pp 1-31 | Cite as

Hypothalamic Integration of the Endocrine Signaling Related to Food Intake

  • Anica Klockars
  • Allen S. Levine
  • Pawel K. Olszewski
Part of the Current Topics in Behavioral Neurosciences book series


Hypothalamic integration of gastrointestinal and adipose tissue-derived hormones serves as a key element of neuroendocrine control of food intake. Leptin, adiponectin, oleoylethanolamide, cholecystokinin, and ghrelin, to name a few, are in a constant “cross talk” with the feeding-related brain circuits that encompass hypothalamic populations synthesizing anorexigens (melanocortins, CART, oxytocin) and orexigens (Agouti-related protein, neuropeptide Y, orexins). While this integrated neuroendocrine circuit successfully ensures that enough energy is acquired, it does not seem to be equally efficient in preventing excessive energy intake, especially in the obesogenic environment in which highly caloric and palatable food is constantly available. The current review presents an overview of intricate mechanisms underlying hypothalamic integration of energy balance-related peripheral endocrine input. We discuss vulnerabilities and maladaptive neuroregulatory processes, including changes in hypothalamic neuronal plasticity that propel overeating despite negative consequences.


Brain Hunger Hypothalamus Obesity Plasticity Satiety 



This work has been supported by the Royal Society of New Zealand and Dairy Goat Coop. (NZ), Ltd., Hamilton, New Zealand. The authors would like to thank Erin Wood for her help in preparing the figures.


  1. Abbott CR et al (2001) Evidence of an orexigenic role for cocaine- and amphetamine-regulated transcript after administration into discrete hypothalamic nuclei. Endocrinology 142(8):3457–3463Google Scholar
  2. Abbott CR et al (2006) The importance of acclimatisation and habituation to experimental conditions when investigating the anorectic effects of gastrointestinal hormones in the rat. Int J Obes 30(2):288–292Google Scholar
  3. Adam TC et al (2009) Insulin sensitivity as an independent predictor of fat mass gain in Hispanic adolescents. Diabetes Care 32(11):2114–2115Google Scholar
  4. Ahima RS et al (1996) Role of leptin in the neuroendocrine response to fasting. Nature 382(6588):250–252Google Scholar
  5. Alsio J et al (2012) Feed-forward mechanisms: addiction-like behavioral and molecular adaptations in overeating. Front Neuroendocrinol 33(2):127–139Google Scholar
  6. Andiran N, Celik N, Andiran F (2011) Homozygosity for two missense mutations in the leptin receptor gene (P316:W646C) in a Turkmenian girl with severe early-onset obesity. J Pediatr Endocrinol Metab 24(11–12):1043–1045Google Scholar
  7. Asakawa A et al (2003) Characterization of the effects of pancreatic polypeptide in the regulation of energy balance. Gastroenterology 124(5):1325–1336Google Scholar
  8. Bagnasco M et al (2002) Evidence for the existence of distinct central appetite, energy expenditure, and ghrelin stimulation pathways as revealed by hypothalamic site-specific leptin gene therapy. Endocrinology 143(11):4409–4421Google Scholar
  9. Bailey AR et al (1999) Chronic central infusion of growth hormone secretagogues: effects on fos expression and peptide gene expression in the rat arcuate nucleus. Neuroendocrinology 70(2):83–92Google Scholar
  10. Baker RA, Herkenham M (1995) Arcuate nucleus neurons that project to the hypothalamic paraventricular nucleus: neuropeptidergic identity and consequences of adrenalectomy on mRNA levels in the rat. J Comp Neurol 358(4):518–530Google Scholar
  11. Balasubramaniam A et al (2006) Neuropeptide Y (NPY) Y4 receptor selective agonists based on NPY(32-36): development of an anorectic Y4 receptor selective agonist with picomolar affinity. J Med Chem 49(8):2661–2665Google Scholar
  12. Batterham RL et al (2002) Gut hormone PYY(3-36) physiologically inhibits food intake. Nature 418(6898):650–654Google Scholar
  13. Batterham RL et al (2003) Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med 349(10):941–948Google Scholar
  14. Bence KK et al (2006) Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med 12(8):917–924Google Scholar
  15. Benoit SC et al (2002) The catabolic action of insulin in the brain is mediated by melanocortins. J Neurosci 22(20):9048–9052Google Scholar
  16. Billington CJ et al (1994) Neuropeptide Y in hypothalamic paraventricular nucleus: a center coordinating energy metabolism. Am J Phys 266(6 Pt 2):R1765–R1770Google Scholar
  17. Blake CB, Smith BN (2012) Insulin reduces excitation in gastric-related neurons of the dorsal motor nucleus of the vagus. Am J Physiol Regul Integr Comp Physiol 303(8):R807–R814Google Scholar
  18. Boggiano MM et al (2005) PYY3-36 as an anti-obesity drug target. Obes Rev 6(4):307–322Google Scholar
