H, Kabigting EB, Kuijper JL, Clifton DK & Steiner RA 1996 Leptin is a metabolic signal to the reproductive system. Endocrinology 137 3144–3147. (doi:10.1210/en.137.7.3144)
11. Baroncini M, Allet C, Leroy D, Beauvillain JC, Francke JP & Prevot V 2007 Morphological evidence for direct interaction between gonadotrophin-releasing hormone neurones and astroglial cells in the human hypothalamus. Journal of Neuroendocrinology 19 691–702. (doi:10.1111/j.1365-2826.2007.01576.x)
12. Baskin DG, Figlewicz Lattemann D, Seeley RJ, Woods SC, Porte D Jr & Schwartz MW 1999 Insulin and leptin: dual adiposity signals to the brain for the regulation of food intake and body weight. Brain Research 848 114–123. (doi:10.1016/S0006-8993(99)01974-5)
13. Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AW, Wang Y, Banks AS, Lavery HJ, Haq AK, Maratos-Flier E, et al. 2003 STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 421 856–859. (doi:10.1038/nature01388)
14. Beak SA, Heath MM, Small CJ, Morgan DG, Ghatei MA, Taylor AD, Buckingham JC, Bloom SR & Smith DM 1998 Glucagon-like peptide-1 stimulates luteinizing hormone-releasing hormone secretion in a rodent hypothalamic neuronal cell line. Journal of Clinical Investigation 101 1334–1341. (doi:10.1172/JCI610)
15. Belgardt BF & Bruning JC 2010 CNS leptin and insulin action in the control of energy homeostasis. Annals of the New York Academy of Sciences 1212 97–113. (doi:10.1111/j.1749-6632.2010.05799.x)
16. Bell-Horner CL, Dohi A, Nguyen Q, Dillon GH & Singh M 2006 ERK/MAPK pathway regulates GABAA receptors. Journal of Neurobiology 66 1467–1474. (doi:10.1002/neu.20327)
17. Bellefontaine N, Chachlaki K, Parkash J, Vanacker C, Colledge W, de Tassigny XD, Garthwaite J, Bouret SG & Prevot V 2014 Leptin-dependent neuronal NO signaling in the preoptic hypothalamus facilitates reproduction. Journal of Clinical Investigation 124 2550–2559. (doi:10.1172/JCI65928)
18. Benoit SC, Air EL, Coolen LM, Strauss R, Jackman A, Clegg DJ, Seeley RJ & Woods SC 2002 The catabolic action of insulin in the brain is mediated by melanocortins. Journal of Neuroscience 22 9048–9052.
19. Benomar Y, Wetzler S, Larue-Achagiotis C, Djiane J, Tome D & Taouis M 2005 In vivo leptin infusion impairs insulin and leptin signalling in liver and hypothalamus. Molecular and Cellular Endocrinology 242 59–66. (doi:10.1016/j.mce.2005.07.003)
20. Berga S 2006 Stress, metabolism and reproductive compromise. Human Reproduction 21 I32–I32. (doi:10.1093/oxfordjournals.humrep. a002529)
21. Berga SL 2008 Stress and reproduction: a tale of false dichotomy? Endocrinology 149 867–868. (doi:10.1210/en.2008-0004)
22. Berga SL, Mortola JF, Girton L, Suh B, Laughlin G, Pham P & Yen SS 1989 Neuroendocrine aberrations in women with functional hypothalamic amenorrhea. Journal of Clinical Endocrinology and Metabolism 68 301–308. (doi:10.1210/jcem-68-2-301)
23. Berthou F, Rouch C, Gertler A, Gerozissis K & Taouis M 2011 Chronic central leptin infusion differently modulates brain and liver insulin signaling. Molecular and Cellular Endocrinology 337 89–95. (doi:10.1016/j.mce.2011.02.005)
24. Bingham NC, Anderson KK, Reuter AL, Stallings NR & Parker KL 2008 Selective loss of leptin receptors in the ventromedial hypothalamic nucleus results in increased adiposity and a metabolic syndrome. Endocrinology 149 2138–2148. (doi:10.1210/en.2007-1200)
25. Boden G, Chen X, Mozzoli M & Ryan I 1996 Effect of fasting on serum leptin in normal human subjects. Journal of Clinical Endocrinology and Metabolism 81 3419–3423. (doi:10.1210/jc.81.9.3419)
26. Brady LS, Smith MA, Gold PW & Herkenham M 1990 Altered expression of hypothalamic neuropeptide mRNAs in food-restricted and food-deprived rats. Neuroendocrinology 52 441–447. (doi:10.1159/000125626)
27. Brann DW & Mahesh VB 1995 Glutamate: a major neuroendocrine excitatory signal mediating steroid effects on gonadotropin secretion. Journal of Steroid Biochemistry and Molecular Biology 53 325–329. (doi:10.1016/0960-0760(95)00070-G)
28. Brothers KJ, Wu S, DiVall SA, Messmer MR, Kahn CR, Miller RS, Radovick S, Wondisford FE & Wolfe A 2010 Rescue of obesity-induced infertility in female mice due to a pituitary-specific knockout of the insulin receptor. Cell Metabolism 12 295–305. (doi:10.1016/j.cmet.2010.06.010)
29. Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Muller-Wieland D & Kahn CR 2000 Role of brain insulin receptor in control of body weight and reproduction. Science 289 2122–2125. (doi:10.1126/science.289.5487.2122)
30. Bucholtz DC, Vidwans NM, Herbosa CG, Schillo KK & Foster DL 1996 Metabolic interfaces between growth and reproduction. V. Pulsatile luteinizing hormone secretion is dependent on glucose availability. Endocrinology 137 601–607. (doi:10.1210/en.137.2.601)
31. Burgos-Ramos E, Chowen JA, Arilla-Ferreiro E, Canelles S, Argente J & Barrios V 2011 Chronic central leptin infusion modifies the response to acute central insulin injection by reducing the interaction of the insulin receptor with IRS2 and increasing its association with SOCS3. Journal of Neurochemistry 117 175–185. (doi:10.1111/j.1471-4159.2011.07191.x)
32. Cameron JL & Nosbisch C 1991 Suppression of pulsatile luteinizing-hormone and testosterone secretion during short-term food restriction in the adult male rhesus-monkey (macaca-mulatta). Endocrinology 128 1532–1540. (doi:10.1210/endo-128-3-1532)
33. Carro E, Pinilla L, Seoane LM, Considine RV, Aguilar E, Casanueva FF & Dieguez C 1997 Influence of endogenous leptin tone on the estrous cycle and luteinizing hormone pulsatility in female rats. Neuroendocrinology 66 375–377. (doi:10.1159/000127262)
34. 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. Obesity Research 13 48–57. (doi:10.1038/oby.2005.7)
35. Castellano JM, Navarro VM, Fernandez-Fernandez R, Nogueiras R, Tovar S, Roa J, Vazquez MJ, Vigo E, Casanueva FF, Aguilar E, et al. 2005 Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology 146 3917–3925. (doi:10.1210/en.2005-0337)
36. Castellano JM, Navarro VM, Fernandez-Fernandez R, Roa J, Vigo E, Pineda R, Dieguez C, Aguilar E, Pinilla L & Tena-Sempere M 2006 Expression of hypothalamic KiSS-1 system and rescue of defective gonadotropic responses by kisspeptin in streptozotocin-induced diabetic male rats. Diabetes 55 2602–2610. (doi:10.2337/db05-1584)
