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Neuroendocrine and Metabolic Adaptations in the Central Nervous System That Facilitate Weight Regain

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Book cover Pediatric Obesity

Part of the book series: Contemporary Endocrinology ((COE))

Abstract

Obesity is reaching epidemic proportions, yet short of surgical approaches, other modalities of treatment, in particular dietary restriction and behavioral modification, have been largely unsuccessful (1). At best, only ∼20% of overweight individuals are able to maintain at least a 10% weight reduction with diet for more than 1 year (2). The explanation for this largely dismal outlook is the remarkable nature of potent, compensatory, homeostatic systems in the brain that function to maintain body weight, uncoupling energy intake and output by increasing appetite, reducing energy expenditure, and promoting the hedonistic aspects of feeding behavior.

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References

  1. Mark AL. Dietary therapy for obesity: an emperor with no clothes. Hypertension. Jun 2008;51(6):1426–34; discussion 34.

    Article  PubMed  CAS  Google Scholar 

  2. Wing RR, Phelan S. Long-term weight loss maintenance. Am J Clin Nutr. Jul 2005;82(1 Suppl):222S–5S.

    PubMed  CAS  Google Scholar 

  3. Rosenbaum M, Goldsmith R, Bloomfield D, et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest. 2005 Dec;115(12):3579–86.

    Article  PubMed  CAS  Google Scholar 

  4. Rosenbaum M, Sy M, Pavlovich K, Leibel RL, Hirsch J. Leptin reverses weight loss-induced changes in regional neural activity responses to visual food stimuli. J Clin Invest. 2008 Jul;118(7):2583–91.

    PubMed  CAS  Google Scholar 

  5. Farooqi IS, O’Rahilly S. Leptin: a pivotal regulator of human energy homeostasis. Am J Clin Nutr. 2009 Mar;89(3):980S–4S.

    Article  PubMed  CAS  Google Scholar 

  6. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1 Dec 1994;372(6505):425–32.

    Article  PubMed  CAS  Google Scholar 

  7. Myers MG Jr, Munzberg H, Leinninger GM, Leshan RL. The geometry of leptin action in the brain: more complicated than a simple ARC. Cell Metab. Feb 2009;9(2):117–23.

    Article  PubMed  CAS  Google Scholar 

  8. Ahima RS, Prabakaran D, Mantzoros C, et al. Role of leptin in the neuroendocrine response to fasting. Nature. 18 Jul 1996;382(6588):250–52.

    Article  PubMed  CAS  Google Scholar 

  9. Ahima RS, Saper CB, Flier JS, Elmquist JK. Leptin regulation of neuroendocrine systems. Front Neuroendocrinol. Jul 2000;21(3):263–307.

    Article  PubMed  CAS  Google Scholar 

  10. Xu AW, Ste-Marie L, Kaelin CB, Barsh GS. Inactivation of signal transducer and activator of transcription 3 in proopiomelanocortin (Pomc) neurons causes decreased pomc expression, mild obesity, and defects in compensatory refeeding. Endocrinology. Jan 2007;148(1):72–80.

    Article  PubMed  CAS  Google Scholar 

  11. Konner AC, Klockener T, Bruning JC. Control of energy homeostasis by insulin and leptin: targeting the arcuate nucleus and beyond. Physiol Behav. 14 Jul 2009;97(5):632–8.

    Article  PubMed  CAS  Google Scholar 

  12. Fukuda M, Jones JE, Olson D, et al. Monitoring FoxO1 localization in chemically identified neurons. J Neurosci. 10 Dec 2008;28(50):13640–8.

    Article  PubMed  CAS  Google Scholar 

  13. Kitamura T, Feng Y, Kitamura YI, et al. Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake. Nat Med. May 2006;12(5):534–40.

    Article  PubMed  CAS  Google Scholar 

  14. Plum L, Belgardt BF, Bruning JC. Central insulin action in energy and glucose homeostasis. J Clin Invest. Jul 2006;116(7):1761–6.