  19. Bojanowska E, Stempniak B (2000) Effects of centrally or systemically injected glucagon-like peptide-1 (7-36) amide on release of neurohypophysial hormones and blood pressure in the rat. Regul Pept 91(1–3):75–81Google Scholar
  20. Broberger C et al (1998) The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. Proc Natl Acad Sci U S A 95(25):15043–15048Google Scholar
  21. Bruning JC et al (2000) Role of brain insulin receptor in control of body weight and reproduction. Science 289(5487):2122–2125Google Scholar
  22. Buffa R, Solcia E, Go VL (1976) Immunohistochemical identification of the cholecystokinin cell in the intestinal mucosa. Gastroenterology 70(4):528–532Google Scholar
  23. Burdyga G et al (2002) Expression of the leptin receptor in rat and human nodose ganglion neurons. Neuroscience 109(2):339–347Google Scholar
  24. Butler AA, Cone RD (2003) Knockout studies defining different roles for melanocortin receptors in energy homeostasis. Ann N Y Acad Sci 994:240–245Google Scholar
  25. Byun K et al (2014) Clusterin/ApoJ enhances central leptin signaling through Lrp2-mediated endocytosis. EMBO Rep 15(7):801–808Google Scholar
  26. Cains S et al (2017) Agrp neuron activity is required for alcohol-induced overeating. Nat Commun 8:14014Google Scholar
  27. Camacho A et al (2017) Obesogenic diet intake during pregnancy programs aberrant synaptic plasticity and addiction-like behavior to a palatable food in offspring. Behav Brain Res 330:46–55Google Scholar
  28. Caruso V et al (2014) Synaptic changes induced by melanocortin signalling. Nat Rev Neurosci 15(2):98–110Google Scholar
  29. Castillo EJ et al (2004) Effect of oral CCK-1 agonist GI181771X on fasting and postprandial gastric functions in healthy volunteers. Am J Physiol Gastrointest Liver Physiol 287(2):G363–G369Google Scholar
  30. Challier J et al (2003) Placental leptin receptor isoforms in normal and pathological pregnancies. Placenta 24(1):92–99Google Scholar
  31. Chang GQ et al (2008) Maternal high-fat diet and fetal programming: increased proliferation of hypothalamic peptide-producing neurons that increase risk for overeating and obesity. J Neurosci 28(46):12107–12119Google Scholar
  32. Chen Y et al (2002) Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity. Endocrinology 143(7):2469–2477Google Scholar
  33. Chuang JC et al (2011) Ghrelin mediates stress-induced food-reward behavior in mice. J Clin Invest 121(7):2684–2692Google Scholar
  34. Cohen MA et al (2003) Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin Endocrinol Metab 88(10):4696–4701Google Scholar
  35. Cone RD et al (2001) The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis. Int J Obes Relat Metab Disord 25(Suppl 5):S63–S67Google Scholar
  36. Covasa M, Ritter RC (2001) Attenuated satiation response to intestinal nutrients in rats that do not express CCK-A receptors. Peptides 22(8):1339–1348Google Scholar
  37. Cowley MA et al (2001) Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411(6836):480–484Google Scholar
  38. Cowley MA et al (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37(4):649–661Google Scholar
  39. Cui H, Lopez M, Rahmouni K (2017) The cellular and molecular bases of leptin and ghrelin resistance in obesity. Nat Rev Endocrinol 13(6):338–351Google Scholar
  40. Cummings DE, Overduin J (2007) Gastrointestinal regulation of food intake. J Clin Invest 117(1):13–23Google Scholar
  41. Dakin CL et al (2001) Oxyntomodulin inhibits food intake in the rat. Endocrinology 142(10):4244–4250Google Scholar
  42. Dakin CL et al (2004) Peripheral oxyntomodulin reduces food intake and body weight gain in rats. Endocrinology 145(6):2687–2695Google Scholar
  43. Date Y (2012) Ghrelin and the vagus nerve. Methods Enzymol 514:261–269Google Scholar
  44. Desai M et al (2014) Maternal obesity and high-fat diet program offspring metabolic syndrome. Am J Obstet Gynecol 211(3):237.e1–237.e13Google Scholar
  45. Diano S et al (1998) Monosynaptic pathway between the arcuate nucleus expressing glial type II iodothyronine 5′-deiodinase mRNA and the median eminence-projective TRH cells of the rat paraventricular nucleus. J Neuroendocrinol 10(10):731–742Google Scholar
  46. Dietrich MO et al (2008) Megalin mediates the transport of leptin across the blood-CSF barrier. Neurobiol Aging 29(6):902–912Google Scholar
  47. Dodd GT et al (2015) Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 160(1–2):88–104Google Scholar
  48. Douglas AJ, Johnstone LE, Leng G (2007) Neuroendocrine mechanisms of change in food intake during pregnancy: a potential role for brain oxytocin. Physiol Behav 91(4):352–365Google Scholar
  49. Druce MR et al (2005) Ghrelin increases food intake in obese as well as lean subjects. Int J Obes 29(9):1130–1136Google Scholar
  50. Dufresne M, Seva C, Fourmy D (2006) Cholecystokinin and gastrin receptors. Physiol Rev 86(3):805–847Google Scholar