37. Castellano JM, Bentsen AH, Mikkelsen JD & Tena-Sempere M 2010 Kisspeptins: bridging energy homeostasis and reproduction. Brain Research 1364 129–138. (doi:10.1016/j.brainres.2010.08.057)
38. Chan JL, Heist K, DePaoli AM, Veldhuis JD & Mantzoros CS 2003 The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. Journal of Clinical Investigation 111 1409–1421. (doi:10.1172/JCI200317490)
39. Chehab FF, Mounzih K, Lu R & Lim ME 1997 Early onset of reproductive function in normal female mice treated with leptin. Science 275 88–90. (doi:10.1126/science.275.5296.88)
40. Chen MD, O’Byrne KT, Chiappini SE, Hotchkiss J & Knobil E 1992 Hypoglycemic ‘stress’ and gonadotropin-releasing hormone pulse generator activity in the rhesus monkey: role of the ovary. Neuroendocrinology 56 666–673. (doi:10.1159/000126291)
41. Chen LL, Jiang QY, Zhu XT, Shu G, Bin YF, Wang XQ, Gao P & Zhang YL 2007 Ghrelin ligand-receptor mRNA expression in hypothalamus, proventriculus and liver of chicken (Gallus gallus domesticus): studies on ontogeny and feeding condition. Comparative Biochemistry and Physiology: Part A Molecular and Integrative Physiology 147 893–902. (doi:10.1016/j.cbpa.2007.02.017)
42. Cheong RY, Czieselsky K, Porteous R & Herbison AE 2015 Expression of ESR1 in glutamatergic and GABAergic neurons is essential for normal puberty onset, estrogen feedback, and fertility in female mice. Journal of Neuroscience 35 14533–14543. (doi:10.1523/JNEUROSCI.1776-15.2015)
43. Christian CA & Moenter SM 2010 The neurobiology of preovulatory and estradiol-induced gonadotropin-releasing hormone surges. Endocrine Reviews 31 544–577. (doi:10.1210/er.2009-0023)
44. Clarkson J & Herbison AE 2011 Dual phenotype kisspeptin-dopamine neurones of the rostral periventricular area of the third ventricle project to gonadotrophin-releasing hormone neurones. Journal of Neuroendocrinology 23 293–301. (doi:10.1111/j.1365-2826.2011.02107.x)
45. Codner E, Merino PM & Tena-Sempere M 2012 Female reproduction and type 1 diabetes: from mechanisms to clinical findings. Human Reproduction Update 18 568–585. (doi:10.1093/humupd/dms024)
46. Comninos AN, Jayasena CN & Dhillo WS 2014 The relationship between gut and adipose hormones, and reproduction. Human Reproduction Update 20 153–174. (doi:10.1093/humupd/dmt033)
47. Compagnucci C, Compagnucci GE, Lomniczi A, Mohn C, Vacas I, Cebral E, Elverdin JC, Friedman S, Rettori V & Boyer PM 2002 Effect of nutritional stress on the hypothalamo-pituitary-gonadal axis in the growing male rat. Neuroimmunomodulation 10 153–162. (doi:10.1159/000067177)
48. Cone RD 2005 Anatomy and regulation of the central melanocortin system. Nature Neuroscience 8 571–578. (doi:10.1038/nn1455)
49. Corr M, De Souza MJ, Toombs RJ & Williams NI 2011 Circulating leptin concentrations do not distinguish menstrual status in exercising women. Human Reproduction 26 685–694. (doi:10.1093/humrep/deq375)
50. Cowley MA, Pronchuk N, Fan W, Dinulescu DM, Colmers WF & Cone RD 1999 Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron 24 155–163. (doi:10.1016/S0896-6273(00)80829-6)
51. 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. (doi:10.1038/35078085)
52. Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML, 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. (doi:10.1016/S0896-6273(03)00063-1)
53. Cravo RM, Frazao R, Perello M, Osborne-Lawrence S, Williams KW, Zigman JM, Vianna C & Elias CF 2013 Leptin signaling in kiss1 neurons arises after pubertal development. PLoS ONE 8 e58698. (doi:10.1371/journal.pone.0058698)
54. Crown A, Clifton DK & Steiner RA 2007 Neuropeptide signaling in the integration of metabolism and reproduction. Neuroendocrinology 86 175–182. (doi:10.1159/000109095)
55. Cunningham MJ 2004 Galanin-like peptide as a link between metabolism and reproduction. Journal of Neuroendocrinology 16 717–723. (doi:10.1111/j.1365-2826.2004.01221.x)
56. Cunningham MJ, Scarlett JM & Steiner RA 2002 Cloning and distribution of galanin-like peptide mRNA in the hypothalamus and pituitary of the macaque. Endocrinology 143 755–763. (doi:10.1210/endo.143.3.8661)
57. De Bond JP, Tolson KP, Nasamran C, Kauffman AS & Smith JT 2016 Unaltered hypothalamic metabolic gene expression in Kiss1r KO mice despite obesity and reduced energy expenditure. Journal of Neuroendocrinology 28 jne.12430. (doi:10.1111/jne.12430)
58. De Souza MJ, Leidy HJ, O’Donnell E, Lasley B & Williams NI 2004 Fasting ghrelin levels in physically active women: relationship with menstrual disturbances and metabolic hormones. Journal of Clinical Endocrinology and Metabolism 89 3536–3542. (doi:10.1210/jc.2003-032007)
59. De Souza MJ, Lee DK, VanHeest JL, Scheid JL, West SL & Williams NI 2007 Severity of energy-related menstrual disturbances increases in proportion to indices of energy conservation in exercising women. Fertility and Sterility 88 971–975. (doi:10.1016/j. fertnstert.2006.11.171)
60. Diggs-Andrews KA, Zhang X, Song Z, Daphna-Iken D, Routh VH & Fisher SJ 2010 Brain insulin action regulates hypothalamic glucose sensing and the counterregulatory response to hypoglycemia. Diabetes 59 2271–2280. (doi:10.2337/db10-0401)
61. Divall SA, Williams TR, Carver SE, Koch L, Bruning JC, Kahn CR, Wondisford F, Radovick S & Wolfe A 2010 Divergent roles of growth factors in the GnRH regulation of puberty in mice. Journal of Clinical Investigation 120 2900–2909. (doi:10.1172/JCI41069)
62. DiVall SA, Herrera D, Sklar B, Wu S, Wondisford F, Radovick S & Wolfe A 2015 Insulin receptor signaling in the GnRH neuron plays a role in the abnormal GnRH pulsatility of obese female mice. PLoS ONE 10 e0119995. (doi:10.1371/journal.pone.0119995)
63. Donato J Jr, Cravo RM, Frazao R, Gautron L, Scott MM, Lachey J, Castro IA, Margatho LO, Lee S, Lee C, et al. 2011 Leptin’s effect on puberty in mice is relayed by the ventral premamillary nucleus and does not require signaling in Kiss1 neurons. Journal of Clinical Investigation 121 355–368. (doi:10.1172/JCI45106)
64. Donoso AO, Seltzer AM, Navarro CE, Cabrera RJ, Lopez FJ & Negro-Vilar A 1994 Regulation of luteinizing hormone-releasing hormone and luteinizing hormone secretion by hypothalamic amino acids. Brazilian Journal of Medical and Biological Research 27 921–932.