  51. Ellacott KL, Halatchev IG, Cone RD (2006) Characterization of leptin-responsive neurons in the caudal brainstem. Endocrinology 147(7):3190–3195Google Scholar
  52. Elliott JC et al (2004) Increases in melanin-concentrating hormone and MCH receptor levels in the hypothalamus of dietary-obese rats. Brain Res Mol Brain Res 128(2):150–159Google Scholar
  53. Elmquist JK et al (1997) Leptin activates neurons in ventrobasal hypothalamus and brainstem. Endocrinology 138(2):839–842Google Scholar
  54. English PJ et al (2002) Food fails to suppress ghrelin levels in obese humans. J Clin Endocrinol Metab 87(6):2984Google Scholar
  55. Farooqi IS et al (2007) Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med 356(3):237–247Google Scholar
  56. Fekete C et al (2000) Alpha-melanocyte-stimulating hormone is contained in nerve terminals innervating thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and prevents fasting-induced suppression of prothyrotropin-releasing hormone gene expression. J Neurosci 20(4):1550–1558Google Scholar
  57. Frederich RC et al (1995) Expression of ob mRNA and its encoded protein in rodents. Impact of nutrition and obesity. J Clin Invest 96(3):1658–1663Google Scholar
  58. Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395(6704):763–770Google Scholar
  59. Fu J et al (2003) Oleoylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature 425(6953):90–93Google Scholar
  60. Fu J et al (2005) Oleoylethanolamide, an endogenous PPAR-alpha agonist, lowers body weight and hyperlipidemia in obese rats. Neuropharmacology 48(8):1147–1153Google Scholar
  61. Fu J et al (2007) Food intake regulates oleoylethanolamide formation and degradation in the proximal small intestine. J Biol Chem 282(2):1518–1528Google Scholar
  62. Fu J et al (2008) Targeted enhancement of oleoylethanolamide production in proximal small intestine induces across-meal satiety in rats. Am J Physiol Regul Integr Comp Physiol 295(1):R45–R50Google Scholar
  63. Gaetani S, Oveisi F, Piomelli D (2003) Modulation of meal pattern in the rat by the anorexic lipid mediator oleoylethanolamide. Neuropsychopharmacology 28(7):1311–1316Google Scholar
  64. Garfield AS et al (2015) A neural basis for melanocortin-4 receptor-regulated appetite. Nat Neurosci 18(6):863–871Google Scholar
  65. Garza JC et al (2008) Adeno-associated virus-mediated knockdown of melanocortin-4 receptor in the paraventricular nucleus of the hypothalamus promotes high-fat diet-induced hyperphagia and obesity. J Endocrinol 197(3):471–482Google Scholar
  66. Ghamari-Langroudi M, Colmers WF, Cone RD (2005) PYY3-36 inhibits the action potential firing activity of POMC neurons of arcuate nucleus through postsynaptic Y2 receptors. Cell Metab 2(3):191–199Google Scholar
  67. Gibbs J, Young RC, Smith GP (1973) Cholecystokinin elicits satiety in rats with open gastric fistulas. Nature 245(5424):323–325Google Scholar
  68. Godfrey KM et al (2011) Epigenetic gene promoter methylation at birth is associated with child’s later adiposity. Diabetes 60(5):1528–1534Google Scholar
  69. Gordon GR et al (2009) Astrocyte-mediated distributed plasticity at hypothalamic glutamate synapses. Neuron 64(3):391–403Google Scholar
  70. Grandt D et al (1994) Two molecular forms of peptide YY (PYY) are abundant in human blood: characterization of a radioimmunoassay recognizing PYY 1-36 and PYY 3-36. Regul Pept 51(2):151–159Google Scholar
  71. Grayson BE et al (2010) Changes in melanocortin expression and inflammatory pathways in fetal offspring of nonhuman primates fed a high-fat diet. Endocrinology 151(4):1622–1632Google Scholar
  72. Gropp E et al (2005) Agouti-related peptide-expressing neurons are mandatory for feeding. Nat Neurosci 8(10):1289–1291Google Scholar
  73. Gruber K et al (1987) Forebrain and brainstem afferents to the arcuate nucleus in the rat: potential pathways for the modulation of hypophyseal secretions. Neurosci Lett 75(1):1–5Google Scholar
  74. Gu T, Zhao T, Hewes RS (2014) Insulin signaling regulates neurite growth during metamorphic neuronal remodeling. Biol Open 3(1):81–93Google Scholar
  75. Guzman M et al (2004) Oleoylethanolamide stimulates lipolysis by activating the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-alpha). J Biol Chem 279(27):27849–27854Google Scholar
  76. Gyengesi E et al (2010) Corticosterone regulates synaptic input organization of POMC and NPY/AgRP neurons in adult mice. Endocrinology 151(11):5395–5402Google Scholar
  77. Hagan MM 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(1):R47–R52Google Scholar
  78. Halatchev IG, Cone RD (2005) Peripheral administration of PYY(3-36) produces conditioned taste aversion in mice. Cell Metab 1(3):159–168Google Scholar
  79. Halatchev IG et al (2004) Peptide YY3-36 inhibits food intake in mice through a melanocortin-4 receptor-independent mechanism. Endocrinology 145(6):2585–2590Google Scholar