65. Dupont C, Cordier AG, Junien C, Mandon-Pepin B, Levy R & Chavatte-Palmer P 2012 Maternal environment and the reproductive function of the offspring. Theriogenology 78 1405–1414. (doi:10.1016/j. theriogenology.2012.06.016)
66. Elias CF, Aschkenasi C, Lee C, Kelly J, Ahima RS, Bjorbaek C, Flier JS, Saper CB & Elmquist JK 1999 Leptin differentially regulates NPY andPOMC neurons projecting to the lateral hypothalamic area. Neuron 23 775–786. (doi:10.1016/S0896-6273(01)80035-0)
67. Evans MC, Rizwan M, Mayer C, Boehm U & Anderson GM 2014a Evidence that insulin signalling in gonadotrophin-releasing hormone and kisspeptin neurones does not play an essential role in metabolic regulation of fertility in mice. Journal of Neuroendocrinology 26 468–479. (doi:10.1111/jne.12166)
68. Evans MC, Rizwan MZ & Anderson GM 2014b Insulin action on GABA neurons is a critical regulator of energy balance but not fertility in mice. Endocrinology 155 4368–4379. (doi:10.1210/en.2014-1412)
69. Evans MC, Rizwan MZ & Anderson GM 2015 Insulin does not target CamkIIalpha neurones to critically regulate the neuroendocrine reproductive axis in mice. Journal of Neuroendocrinology 27 899–910. (doi:10.1111/jne.12330)
70. Farkas I, Vastagh C, Sarvari M & Liposits Z 2013 Ghrelin decreases firing activity of gonadotropin-releasing hormone (GnRH) neurons in an estrous cycle and endocannabinoid signaling dependent manner. PLoS ONE 8 e78178. (doi:10.1371/journal.pone.0078178)
71. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA & O’Rahilly S 1999 Effects of recombinant leptin therapy in a child with congenital leptin deficiency. New England Journal of Medicine 341 879–884. (doi:10.1056/NEJM199909163411204)
72. Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, Sanna V, Jebb SA, Perna F, Fontana S, et al. 2002 Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. Journal of Clinical Investigation 110 1093–1103. (doi:10.1172/JCI0215693)
73. Forbes S, Li XF, Kinsey-Jones J & O’Byrne K 2009 Effects of ghrelin on Kisspeptin mRNA expression in the hypothalamic medial preoptic area and pulsatile luteinising hormone secretion in the female rat. Neuroscience Letters 460 143–147. (doi:10.1016/j.neulet.2009.05.060)
74. Fraley GS, Scarlett JM, Shimada I, Teklemichael DN, Acohido BV, Clifton DK & Steiner RA 2004 Effects of diabetes and insulin on the expression of galanin-like peptide in the hypothalamus of the rat. Diabetes 53 1237–1242. (doi:10.2337/diabetes.53.5.1237)
75. Frayling C, Britton R & Dale N 2011 ATP-mediated glucosensing by hypothalamic tanycytes. Journal of Physiology 589 2275–2286. (doi:10.1113/jphysiol.2010.202051)
76. Fu LY & van den Pol AN 2010 Kisspeptin directly excites anorexigenic proopiomelanocortin neurons but inhibits orexigenic neuropeptide Y cells by an indirect synaptic mechanism. Journal of Neuroscience 30 10205–10219. (doi:10.1523/JNEUROSCI.2098-10.2010)
77. Furuta M, Funabashi T & Kimura F 2001 Intracerebroventricular administration of ghrelin rapidly suppresses pulsatile luteinizing hormone secretion in ovariectomized rats. Biochemical and Biophysical Research Communications 288 780–785. (doi:10.1006/bbrc.2001.5854)
78. Gao Q, Wolfgang MJ, Neschen S, Morino K, Horvath TL, Shulman GI & Fu XY 2004 Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. PNAS 101 4661–4666. (doi:10.1073/pnas.0303992101)
79. Garcia MA, Millan C, Balmaceda-Aguilera C, Castro T, Pastor P, Montecinos H, Reinicke K, Zuniga F, Vera JC, Onate SA, et al. 2003 Hypothalamic ependymal-glial cells express the glucose transporter GLUT2, a protein involved in glucose sensing. Journal of Neurochemistry 86 709–724. (doi:10.1046/j.1471-4159.2003.01892.x)
80. Garcia-Galiano D, van Ingen Schenau D, Leon S, Krajnc-Franken MA, Manfredi-Lozano M, Romero-Ruiz A, Navarro VM, Gaytan F, van Noort PI, Pinilla L, et al. 2012 Kisspeptin signaling is indispensable for neurokinin B, but not glutamate, stimulation of gonadotropin secretion in mice. Endocrinology 153 316–328. (doi:10.1210/en.2011-1260)
81. Garcia-Caceres C, Quarta C, Varela L, Gao Y, Gruber T, Legutko B, Jastroch M, Johansson P, Ninkovic J, Yi CX, et al. 2016 Astrocytic insulin signaling couples brain glucose uptake with nutrient availability. Cell 166 867–880. (doi:10.1016/j.cell.2016.07.028)
82. Guan JL, Okuda H, Takenoya F, Kintaka Y, Yagi M, Wang L, Seki M, Hori Y, Kageyama H & Shioda S 2008 Synaptic relationships between proopiomelanocortin- and ghrelin-containing neurons in the rat arcuate nucleus. Regulatory Peptides 145 128–132. (doi:10.1016/j. regpep.2007.09.028)
83. Gyurko R, Leupen S & Huang PL 2002 Deletion of exon 6 of the neuronal nitric oxide synthase gene in mice results in hypogonadism and infertility. Endocrinology 143 2767–2774. (doi:10.1210/endo.143.7.8921)
84. Han SK, Gottsch ML, Lee KJ, Popa SM, Smith JT, Jakawich SK, Clifton DK, Steiner RA & Herbison AE 2005 Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. Journal of Neuroscience 25 11349–11356. (doi:10.1523/JNEUROSCI.3328-05.2005)
85. Havel PJ, Hahn TM, Sindelar DK, Baskin DG, Dallman MF, Weigle DS & Schwartz MW 2000 Effects of streptozotocin-induced diabetes and insulin treatment on the hypothalamic melanocortin system and muscle uncoupling protein 3 expression in rats. Diabetes 49 244–252. (doi:10.2337/diabetes.49.2.244)
86. Heni M, Hennige AM, Peter A, Siegel-Axel D, Ordelheide AM, Krebs N, Machicao F, Fritsche A, Haring HU & Staiger H 2011 Insulin promotes glycogen storage and cell proliferation in primary human astrocytes. PLoS ONE 6 e21594. (doi:10.1371/journal.pone.0021594)
87. Herbison AE 2016 Control of puberty onset and fertility by gonadotropin-releasing hormone neurons. Nature Reviews Endocrinology 12 452–466. (doi:10.1038/nrendo.2016.70)
88. Herbison AE & Moenter SM 2011 Depolarising and hyperpolarising actions of GABA(A) receptor activation on gonadotrophin-releasing hormone neurones: towards an emerging consensus. Journal of Neuroendocrinology 23 557–569. (doi:10.1111/j.1365-2826.2011.02145.x)
89. Hill JW & Levine JE 2003 Abnormal response of the neuropeptide Y-deficient mouse reproductive axis to food deprivation but not lactation. Endocrinology 144 1780–1786. (doi:10.1210/en.2002-221024)
90. Hill JW, Elias CF, Fukuda M, Williams KW, Berglund ED, Holland WL, Cho YR, Chuang JC, Xu Y, Choi M, et al. 2010 Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metabolism 11 286–297. (doi:10.1016/j.cmet.2010.03.002)
91. Holst B & Schwartz TW 2004 Constitutive ghrelin receptor activity as a signaling set-point in appetite regulation. Trends in Pharmacological Sciences 25 113–117. (doi:10.1016/j.tips.2004.01.010)
92. Holst B, Cygankiewicz A, Jensen TH, Ankersen M & Schwartz TW 2003 High constitutive signaling of the ghrelin receptor–identification of a potent inverse agonist. Molecular Endocrinology 17 2201–2210. (doi:10.1210/me.2003-0069)
93. Hommel JD, Trinko R, Sears RM, Georgescu D, Liu ZW, Gao XB, Thurmon JJ, Marinelli M & DiLeone RJ 2006 Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron 51 801–810. (doi:10.1016/j.neuron.2006.08.023)
94. Howland BE 1980 Effect of glucoprivation induced by 2-deoxy-d-glucose on serum gonadotropin levels, pituitary response to GnRH and progesterone-induced release of luteinizing hormone in rats. Hormone and Metabolic Research 12 520–523. (doi:10.1055/s-2007-999190)
95. Huang PL 2000 Mouse models of nitric oxide synthase deficiency. Journal of the American Society of Nephrology 11 S120–S123.