  80. Harthoorn LF et al (2005) Multi-transcriptional profiling of melanin-concentrating hormone and orexin-containing neurons. Cell Mol Neurobiol 25(8):1209–1223Google Scholar
  81. Herisson FM et al (2014) Functional relationship between oxytocin and appetite for carbohydrates versus saccharin. Neuroreport 25(12):909–914Google Scholar
  82. Herisson FM et al (2016) Oxytocin acting in the nucleus accumbens core decreases food intake. J Neuroendocrinol 28(4)Google Scholar
  83. Hewson AK, Dickson SL (2000) Systemic administration of ghrelin induces Fos and Egr-1 proteins in the hypothalamic arcuate nucleus of fasted and fed rats. J Neuroendocrinol 12(11):1047–1049Google Scholar
  84. Hill MN et al (2009) Circulating endocannabinoids and N-acyl ethanolamines are differentially regulated in major depression and following exposure to social stress. Psychoneuroendocrinology 34(8):1257–1262Google Scholar
  85. Holst JJ (2007) The physiology of glucagon-like peptide 1. Physiol Rev 87(4):1409–1439Google Scholar
  86. Horvath TL (2006) Synaptic plasticity in energy balance regulation. Obesity (Silver Spring) 14(Suppl 5):228S–233SGoogle Scholar
  87. Horvath TL et al (2010) Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc Natl Acad Sci U S A 107(33):14875–14880Google Scholar
  88. Hou J et al (2010) Orexigenic effect of cocaine- and amphetamine-regulated transcript (CART) after injection into hypothalamic nuclei in streptozotocin-diabetic rats. Clin Exp Pharmacol Physiol 37(10):989–995Google Scholar
  89. Huszar D et al (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88(1):131–141Google Scholar
  90. Jacobowitz DM, O’Donohue TL (1978) Alpha-melanocyte stimulating hormone: immunohistochemical identification and mapping in neurons of rat brain. Proc Natl Acad Sci U S A 75(12):6300–6304Google Scholar
  91. Jordan J et al (2008) Stimulation of cholecystokinin-A receptors with GI181771X does not cause weight loss in overweight or obese patients. Clin Pharmacol Ther 83(2):281–287Google Scholar
  92. Kamegai J et al (2001) Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats. Diabetes 50(11):2438–2443Google Scholar
  93. Katsurada K et al (2014) Endogenous GLP-1 acts on paraventricular nucleus to suppress feeding: projection from nucleus tractus solitarius and activation of corticotropin-releasing hormone, nesfatin-1 and oxytocin neurons. Biochem Biophys Res Commun 451(2):276–281Google Scholar
  94. Kawano H, Masuko S (2000) Beta-endorphin-, adrenocorticotrophic hormone- and neuropeptide y-containing projection fibers from the arcuate hypothalamic nucleus make synaptic contacts on to nucleus preopticus medianus neurons projecting to the paraventricular hypothalamic nucleus in the rat. Neuroscience 98(3):555–565Google Scholar
  95. Khalyfa A et al (2013) Effects of late gestational high-fat diet on body weight, metabolic regulation and adipokine expression in offspring. Int J Obes 37(11):1481–1489Google Scholar
  96. Kim JG et al (2014) Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nat Neurosci 17(7):908–910Google Scholar
  97. Kim DW et al (2016) Maternal obesity in the mouse compromises the blood-brain barrier in the arcuate nucleus of offspring. Endocrinology 157(6):2229–2242Google Scholar
  98. Kirchgessner AL, Sclafani A (1988) PVN-hindbrain pathway involved in the hypothalamic hyperphagia-obesity syndrome. Physiol Behav 42(6):517–528Google Scholar
  99. Kirk SL et al (2009) Maternal obesity induced by diet in rats permanently influences central processes regulating food intake in offspring. PLoS One 4(6):e5870Google Scholar
  100. Kissileff HR et al (1981) C-terminal octapeptide of cholecystokinin decreases food intake in man. Am J Clin Nutr 34(2):154–160Google Scholar
  101. Kobelt P et al (2006) Peripheral injection of CCK-8S induces Fos expression in the dorsomedial hypothalamic nucleus in rats. Brain Res 1117(1):109–117Google Scholar
  102. Koda S et al (2005) The role of the vagal nerve in peripheral PYY3-36-induced feeding reduction in rats. Endocrinology 146(5):2369–2375Google Scholar
  103. Kojima M et al (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402(6762):656–660Google Scholar
  104. Krashes MJ et al (2013) Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Cell Metab 18(4):588–595Google Scholar
  105. Kristensen P et al (1998) Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393(6680):72–76Google Scholar
  106. Kubota N et al (2007) Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab 6(1):55–68Google Scholar
  107. Labarthe A et al (2014) Ghrelin-derived peptides: a link between appetite/reward, GH axis, and psychiatric disorders? Front Endocrinol (Lausanne) 5:163Google Scholar
  108. le Roux CW et al (2005) Postprandial plasma ghrelin is suppressed proportional to meal calorie content in normal-weight but not obese subjects. J Clin Endocrinol Metab 90(2):1068–1071Google Scholar
  109. Leibowitz SF, Hammer NJ, Chang K (1981) Hypothalamic paraventricular nucleus lesions produce overeating and obesity in the rat. Physiol Behav 27(6):1031–1040Google Scholar
  110. Levin BE, Dunn-Meynell AA (2002) Maternal obesity alters adiposity and monoamine function in genetically predisposed offspring. Am J Physiol Regul Integr Comp Physiol 283(5):R1087–R1093Google Scholar
  111. Liddle RA et al (1985) Cholecystokinin bioactivity in human plasma. Molecular forms, responses to feeding, and relationship to gallbladder contraction. J Clin Invest 75(4):1144–1152Google Scholar
  112. Lin S et al (2009) Critical role of arcuate Y4 receptors and the melanocortin system in pancreatic polypeptide-induced reduction in food intake in mice. PLoS One 4(12):e8488Google Scholar
  113. Liu X, York DA, Bray GA (2004) Regulation of ghrelin gene expression in stomach and feeding response to a ghrelin analogue in two strains of rats. Peptides 25(12):2171–2177Google Scholar
  114. Liu T et al (2012) Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone. Neuron 73(3):511–522Google Scholar
  115. Loh K et al (2011) Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. Cell Metab 14(5):684–699Google Scholar
  116. Luquet S, Phillips CT, Palmiter RD (2007) NPY/AgRP neurons are not essential for feeding responses to glucoprivation. Peptides 28(2):214–225Google Scholar
  117. Maffei M et al (1995) Increased expression in adipocytes of ob RNA in mice with lesions of the hypothalamus and with mutations at the db locus. Proc Natl Acad Sci U S A 92(15):6957–6960Google Scholar
  118. Maida A et al (2008) The glucagon-like peptide-1 receptor agonist oxyntomodulin enhances beta-cell function but does not inhibit gastric emptying in mice. Endocrinology 149(11):5670–5678Google Scholar
  119. Malaisse-Lagae F et al (1977) Pancreatic polypeptide: a possible role in the regulation of food intake in the mouse. Hypothesis. Experientia 33(7):915–917Google Scholar
  120. Marks JL et al (1990) Localization of insulin receptor mRNA in rat brain by in situ hybridization. Endocrinology 127(6):3234–3236Google Scholar
  121. Matson CA, Reid DF, Ritter RC (2002) Daily CCK injection enhances reduction of body weight by chronic intracerebroventricular leptin infusion. Am J Physiol Regul Integr Comp Physiol 282(5):R1368–R1373Google Scholar
  122. Mavanji V et al (2015) Promotion of wakefulness and energy expenditure by orexin-a in the ventrolateral preoptic area. Sleep 38(9):1361–1370Google Scholar
  123. Mayer J, Thomas DW (1967) Regulation of food intake and obesity. Science 156(3773):328–337Google Scholar
  124. Mazen I et al (2011) Homozygosity for a novel missense mutation in the leptin receptor gene (P316T) in two Egyptian cousins with severe early onset obesity. Mol Genet Metab 102(4):461–464Google Scholar
  125. McGowan MK, Andrews KM, Grossman SP (1992a) Chronic intrahypothalamic infusions of insulin or insulin antibodies alter body weight and food intake in the rat. Physiol Behav 51(4):753–766Google Scholar
  126. McGowan MK, Andrews KM, Grossman SP (1992b) Role of intrahypothalamic insulin in circadian patterns of food intake, activity, and body temperature. Behav Neurosci 106(2):380–385Google Scholar
  127. Minokoshi Y et al (2004) AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428(6982):569–574Google Scholar
  128. Miyata S (2015) New aspects in fenestrated capillary and tissue dynamics in the sensory circumventricular organs of adult brains. Front Neurosci 9:390Google Scholar
  129. Monnikes H, Lauer G, Arnold R (1997) Peripheral administration of cholecystokinin activates c-fos expression in the locus coeruleus/subcoeruleus nucleus, dorsal vagal complex and paraventricular nucleus via capsaicin-sensitive vagal afferents and CCK-A receptors in the rat. Brain Res 770(1–2):277–288Google Scholar
  130. Moran TH, Bi S (2006) Hyperphagia and obesity in OLETF rats lacking CCK-1 receptors. Philos Trans R Soc Lond Ser B Biol Sci 361(1471):1211–1218Google Scholar
  131. Moran TH et al (1998) Disordered food intake and obesity in rats lacking cholecystokinin A receptors. Am J Phys 274(3 Pt 2):R618–R625Google Scholar
  132. Mori H et al (2004) Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat Med 10(7):739–743Google Scholar
  133. Moriarty P et al (1997) Characterization of cholecystokininA and cholecystokininB receptors expressed by vagal afferent neurons. Neuroscience 79(3):905–913Google Scholar
  134. Morita S et al (2016) Heterogeneous vascular permeability and alternative diffusion barrier in sensory circumventricular organs of adult mouse brain. Cell Tissue Res 363(2):497–511Google Scholar
  135. Murphy KG, Bloom SR (2004) Gut hormones in the control of appetite. Exp Physiol 89(5):507–516Google Scholar