96. Huang W, Acosta-Martinez M, Horton TH & Levine JE 2008 Fasting-induced suppression of LH secretion does not require activation of ATP-sensitive potassium channels. American Journal of Physiology: Endocrinology and Metabolism 295 E1439–E1446. (doi:10.1152/ajpendo.90615.2008)
97. Hummel KP, Dickie MM & Coleman DL 1966 Diabetes, a new mutation in the mouse. Science 153 1127–1128. (doi:10.1126/science.153.3740.1127)
98. Huo L, Gamber K, Greeley S, Silva J, Huntoon N, Leng XH & Bjorbaek C 2009 Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metabolism 9 537–547.
99. Ingalls AM, Dickie MM & Snell GD 1950 Obese, a new mutation in the house mouse. Journal of Heredity 41 317–318.
100. Iremonger KJ, Constantin S, Liu X & Herbison AE 2010 Glutamate regulation of GnRH neuron excitability. Brain Research 1364 35–43. (doi:10.1016/j.brainres.2010.08.071)
101. Irwig MS, Fraley GS, Smith JT, Acohido BV, Popa SM, Cunningham MJ, Gottsch ML, Clifton DK & Steiner RA 2004 Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinology 80 264–272. (doi:10.1159/000083140)
102. Jayasena CN, Nijher GM, Chaudhri OB, Murphy KG, Ranger A, Lim A, Patel D, Mehta A, Todd C, Ramachandran R, et al. 2009 Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis. Journal of Clinical Endocrinology and Metabolism 94 4315–4323. (doi:10.1210/jc.2009-0406)
103. Jayasena CN, Nijher GM, Abbara A, Murphy KG, Lim A, Patel D, Mehta A, Todd C, Donaldson M, Trew GH, et al. 2010 Twice-weekly administration of kisspeptin-54 for 8 weeks stimulates release of reproductive hormones in women with hypothalamic amenorrhea. Clinical Pharmacology and Therapeutics 88 840–847. (doi:10.1038/clpt.2010.204)
104. Jureus A, Cunningham MJ, McClain ME, Clifton DK & Steiner RA 2000 Galanin-like peptide (GALP) is a target for regulation by leptin in the hypothalamus of the rat. Endocrinology 141 2703–2706. (doi:10.1210/en.141.7.2703)
105. Kalamatianos T, Grimshaw SE, Poorun R, Hahn JD & Coen CW 2008 Fasting reduces KiSS-1 expression in the anteroventral periventricular nucleus (AVPV): effects of fasting on the expression of KiSS-1 and neuropeptide Y in the AVPV or arcuate nucleus of female rats. Journal of Neuroendocrinology 20 1089–1097. (doi:10.1111/j.1365-2826.2008.01757.x)
106. Kalra SP, Ueno N & Kalra PS 2005 Stimulation of appetite by ghrelin is regulated by leptin restraint: peripheral and central sites of action. Journal of Nutrition 135 1331–1335.
107. Katsiki N & Hatzitolios AI 2010 Insulin-sensitizing agents in the treatment of polycystic ovary syndrome: an update. Current Opinion in Obstetrics and Gynecology 22 466–476. (doi:10.1097/GCO.0b013e32833e1264)
108. Kauffman AS, Buenzle J, Fraley GS & Rissman EF 2005 Effects of galanin-like peptide (GALP) on locomotion, reproduction, and body weight in female and male mice. Hormones and Behavior 48 141–151. (doi:10.1016/j.yhbeh.2005.01.010)
109. Kawano M, Kawasaki A, Sakata-Haga H, Fukui Y, Kawano H, Nogami H & Hisano S 2006 Particular subpopulations of midbrain and hypothalamic dopamine neurons express vesicular glutamate transporter 2 in the rat brain. Journal of Comparative Neurology 498 581–592. (doi:10.1002/cne.21054)
110. Khanh DV, Choi YH, Moh SH, Kinyua AW & Kim KW 2014 Leptin and insulin signaling in dopaminergic neurons: relationship between energy balance and reward system. Frontiers in Psychology 5 846. (doi:10.3389/fpsyg.2014.00846)
111. Kim KW, Li S, Zhao H, Peng B, Tobet SA, Elmquist JK, Parker KL & Zhao L 2010 CNS-specific ablation of steroidogenic factor 1 results in impaired female reproductive function. Molecular Endocrinology 24 1240–1250. (doi:10.1210/me.2009-0206)
112. Kim JG, Suyama S, Koch M, Jin S, Argente-Arizon P, Argente J, Liu ZW, Zimmer MR, Jeong JK, Szigeti-Buck K, et al. 2014 Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nature Neuroscience 17 908–910. (doi:10.1038/nn.3725)
113. Kinsey-Jones JS, Li XF, Knox AM, Wilkinson ES, Zhu XL, Chaudhary AA, Milligan SR, Lightman SL & O’Byrne KT 2009 Down-regulation of hypothalamic kisspeptin and its receptor, Kiss1r, mRNA expression is associated with stress-induced suppression of luteinising hormone secretion in the female rat. Journal of Neuroendocrinology 21 20–29. (doi:10.1111/j.1365-2826.2008.01807.x)
114. Klenke U, Taylor-Burds C & Wray S 2014 Metabolic influences on reproduction: adiponectin attenuates GnRH neuronal activity in female mice. Endocrinology 155 1851–1863. (doi:10.1210/en.2013-1677)
115. Kluge M 2012 Ghrelin suppresses secretion of gonadotropins in women. Reproductive Sciences 19 Np3–Np3. (doi:10.1177/1933719112459242)
116. Kluge M, Schussler P, Uhr M, Yassouridis A & Steiger A 2007 Ghrelin suppresses secretion of luteinizing hormone in humans. Journal of Clinical Endocrinology and Metabolism 92 3202–3205. (doi:10.1210/jc.2007-0593)
117. Kluge M, Uhr M, Bleninger P, Yassouridis A & Steiger A 2009 Ghrelin suppresses secretion of FSH in males. Clinical Endocrinology 70 920–923. (doi:10.1111/j.1365-2265.2008.03440.x)
118. Kluge M, Schussler P, Schmidt D, Uhr M & Steiger A 2012 Ghrelin suppresses secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in women. Journal of Clinical Endocrinology and Metabolism 97 E448–E451. (doi:10.1210/jc.2011-2607)
119. Kluge M, Schmidt D, Uhr M & Steiger A 2013 Ghrelin suppresses nocturnal secretion of luteinizing hormone (LH) and thyroid stimulating hormone (TSH) in patients with major depression. Journal of Psychiatric Research 47 1236–1239. (doi:10.1016/j. jpsychires.2013.05.010)