  136. Nakagawa A et al (2004) Receptor gene expression of glucagon-like peptide-1, but not glucose-dependent insulinotropic polypeptide, in rat nodose ganglion cells. Auton Neurosci 110(1):36–43Google Scholar
  137. Navarro M et al (2011) Assessment of voluntary ethanol consumption and the effects of a melanocortin (MC) receptor agonist on ethanol intake in mutant C57BL/6J mice lacking the MC-4 receptor. Alcohol Clin Exp Res 35(6):1058–1066Google Scholar
  138. Nelson DW et al (2007) Localization and activation of glucagon-like peptide-2 receptors on vagal afferents in the rat. Endocrinology 148(5):1954–1962Google Scholar
  139. Noetzel S et al (2009) CCK-8S activates c-Fos in a dose-dependent manner in nesfatin-1 immunoreactive neurons in the paraventricular nucleus of the hypothalamus and in the nucleus of the solitary tract of the brainstem. Regul Pept 157(1–3):84–91Google Scholar
  140. Obici S et al (2002) Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci 5(6):566–572Google Scholar
  141. Olney JW (1969) Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 164(3880):719–721Google Scholar
  142. Olszewski PK, Levine AS (2007) Central opioids and consumption of sweet tastants: when reward outweighs homeostasis. Physiol Behav 91(5):506–512Google Scholar
  143. Olszewski PK, Levine AS (2016) Basic research on appetite regulation: social context of a meal is missing. Pharmacol Biochem Behav 148:106–107Google Scholar
  144. Olszewski PK et al (2001) Role of alpha-MSH in the regulation of consummatory behavior: immunohistochemical evidence. Am J Physiol Regul Integr Comp Physiol 281(2):R673–R680Google Scholar
  145. Olszewski P et al (2003) Agouti-related protein: appetite or reward? Ann N Y Acad Sci 994:187–191Google Scholar
  146. Olszewski PK et al (2010) Molecular, immunohistochemical, and pharmacological evidence of oxytocin’s role as inhibitor of carbohydrate but not fat intake. Endocrinology 151(10):4736–4744Google Scholar
  147. Olszewski PK, Allen K, Levine AS (2015) Effect of oxytocin receptor blockade on appetite for sugar is modified by social context. Appetite 86:81–87Google Scholar
  148. Olszewski PK, Klockars A, Levine AS (2016) Oxytocin: a conditional anorexigen whose effects on appetite depend on the physiological, behavioural and social contexts. J Neuroendocrinol 28(4)Google Scholar
  149. Ottaway N et al (2015) Diet-induced obese mice retain endogenous leptin action. Cell Metab 21(6):877–882Google Scholar
  150. Pandit R et al (2015) Central melanocortins regulate the motivation for sucrose reward. PLoS One 10(3):e0121768Google Scholar
  151. Parkinson JR et al (2008) PYY3-36 injection in mice produces an acute anorexigenic effect followed by a delayed orexigenic effect not observed with other anorexigenic gut hormones. Am J Physiol Endocrinol Metab 294(4):E698–E708Google Scholar
  152. Perello M et al (2010) Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner. Biol Psychiatry 67(9):880–886Google Scholar
  153. Pierce AA, Xu AW (2010) De novo neurogenesis in adult hypothalamus as a compensatory mechanism to regulate energy balance. J Neurosci 30(2):723–730Google Scholar
  154. Pinto S et al (2004) Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304(5667):110–115Google Scholar
  155. Provensi G et al (2014) Satiety factor oleoylethanolamide recruits the brain histaminergic system to inhibit food intake. Proc Natl Acad Sci U S A 111(31):11527–11532Google Scholar
  156. Qian S et al (2002) Neither agouti-related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice. Mol Cell Biol 22(14):5027–5035Google Scholar
  157. Rajia S, Chen H, Morris MJ (2010) Maternal overnutrition impacts offspring adiposity and brain appetite markers-modulation by postweaning diet. J Neuroendocrinol 22(8):905–914Google Scholar
  158. Reynolds RM et al (2010) Maternal BMI, parity, and pregnancy weight gain: influences on offspring adiposity in young adulthood. J Clin Endocrinol Metab 95(12):5365–5369Google Scholar
  159. Riediger T et al (2010) Effects of glucagon-like peptide 1 and oxyntomodulin on neuronal activity of ghrelin-sensitive neurons in the hypothalamic arcuate nucleus. Am J Physiol Regul Integr Comp Physiol 298(4):R1061–R1067Google Scholar
  160. Rivera HM et al (2015) Maternal high-fat diet and obesity impact palatable food intake and dopamine signaling in nonhuman primate offspring. Obesity (Silver Spring) 23(11):2157–2164Google Scholar
  161. Rocha PM et al (2011) Visceral abdominal and subfascial femoral adipose tissue have opposite associations with liver fat in overweight and obese premenopausal caucasian women. J Lipids 2011:154672Google Scholar
  162. Rodriguez de Fonseca F et al (2001) An anorexic lipid mediator regulated by feeding. Nature 414(6860):209–212Google Scholar
  163. Rodriguez-Pacheco F et al (2007) Regulation of pituitary cell function by adiponectin. Endocrinology 148(1):401–410Google Scholar
  164. Romano A et al (2014) High dietary fat intake influences the activation of specific hindbrain and hypothalamic nuclei by the satiety factor oleoylethanolamide. Physiol Behav 136:55–62Google Scholar
  165. Romano A et al (2017) Role of the area postrema in the hypophagic effects of oleoylethanolamide. Pharmacol Res 122:20–34Google Scholar
  166. Romero-Pico A et al (2013) Hypothalamic kappa-opioid receptor modulates the orexigenic effect of ghrelin. Neuropsychopharmacology 38(7):1296–1307Google Scholar
  167. Ruter J et al (2003) Intraperitoneal injection of ghrelin induces Fos expression in the paraventricular nucleus of the hypothalamus in rats. Brain Res 991(1–2):26–33Google Scholar
  168. Sabatier N et al (2003) Alpha-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(32):10351–10358Google Scholar
  169. Sainsbury A et al (2010) Y4 receptors and pancreatic polypeptide regulate food intake via hypothalamic orexin and brain-derived neurotropic factor dependent pathways. Neuropeptides 44(3):261–268Google Scholar
  170. Schaeffer M et al (2013) Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons. Proc Natl Acad Sci U S A 110(4):1512–1517Google Scholar
  171. Scherag A et al (2010) Two new loci for body-weight regulation identified in a joint analysis of genome-wide association studies for early-onset extreme obesity in French and German study groups. PLoS Genet 6(4):e1000916Google Scholar
  172. Schioth HB et al (2005) Evolutionary conservation of the structural, pharmacological, and genomic characteristics of the melanocortin receptor subtypes. Peptides 26(10):1886–1900Google Scholar
  173. Schwartz GJ (2000) The role of gastrointestinal vagal afferents in the control of food intake: current prospects. Nutrition 16(10):866–873Google Scholar
  174. Schwartz GJ (2010) Brainstem integrative function in the central nervous system control of food intake. Forum Nutr 63:141–151Google Scholar
  175. Schwartz GJ et al (1999) Gut vagal afferent lesions increase meal size but do not block gastric preload-induced feeding suppression. Am J Phys 276(6 Pt 2):R1623–R1629Google Scholar
  176. Shi YC et al (2013) PYY3-36 and pancreatic polypeptide reduce food intake in an additive manner via distinct hypothalamic dependent pathways in mice. Obesity (Silver Spring) 21(12):E669–E678Google Scholar
  177. Shor-Posner G et al (1985) Deficits in the control of food intake after hypothalamic paraventricular nucleus lesions. Physiol Behav 35(6):883–890Google Scholar
  178. Shrestha YB, Wickwire K, Giraudo SQ (2004) Action of MT-II on ghrelin-induced feeding in the paraventricular nucleus of the hypothalamus. Neuroreport 15(8):1365–1367Google Scholar
  179. Siegenthaler JA, Sohet F, Daneman R (2013) ‘Sealing off the CNS’: cellular and molecular regulation of blood-brain barriergenesis. Curr Opin Neurobiol 23(6):1057–1064Google Scholar
  180. Sims JS, Lorden JF (1986) Effect of paraventricular nucleus lesions on body weight, food intake and insulin levels. Behav Brain Res 22(3):265–281Google Scholar
  181. Skibicka KP et al (2013) Divergent circuitry underlying food reward and intake effects of ghrelin: dopaminergic VTA-accumbens projection mediates ghrelin’s effect on food reward but not food intake. Neuropharmacology 73:274–283Google Scholar
  182. Sobhani I et al (2000) Leptin secretion and leptin receptor in the human stomach. Gut 47(2):178–183Google Scholar
  183. Solomon A, De Fanti BA, Martinez JA (2007) Peripheral ghrelin interacts with orexin neurons in glucostatic signalling. Regul Pept 144(1–3):17–24Google Scholar
  184. Stanley BG et al (1986) Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity. Peptides 7(6):1189–1192Google Scholar
  185. Sternson SM (2013) Hypothalamic survival circuits: blueprints for purposive behaviors. Neuron 77(5):810–824Google Scholar
  186. Sternson SM, Nicholas Betley J, Cao ZF (2013) Neural circuits and motivational processes for hunger. Curr Opin Neurobiol 23(3):353–360Google Scholar
  187. Sun J et al (2016) Adiponectin potentiates the acute effects of leptin in arcuate Pomc neurons. Mol Metab 5(10):882–891Google Scholar
  188. Suyama S et al (2016) Glucose level determines excitatory or inhibitory effects of adiponectin on arcuate POMC neuron activity and feeding. Sci Rep 6:30796Google Scholar
  189. Suyama S et al (2017) Adiponectin at physiological level glucose-independently enhances inhibitory postsynaptic current onto NPY neurons in the hypothalamic arcuate nucleus. Neuropeptides 65:1–9Google Scholar
  190. Suzuki Y et al (2014) Changes in mRNA expression of arcuate nucleus appetite-regulating peptides during lactation in rats. J Mol Endocrinol 52(2):97–109Google Scholar
  191. Swanson LW, Simmons DM (1989) Differential steroid hormone and neural influences on peptide mRNA levels in CRH cells of the paraventricular nucleus: a hybridization histochemical study in the rat. J Comp Neurol 285(4):413–435Google Scholar