120. Knox AM, Li XF, Kinsey-Jones JS, Wilkinson ES, Wu XQ, Cheng YS, Milligan SR, Lightman SL & O’Byrne KT 2009 Neonatal lipopolysaccharide exposure delays puberty and alters hypothalamic Kiss1 and Kiss1r mRNA expression in the female rat. Journal of Neuroendocrinology 21 683–689. (doi:10.1111/j.1365-2826.2009.01885.x)
121. Kocsis K, Kiss J, Csaki A & Halasz B 2003 Location of putative glutamatergic neurons projecting to the medial preoptic area of the rat hypothalamus. Brain Research Bulletin 61 459–468. (doi:10.1016/S0361-9230(03)00180-1)
122. Konner AC, Janoschek R, Plum L, Jordan SD, Rother E, Ma X, Xu C, Enriori P, Hampel B, Barsh GS, et al. 2007 Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metabolism 5 438–449. (doi:10.1016/j.cmet.2007.05.004)
123. Konner AC, Hess S, Tovar S, Mesaros A, Sanchez-Lasheras C, Evers N, Verhagen LA, Bronneke HS, Kleinridders A, Hampel B, et al. 2011 Role for insulin signaling in catecholaminergic neurons in control of energy homeostasis. Cell Metabolism 13 720–728. (doi:10.1016/j. cmet.2011.03.021)
124. Korner J, Savontaus E, Chua SC Jr, Leibel RL & Wardlaw SL 2001 Leptin regulation of Agrp and Npy mRNA in the rat hypothalamus. Journal of Neuroendocrinology 13 959–966. (doi:10.1046/j.1365-2826.2001.00716.x)
125. Kuramochi M, Kohno D, Onaka T, Kato S & Yada T 2005 Galanin-like peptide and ghrelin increase cytosolic Ca2+ in neurons containing growth hormone-releasing hormone in the arcuate nucleus. Regulatory Peptides 126 85–89. (doi:10.1016/j.regpep.2004.08.017)
126. Kuramochi M, Onaka T, Kohno D, Kato S & Yada T 2006 Galanin-like peptide stimulates food intake via activation of neuropeptide Y neurons in the hypothalamic dorsomedial nucleus of the rat. Endocrinology 147 1744–1752. (doi:10.1210/en.2005-0907)
127. Laughlin GA & Yen SS 1996 Nutritional and endocrine-metabolic aberrations in amenorrheic athletes. Journal of Clinical Endocrinology and Metabolism 81 4301–4309. (doi:10.1210/jc.81.12.4301)
128. Laughlin GA & Yen SS 1997 Hypoleptinemia in women athletes: absence of a diurnal rhythm with amenorrhea. Journal of Clinical Endocrinology and Metabolism 82 318–321. (doi:10.1210/jcem.82.1.3840)
129. Laughlin GA, Morales AJ & Yen SS 1997 Serum leptin levels in women with polycystic ovary syndrome: the role of insulin resistance/hyperinsulinemia. Journal of Clinical Endocrinology and Metabolism 82 1692–1696. (doi:10.1210/jc.82.6.1692)
130. Laughlin GA, Dominguez CE & Yen SS 1998 Nutritional and endocrine-metabolic aberrations in women with functional hypothalamic amenorrhea. Journal of Clinical Endocrinology and Metabolism 83 25–32. (doi:10.1210/jc.83.1.25)
131. Lebrethon MC, Aganina A, Fournier M, Gerard A, Parent AS & Bourguignon JP 2007 Effects of in vivo and in vitro administration of ghrelin, leptin and neuropeptide mediators on pulsatile gonadotrophin-releasing hormone secretion from male rat hypothalamus before and after puberty. Journal of Neuroendocrinology 19 181–188. (doi:10.1111/j.1365-2826.2006.01518.x)
132. Leranth C, MacLusky NJ, Shanabrough M & Naftolin F 1988 Immunohistochemical evidence for synaptic connections between pro-opiomelanocortin-immunoreactive axons and LH-RH neurons in the preoptic area of the rat. Brain Research 449 167–176. (doi:10.1016/0006-8993(88)91035-9)
133. Leshan RL, Greenwald-Yarnell M, Patterson CM, Gonzalez IE & Myers MG 2012 Leptin action through hypothalamic nitric oxide synthase-1-expressing neurons controls energy balance. Nature Medicine 18 820-U236. (doi:10.1038/nm.2724)
134. Levin BE, Routh VH, Kang L, Sanders NM & Dunn-Meynell AA 2004 Neuronal glucosensing: what do we know after 50 years? Diabetes 53 2521–2528. (doi:10.2337/diabetes.53.10.2521)
135. Li XF, Bowe JE, Mitchell JC, Brain SD, Lightman SL & O’Byrne KT 2004a Stress-induced suppression of the gonadotropin-releasing hormone pulse generator in the female rat: a novel neural action for calcitonin gene-related peptide. Endocrinology 145 1556–1563. (doi:10.1210/en.2003-1609)
136. Li XF, Edward J, Mitchell JC, Shao B, Bowes JE, Coen CW, Lightman SL & O’Byrne KT 2004b Differential effects of repeated restraint stress on pulsatile lutenizing hormone secretion in female Fischer, Lewis and Wistar rats. Journal of Neuroendocrinology 16 620–627. (doi:10.1111/j.1365-2826.2004.01209.x)
137. Lin LH, Edwards RH, Fremeau RT, Fujiyama F, Kaneko T & Talman WT 2004 Localization of vesicular glutamate transporters and neuronal nitric oxide synthase in rat nucleus tractus solitarii. Neuroscience 123 247–255. (doi:10.1016/j.neuroscience.2003.08.063)
138. Liu X & Herbison AE 2013 Dopamine regulation of gonadotropin-releasing hormone neuron excitability in male and female mice. Endocrinology 154 340–350. (doi:10.1210/en.2012-1602)
139. Liu J, Perez SM, Zhang W, Lodge DJ & Lu XY 2011 Selective deletion of the leptin receptor in dopamine neurons produces anxiogenic-like behavior and increases dopaminergic activity in amygdala. Molecular Psychiatry 16 1024–1038. (doi:10.1038/mp.2011.36)
140. Lopez FJ, Donoso AO & Negro-Vilar A 1990 Endogenous excitatory amino acid neurotransmission regulates the estradiol-induced LH surge in ovariectomized rats. Endocrinology 126 1771–1773. (doi:10.1210/endo-126-3-1771)
141. Loucks AB & Thuma JR 2003 Luteinizing hormone pulsatility is disrupted at a threshold of energy availability in regularly menstruating women. Journal of Clinical Endocrinology and Metabolism 88 297–311. (doi:10.1210/jc.2002-020369)
142. Loucks AB & Redman LM 2004 The effect of stress on menstrual function. Trends in Endocrinology and Metabolism 15 466–471. (doi:10.1016/j.tem.2004.10.005)
143. Loucks AB, Verdun M & Heath EM 1998 Low energy availability, not stress of exercise, alters LH pulsatility in exercising women. Journal of Applied Physiology 84 37–46.
144. Louis GW, Greenwald-Yarnell M, Phillips R, Coolen LM, Lehman MN & Myers MG Jr 2011 Molecular mapping of the neural pathways linking leptin to the neuroendocrine reproductive axis. Endocrinology 152 2302–2310. (doi:10.1210/en.2011-0096)
145. MacLusky NJ, Cook S, Scrocchi L, Shin J, Kim J, Vaccarino F, Asa SL & Drucker DJ 2000 Neuroendocrine function and response to stress in mice with complete disruption of glucagon-like peptide-1 receptor signaling. Endocrinology 141 752–762. (doi:10.1210/en.141.2.752)
146. Maeda KI, Cagampang FRA, Coen CW & Tsukamura H 1994 Involvement of the catecholaminergic input to the paraventricular nucleus and of corticotropin-releasing hormone in the fasting-induced suppression of luteinizing-hormone release in female rats. Endocrinology 134 1718–1722. (doi:10.1210/en.134.4.1718)
147. Manfredi-Lozano M, Roa J, Ruiz-Pino F, Piet R, Garcia-Galiano D, Pineda R, Zamora A, Leon S, Sanchez-Garrido MA, Romero-Ruiz A, et al. 2016 Defining a novel leptin-melanocortin-kisspeptin pathway involved in the metabolic control of puberty. Molecular Metabolism 5 844–857. (doi:10.1016/j.molmet.2016.08.003)
148. Marshall CJ, Desroziers E, McLennan T & Campbell RE 2016 Defining subpopulations of arcuate nucleus GABA neurons in male, female and prenatally androgenized female mice. Neuroendocrinology. [in press]. (doi:10.1159/000452105)
149. McShane TM, May T, Miner JL & Keisler DH 1992 Central actions of neuropeptide-Y may provide a neuromodulatory link between nutrition and reproduction. Biology of Reproduction 46 1151–1157. (doi:10.1095/biolreprod46.6.1151)
150. Mebel DM, Wong JC, Dong YJ & Borgland SL 2012 Insulin in the ventral tegmental area reduces hedonic feeding and suppresses dopamine concentration via increased reuptake. European Journal of Neuroscience 36 2336–2346. (doi:10.1111/j.1460-9568.2012.08168.x)
151. Meister B 2007 Neurotransmitters in key neurons of the hypothalamus that regulate feeding behavior and body weight. Physiology and Behavior 92 263–271. (doi:10.1016/j.physbeh.2007.05.021)
152. Merrill CB, Friend LN, Newton ST, Hopkins ZH & Edwards JG 2015 Ventral tegmental area dopamine and GABA neurons: Physiological properties and expression of mRNA for endocannabinoid biosynthetic elements. Scientific Reports 5 16176. (doi:10.1038/srep16176)
153. Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ, et al. 2004 AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428 569–574. (doi:10.1038/nature02440)
154. Mirshamsi S, Laidlaw HA, Ning K, Anderson E, Burgess LA, Gray A, Sutherland C & Ashford ML 2004 Leptin and insulin stimulation of signalling pathways in arcuate nucleus neurones: PI3K dependent actin reorganization and KATP channel activation. BMC Neuroscience 5 54. (doi:10.1186/1471-2202-5-54)
155. Mitsushima D, Hei DL & Terasawa E 1994 gamma-Aminobutyric acid is an inhibitory neurotransmitter restricting the release of luteinizing hormone-releasing hormone before the onset of puberty. PNAS 91 395–399. (doi:10.1073/pnas.91.1.395)
156. Mohr MA, Leathley E & Fraley GS 2012 Hypothalamic galanin-like peptide (GALP) rescues the onset of puberty in food-restricted weanling rats. Journal of Neuroendocrinology 24 1412–1422. (doi:10.1111/j.1365-2826.2012.02351.x)
157. Morris DL & Rui LY 2009 Recent advances in understanding leptin signaling and leptin resistance. American Journal of Physiology: Endocrinology and Metabolism 297 E1247–E1259. (doi:10.1152/ajpendo.00274.2009)
158. Mounzih K, Lu R & Chehab FF 1997 Leptin treatment rescues the sterility of genetically obese ob/ob males. Endocrinology 138 1190–1193. (doi:10.1210/en.138.3.1190)
159. Nandi A, Wang X, Accili D & Wolgemuth DJ 2010 The effect of insulin signaling on female reproductive function independent of adiposity and hyperglycemia. Endocrinology 151 1863–1871. (doi:10.1210/en.2009-0788)
160. Nikolarakis KE, Loeffler JP, Almeida OF & Herz A 1988 Pre- and postsynaptic actions of GABA on the release of hypothalamic gonadotropin-releasing hormone (GnRH). Brain Research Bulletin 21 677–683. (doi:10.1016/0361-9230(88)90208-0)
161. Niswender KD & Schwartz MW 2003 Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities. Frontiers in Neuroendocrinology 24 1–10. (doi:10.1016/S0091-3022(02)00105-X)
162. Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers MG Jr & Schwartz MW 2001 Intracellular signalling. Key enzyme in leptin-induced anorexia. Nature 413 794–795. (doi:10.1038/35101657)
163. Niswender KD, Gallis B, Blevins JE, Corson MA, Schwartz MW & Baskin DG 2003 Immunocytochemical detection of phosphatidylinositol 3-kinase activation by insulin and leptin. Journal of Histochemistry and Cytochemistry 51 275–283. (doi:10.1177/002215540305100302)
164. O’Byrne KT, Lunn SF & Dixson AF 1988 Effects of acute stress on the patterns of LH secretion in the common marmoset (Callithrix jacchus). Journal of Endocrinology 118 259–264. (doi:10.1677/joe.0.1180259)
165. Ojeda SR, Lomniczi A & Sandau US 2008 Glial-gonadotrophin hormone (GnRH) neurone interactions in the median eminence and the control of GnRH secretion. Journal of Neuroendocrinology 20 732–742. (doi:10.1111/j.1365-2826.2008.01712.x)
166. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I & Barsh GS 1997 Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278 135–138. (doi:10.1126/science.278.5335.135)
167. Olson VG & Nestler EJ 2007 Topographical organization of GABAergic neurons within the ventral tegmental area of the rat. Synapse 61 87–95. (doi:10.1002/syn.20345)
168. Ovesjo ML, Gamstedt M, Collin M & Meister B 2001 GABAergic nature of hypothalamic leptin target neurones in the ventromedial arcuate nucleus. Journal of Neuroendocrinology 13 505–516. (doi:10.1046/j.1365-2826.2001.00662.x)
169. Ping L, Mahesh VB, Bhat GK & Brann DW 1997 Regulation of gonadotropin-releasing hormone and luteinizing hormone secretion by AMPA receptors. Evidence for a physiological role of AMPA receptors in the steroid-induced luteinizing hormone surge. Neuroendocrinology 66 246–253. (doi:10.1159/000127245)
170. Pinilla L, Fernandez-Fernandez R, Vigo E, Navarro VM, Roa J, Castellano JM, Pineda R, Tena-Sempere M & Aguilar E 2006 Stimulatory effect of PYY-(3-36) on gonadotropin secretion is potentiated in fasted rats. American Journal of Physiology: Endocrinology and Metabolism 290 E1162–E1171. (doi:10.1152/ajpendo.00469.2005)
171. Pinilla L, Fernandez-Fernandez R, Roa J, Castellano JM, Tena-Sempere M & Aguilar E 2007 Selective role of neuropeptide Y receptor subtype Y2 in the control of gonadotropin secretion in the rat. American Journal of Physiology: Endocrinology and Metabolism 293 E1385–E1392. (doi:10.1152/ajpendo.00274.2007)
172. Poling MC, Shieh MP, Munaganuru N, Luo E & Kauffman AS 2014 Examination of the influence of leptin and acute metabolic challenge on RFRP-3 neurons of mice in development and adulthood. Neuroendocrinology 100 317–333. (doi:10.1159/000369276)
173. Qi Y, Inoue K, Fu M, Inui A & Herzog H 2015 Chronic overproduction of ghrelin in the hypothalamus leads to temporal increase in food intake and body weight. Neuropeptides 50 23–28. (doi:10.1016/j. npep.2015.02.002)