  192. Sweet DC et al (1999) Feeding response to central orexins. Brain Res 821(2):535–538Google Scholar
  193. Takayama K et al (2007) Expression of c-Fos protein in the brain after intravenous injection of ghrelin in rats. Neurosci Lett 417(3):292–296Google Scholar
  194. Theodosis DT, Poulain DA (1984) Evidence that oxytocin-secreting neurons are involved in the ultrastructural reorganisation of the rat supraoptic nucleus apparent at lactation. Cell Tissue Res 235(1):217–219Google Scholar
  195. Tracy AL et al (2008) The melanocortin antagonist AgRP (83-132) increases appetitive responding for a fat, but not a carbohydrate, reinforcer. Pharmacol Biochem Behav 89(3):263–271Google Scholar
  196. Trevaskis JL et al (2010) Multi-hormonal weight loss combinations in diet-induced obese rats: therapeutic potential of cholecystokinin? Physiol Behav 100(2):187–195Google Scholar
  197. Tuma P, Hubbard AL (2003) Transcytosis: crossing cellular barriers. Physiol Rev 83(3):871–932Google Scholar
  198. Umehara H et al (2016) The hypophagic factor oleoylethanolamide differentially increases c-fos expression in appetite regulating centres in the brain of wild type and histamine deficient mice. Pharmacol Res 113(Pt A):100–107Google Scholar
  199. Vaisse C et al (2000) Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 106(2):253–262Google Scholar
  200. Vong L et al (2011) Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71(1):142–154Google Scholar
  201. Wan Q et al (1997) Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin. Nature 388(6643):686–690Google Scholar
  202. Wang D et al (2015) Whole-brain mapping of the direct inputs and axonal projections of POMC and AgRP neurons. Front Neuroanat 9:40Google Scholar
  203. Wang S et al (2017) Rs12970134 near MC4R is associated with appetite and beverage intake in overweight and obese children: a family-based association study in Chinese population. PLoS One 12(5):e0177983Google Scholar
  204. West DB, Fey D, Woods SC (1984) Cholecystokinin persistently suppresses meal size but not food intake in free-feeding rats. Am J Phys 246(5 Pt 2):R776–R787Google Scholar
  205. Wilkinson M et al (2007) Adipokine gene expression in brain and pituitary gland. Neuroendocrinology 86(3):191–209Google Scholar
  206. Wirth MM, Giraudo SQ (2001) Effect of Agouti-related protein delivered to the dorsomedial nucleus of the hypothalamus on intake of a preferred versus a non-preferred diet. Brain Res 897(1–2):169–174Google Scholar
  207. Wirth MM et al (2001) Paraventricular hypothalamic alpha-melanocyte-stimulating hormone and MTII reduce feeding without causing aversive effects. Peptides 22(1):129–134Google Scholar
  208. Wirth MM et al (2002) Effect of Agouti-related protein on development of conditioned taste aversion and oxytocin neuronal activation. Neuroreport 13(10):1355–1358Google Scholar
  209. Wren AM et al (2001) Ghrelin causes hyperphagia and obesity in rats. Diabetes 50(11):2540–2547Google Scholar
  210. Wren AM et al (2002) The hypothalamic mechanisms of the hypophysiotropic action of ghrelin. Neuroendocrinology 76(5):316–324Google Scholar
  211. Xu B et al (2003) Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci 6(7):736–742Google Scholar
  212. Yang Y et al (2007) Mechanism of oleoylethanolamide on fatty acid uptake in small intestine after food intake and body weight reduction. Am J Physiol Regul Integr Comp Physiol 292(1):R235–R241Google Scholar
  213. Yang Y et al (2011) Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell 146(6):992–1003Google Scholar
  214. Yang L, Qi Y, Yang Y (2015) Astrocytes control food intake by inhibiting AGRP neuron activity via adenosine A1 receptors. Cell Rep 11(5):798–807Google Scholar
  215. Yaswen L et al (1999) Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat Med 5(9):1066–1070Google Scholar
  216. Zambrano E et al (2006) A low maternal protein diet during pregnancy and lactation has sex- and window of exposure-specific effects on offspring growth and food intake, glucose metabolism and serum leptin in the rat. J Physiol 571(Pt 1):221–230Google Scholar
  217. Zhang Y et al (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505):425–432Google Scholar
  218. Zhang ZY, Dodd GT, Tiganis T (2015) Protein tyrosine phosphatases in hypothalamic insulin and leptin signaling. Trends Pharmacol Sci 36(10):661–674Google Scholar
  219. Zigman JM et al (2006) Expression of ghrelin receptor mRNA in the rat and the mouse brain. J Comp Neurol 494(3):528–548Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Anica Klockars
    • 1
  • Allen S. Levine
    • 2
  • Pawel K. Olszewski
    • 1
    • 2
  1. 1.Department of Biological SciencesUniversity of WaikatoHamiltonNew Zealand
  2. 2.Department of Food Science and NutritionUniversity of MinnesotaSaint PaulUSA

Personalised recommendations