174. Qiu X, Dao H, Wang M, Heston A, Garcia KM, Sangal A, Dowling AR, Faulkner LD, Molitor SC, Elias CF, et al. 2015 Insulin and leptin signaling interact in the mouse kiss1 neuron during the peripubertal period. PLoS ONE 10 e0121974. (doi:10.1371/journal.pone.0121974)
175. Quennell JH, Mulligan AC, Tups A, Liu X, Phipps SJ, Kemp CJ, Herbison AE, Grattan DR & Anderson GM 2009 Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology 150 2805–2812. (doi:10.1210/en.2008-1693)
176. Quennell JH, Howell CS, Roa J, Augustine RA, Grattan DR & Anderson GM 2011 Leptin deficiency and diet-induced obesity reduce hypothalamic kisspeptin expression in mice. Endocrinology 152 1541–1550. (doi:10.1210/en.2010-1100)
177. Ramamurthy S & Ronnett GV 2006 Developing a head for energy sensing: AMP-activated protein kinase as a multifunctional metabolic sensor in the brain. Journal of Physiology 574 85–93. (doi:10.1113/jphysiol.2006.110122)
178. Rizwan MZ, Harbid AA, Inglis MA, Quennell JH & Anderson GM 2014 Evidence that hypothalamic RFamide related peptide-3 neurones are not leptin-responsive in mice and rats. Journal of Neuroendocrinology 26 247–257. (doi:10.1111/jne.12140)
179. Roa J & Herbison AE 2012 Direct regulation of GnRH neuron excitability by arcuate nucleus POMC and NPY neuron neuropeptides in female mice. Endocrinology 153 5587–5599. (doi:10.1210/en.2012-1470)
180. Roa J & Tena-Sempere M 2014 Connecting metabolism and reproduction: roles of central energy sensors and key molecular mediators. Molecular and Cellular Endocrinology 397 4–14. (doi:10.1016/j.mce.2014.09.027)
181. Roa J, Garcia-Galiano D, Varela L, Sanchez-Garrido MA, Pineda R, Castellano JM, Ruiz-Pino F, Romero M, Aguilar E, Lopez M, et al. 2009 The mammalian target of rapamycin as novel central regulator of puberty onset via modulation of hypothalamic Kiss1 system. Endocrinology 150 5016–5026. (doi:10.1210/en.2009-0096)
182. Rodriguez EM, Blazquez JL, Pastor FE, Pelaez B, Pena P, Peruzzo B & Amat P 2005 Hypothalamic tanycytes: a key component of brain-endocrine interaction. International Review of Cytology 247 89–164. (doi:10.1016/S0074-7696(05)47003-5)
183. Roland AV & Moenter SM 2011 Regulation of gonadotropin-releasing hormone neurons by glucose. Trends in Endocrinology and Metabolism 22 443–449. (doi:10.1016/j.tem.2011.07.001)
184. Sandau US, Mungenast AE, Alderman Z, Sardi SP, Fogel AI, Taylor B, Parent AS, Biederer T, Corfas G & Ojeda SR 2011a SynCAM1, a synaptic adhesion molecule, is expressed in astrocytes and contributes to erbB4 receptor-mediated control of female sexual development. Endocrinology 152 2364–2376. (doi:10.1210/en.2010-1435)
185. Sandau US, Mungenast AE, McCarthy J, Biederer T, Corfas G & Ojeda SR 2011b The synaptic cell adhesion molecule, SynCAM1, mediates astrocyte-to-astrocyte and astrocyte-to-GnRH neuron adhesiveness in the mouse hypothalamus. Endocrinology 152 2353–2363. (doi:10.1210/en.2010-1434)
186. Sanz E, Quintana A, Deem JD, Steiner RA, Palmiter RD & McKnight GS 2015 Fertility-regulating Kiss1 neurons arise from hypothalamic POMC-expressing progenitors. Journal of Neuroscience 35 5549–5556. (doi:10.1523/JNEUROSCI.3614-14.2015)
187. Sato I, Arima H, Ozaki N, Watanabe M, Goto M, Hayashi M, Banno R, Nagasaki H & Oiso Y 2005 Insulin inhibits neuropeptide Y gene expression in the arcuate nucleus through GABAergic systems. Journal of Neuroscience 25 8657–8664. (doi:10.1523/JNEUROSCI.2739-05.2005)
188. Schaeffer M, Langlet F, Lafont C, Molino F, Hodson DJ, Roux T, Lamarque L, Verdie P, Bourrier E, Dehouck B, et al. 2013 Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons. PNAS 110 1512–1517. (doi:10.1073/pnas.1212137110)
189. Scheid JL & De Souza MJ 2010 Menstrual irregularities and energy deficiency in physically active women: the role of ghrelin, PYY and adipocytokines. Medicine and Sport Science 55 82–102. (doi:10.1159/000321974)
190. Schneider LF & Warren MP 2006 Functional hypothalamic amenorrhea is associated with elevated ghrelin and disordered eating. Fertility and Sterility 86 1744–1749. (doi:10.1016/j.fertnstert.2006.05.051)
191. Schneider LF, Monaco SE & Warren MP 2008 Elevated ghrelin level in women of normal weight with amenorrhea is related to disordered eating. Fertility and Sterility 90 121–128. (doi:10.1016/j. fertnstert.2007.06.002)
192. Schwartz MW, Marks JL, Sipols AJ, Baskin DG, Woods SC, Kahn SE & Porte D Jr 1991 Central insulin administration reduces neuropeptide Y mRNA expression in the arcuate nucleus of food-deprived lean (Fa/Fa) but not obese (fa/fa) Zucker rats. Endocrinology 128 2645–2647. (doi:10.1210/endo-128-5-2645)
193. Sheffer-Babila S, Sun Y, Israel DD, Liu SM, Neal-Perry G & Chua SC Jr 2013 Agouti-related peptide plays a critical role in leptin’s effects on female puberty and reproduction. American Journal of Physiology: Endocrinology and Metabolism 305 E1512–E1520. (doi:10.1152/ajpendo.00241.2013)
194. Shi H, Sorrell JE, Clegg DJ, Woods SC & Seeley RJ 2010 The roles of leptin receptors on POMC neurons in the regulation of sex-specific energy homeostasis. Physiology & Behavior 100 165–172. (doi:10.1016/j.physbeh.2010.02.018)
195. Shioda S, Kageyama H, Takenoya F & Shiba K 2011 Galanin-like peptide: a key player in the homeostatic regulation of feeding and energy metabolism? International Journal of Obesity 35 619–628. (doi:10.1038/ijo.2010.202)
196. Singireddy AV, Inglis MA, Zuure WA, Kim JS & Anderson GM 2013 Neither signal transducer and activator of transcription 3 (STAT3) or STAT5 signaling pathways are required for leptin’s effects on fertility in mice. Endocrinology 154 2434–2445. (doi:10.1210/en.2013-1109)
197. Skrapits K, Kanti V, Savanyu Z, Maurnyi C, Szenci O, Horvath A, Borsay BA, Herczeg L, Liposits Z & Hrabovszky E 2015 Lateral hypothalamic orexin and melanin-concentrating hormone neurons provide direct input to gonadotropin-releasing hormone neurons in the human. Frontiers in Cellular Neuroscience 9 348. (doi:10.3389/fncel.2015.00348)
198. Smith JT 2009 Sex steroid control of hypothalamic Kiss1 expression in sheep and rodents: comparative aspects. Peptides 30 94–102. (doi:10.1016/j.peptides.2008.08.013)
199. Smith JT, Acohido BV, Clifton DK & Steiner RA 2006 KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. Journal of Neuroendocrinology 18 298–303. (doi:10.1111/j.1365-2826.2006.01417.x)
200. Souter I, Baltagi LM, Kuleta D, Meeker JD & Petrozza JC 2011 Women, weight, and fertility: the effect of body mass index on the outcome of superovulation/intrauterine insemination cycles. Fertility and Sterility 95 1042–1047. (doi:10.1016/j.fertnstert.2010.11.062)
201. 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. Nature Neuroscience 3 757–758. (doi:10.1038/77660)
202. Stoyanovitch AG, Johnson MA, Clifton DK, Steiner RA & Fraley GS 2005 Galanin-like peptide rescues reproductive function in the diabetic rat. Diabetes 54 2471–2476. (doi:10.2337/diabetes.54.8.2471)
203. Sullivan SD & Moenter SM 2004 Gamma-aminobutyric acid neurons integrate and rapidly transmit permissive and inhibitory metabolic cues to gonadotropin-releasing hormone neurons. Endocrinology 145 1194–1202. (doi:10.1210/en.2003-1374)
204. Sullivan SD, DeFazio RA & Moenter SM 2003 Metabolic regulation of fertility through presynaptic and postsynaptic signaling to gonadotropin-releasing hormone neurons. Journal of Neuroscience 23 8578–8585.
205. Sun YX, Ahmed S & Smith RG 2003 Deletion of ghrelin impairs neither growth nor appetite. Molecular and Cellular Biology 23 7973–7981. (doi:10.1128/MCB.23.22.7973-7981.2003)
206. Sun YX, Butte NF, Garcia JM & Smith RG 2008 Characterization of adult ghrelin and ghrelin receptor knockout mice under positive and negative energy balance. Endocrinology 149 843–850. (doi:10.1210/en.2007-0271)
207. Takatsu Y, Matsumoto H, Ohtaki T, Kumano S, Kitada C, Onda H, Nishimura O & Fujino M 2001 Distribution of galanin-like peptide in the rat brain. Endocrinology 142 1626–1634. (doi:10.1210/endo.142.4.8089)
208. Takenoya F, Guan JL, Kato M, Sakuma Y, Kintaka Y, Kitamura Y, Kitamura S, Okuda H, Takeuchi M, Kageyama H, et al. 2006 Neural interaction between galanin-like peptide (GALP)- and luteinizing hormone-releasing hormone (LHRH)-containing neurons. Peptides 27 2885–2893. (doi:10.1016/j.peptides.2006.05.012)
209. Tena-Sempere M 2006 KiSS-1 and reproduction: focus on its role in the metabolic regulation of fertility. Neuroendocrinology 83 275–281. (doi:10.1159/000095549)
210. Tilbrook AJ, Turner AI & Clarke IJ 2000 Effects of stress on reproduction in non-rodent mammals: the role of glucocorticoids and sex differences. Reviews of Reproduction 5 105–113. (doi:10.1530/ror.0.0050105)
211. Tilbrook AJ, Turner AI & Clarke IJ 2002 Stress and reproduction: central mechanisms and sex differences in non-rodent species. Stress 5 83–100. (doi:10.1080/10253890290027912)
212. Tong Q, Ye C, McCrimmon RJ, Dhillon H, Choi B, Kramer MD, Yu J, Yang Z, Christiansen LM, Lee CE, et al. 2007a Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia. Cell Metabolism 5 383–393. (doi:10.1016/j.cmet.2007.04.001)
213. Tong QC, Ye CP, McCrimmon RJ, Dhillon H, Choi B, Kramer MD, Yu J, Yang ZF, Christiansen LM, Lee CE, et al. 2007b Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia. Cell Metabolism 5 383–393. (doi:10.1016/j.cmet.2007.04.001)
214. Trinko R, Gan GL, Gao XB, Sears RM, Guarnieri DJ & DiLeone RJ 2011 Erk1/2 mediates leptin receptor signaling in the ventral tegmental area. PLoS ONE 6 e27180. (doi:10.1371/journal.pone.0027180)
215. True C, Verma S, Grove KL & Smith MS 2013 Cocaine- and amphetamine-regulated transcript is a potent stimulator of GnRH and kisspeptin cells and may contribute to negative energy balance-induced reproductive inhibition in females. Endocrinology 154 2821–2832. (doi:10.1210/en.2013-1156)
216. van de Wall E, Leshan R, Xu AW, Balthasar N, Coppari R, Liu SM, Jo YH, MacKenzie RG, Allison DB, Dun NJ, et al. 2008 Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion. Endocrinology 149 1773–1785.
217. Volkow ND, Wang GJ & Baler RD 2011 Reward, dopamine and the control of food intake: implications for obesity. Trends in Cognitive Sciences 15 37–46. (doi:10.1016/j.tics.2010.11.001)
218. Vulliemoz NR, Xiao E, Xia-Zhang L, Wardlaw SL & Ferin M 2005 Central infusion of agouti-related peptide suppresses pulsatile luteinizing hormone release in the ovariectomized rhesus monkey. Endocrinology 146 784–789. (doi:10.1210/en.2004-1093)
219. Wade GN & Jones JE 2004 Neuroendocrinology of nutritional infertility. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 287 R1277–R1296. (doi:10.1152/ajpregu.00475.2004)
220. Wan Q, Xiong ZG, Man HY, Ackerley CA, Braunton J, Lu WY, Becker LE, MacDonald JF & Wang YT 1997 Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin. Nature 388 686–690. (doi:10.1038/41792)
221. Wang J & Leibowitz KL 1997 Central insulin inhibits hypothalamic galanin and neuropeptide Y gene expression and peptide release in intact rats. Brain Research 777 231–236. (doi:10.1016/S0006-8993(97)00963-3)
222. Wattez JS, Delahaye F, Lukaszewski MA, Risold PY, Eberle D, Vieau D & Breton C 2013 Perinatal nutrition programs the hypothalamic melanocortin system in offspring. Hormone and Metabolic Research 45 980–990. (doi:10.1055/s-0033-1357182)
223. Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, Karalis A & Mantzoros CS 2004 Recombinant human leptin in women with hypothalamic amenorrhea. New England Journal of Medicine 351 987–997. (doi:10.1056/NEJMoa040388)
224. Williams NI, Berga SL & Cameron JL 2007 Synergism between psychosocial and metabolic stressors: impact on reproductive function in cynomolgus monkeys. American Journal of Physiology: Endocrinology and Metabolism 293 E270–E276. (doi:10.1152/ajpendo.00108.2007)
225. 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. Journal of Neuroscience 30 2472–2479. (doi:10.1523/JNEUROSCI.3118-09.2010)
226. 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. Journal of Comparative Neurology 521 3287–3302.
227. Wu M, Dumalska I, Morozova E, van den Pol A & Alreja M 2009 Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction. PNAS 106 17217–17222. (doi:10.1073/pnas.0908200106)
228. Wu Q, Whiddon BB & Palmiter RD 2012 Ablation of neurons expressing agouti-related protein, but not melanin concentrating hormone, in leptin-deficient mice restores metabolic functions and fertility. PNAS 109 3155–3160. (doi:10.1073/pnas.1120501109)
229. Yang L, Qi Y & Yang Y 2015 Astrocytes control food intake by inhibiting AGRP neuron activity via adenosine A1 receptors. Cell Reports 11 798–807. (doi:10.1016/j.celrep.2015.04.002)
230. Yi CX, Habegger KM, Chowen JA, Stern J & Tschop MH 2011 A role for astrocytes in the central control of metabolism. Neuroendocrinology 93 143–149. (doi:10.1159/000324888)
231. Zhang X & van den Pol AN 2016 Hypothalamic arcuate nucleus tyrosine hydroxylase neurons play orexigenic role in energy homeostasis. Nature Neuroscience 19 1341–1347. (doi:10.1038/nn.4372)
232. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L & Friedman JM 1994 Positional cloning of the mouse obese gene and its human homologue. Nature 372 425–432.
233. Zhang C, Bosch MA, Levine JE, Ronnekleiv OK & Kelly MJ 2007 Gonadotropin-releasing hormone neurons express K(ATP) channels that are regulated by estrogen and responsive to glucose and metabolic inhibition. Journal of Neuroscience 27 10153–10164. (doi:10.1523/JNEUROSCI.1657-07.2007)
234. Zhu CC, Zhang H, Zhang JS, Li Z, Zhao J, Li W & Zhang YQ 2013 Inhibition of ghrelin signaling improves the reproductive phenotype of male ob/ob mouse. Fertility and Sterility 99 918–926. (doi:10.1016/j.fertnstert.2012.11.022)
235. Zuure WA, Roberts AL, Quennell JH & Anderson GM 2013 Leptin signaling in GABA neurons, but not glutamate neurons, is required for reproductive function. Journal of Neuroscience 33 17874–17883. (doi:10.1523/JNEUROSCI.2278-13.2013)
236. Zuure WA, Quennell JH & Anderson GM 2016 Leptin responsive and GABAergic projections to the rostral preoptic area in mice. Journal of Neuroendocrinology 28 12357. (doi:10.1111/jne.12357)