    Article  PubMed  CAS  Google Scholar 

  15. Minokoshi Y, Shiuchi T, Lee S, Suzuki A, Okamoto S. Role of hypothalamic AMP-kinase in food intake regulation. Nutrition. Sept 2008;24(9):786–90.

    Article  PubMed  CAS  Google Scholar 

  16. Pinto S, Roseberry AG, Liu H, et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science. 2 Apr 2004;304(5667):110–5.

    Article  PubMed  CAS  Google Scholar 

  17. Morton GJ, Schwartz MW. The NPY/AgRP neuron and energy homeostasis. Int J Obes Relat Metab Disord. Dec 2001;25(Suppl 5):S56–62.

    Article  PubMed  CAS  Google Scholar 

  18. Egawa M, Yoshimatsu H, Bray GA. Effect of corticotropin releasing hormone and neuropeptide Y on electrophysiological activity of sympathetic nerves to interscapular brown adipose tissue. Neuroscience. 1990;34(3):771–5.

    Article  PubMed  CAS  Google Scholar 

  19. Vettor R, Zarjevski N, Cusin I, Rohner-Jeanrenaud F, Jeanrenaud B. Induction and reversibility of an obesity syndrome by intracerebroventricular neuropeptide Y administration to normal rats. Diabetologia. Dec 1994;37(12):1202–8.

    Article  PubMed  CAS  Google Scholar 

  20. Ong JM, Kirchgessner TG, Schotz MC, Kern PA. Insulin increases the synthetic rate and messenger RNA level of lipoprotein lipase in isolated rat adipocytes. J Biol Chem. 15 Sept 1988;263(26):12933–8.

    PubMed  CAS  Google Scholar 

  21. Qian S, Chen H, Weingarth D, et al. Neither agouti-related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice. Mol Cell Biol. Jul 2002;22(14):5027–35.

    Article  PubMed  CAS  Google Scholar 

  22. Erickson JC, Clegg KE, Palmiter RD. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature. 30 May 1996;381(6581):415–21.

    Article  PubMed  CAS  Google Scholar 

  23. Huszar D, Lynch CA, Fairchild-Huntress V, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 10 Jan 1997;88(1):131–41.

    Article  PubMed  CAS  Google Scholar 

  24. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet. Jun 1998;19(2):155–7.

    Article  PubMed  CAS  Google Scholar 

  25. Farooqi IS, Yeo GS, Keogh JM, et al. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest. Jul 2000;106(2):271–9.

    Article  PubMed  CAS  Google Scholar 

  26. Xu AW, Kaelin CB, Morton GJ, et al. Effects of hypothalamic neurodegeneration on energy balance. PLoS Biol. Dec 2005;3(12):e415.

    Article  PubMed  CAS  Google Scholar 

  27. Tolle V, Low MJ. In vivo evidence for inverse agonism of Agouti-related peptide in the central nervous system of proopiomelanocortin-deficient mice. Diabetes. Jan 2008;57(1):86–94.

    Article  PubMed  CAS  Google Scholar 

  28. Cowley MA, Smart JL, Rubinstein M, et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 24 May 2001;411(6836):480–4.

    Article  PubMed  CAS  Google Scholar 

  29. Swanson LW, Sawchenko PE. Paraventricular nucleus: a site for the integration of neuroendocrine and autonomic mechanisms. Neuroendocrinology. Dec 1980;31(6):410–7.

    Article  PubMed  CAS  Google Scholar 

  30. Kublaoui BM, Gemelli T, Tolson KP, Wang Y, Zinn AR. Oxytocin deficiency mediates hyperphagic obesity of Sim1 haploinsufficient mice. Mol Endocrinol. Jul 2008;22(7):1723–34.

    Article  PubMed  CAS  Google Scholar 

  31. Michaud JL, Boucher F, Melnyk A, et al. Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus. Hum Mol Genet. 1 Jul 2001;10(14):1465–73.

    Article  PubMed  CAS  Google Scholar 

  32. Liu H, Kishi T, Roseberry AG, et al. Transgenic mice expressing green fluorescent protein under the control of the melanocortin-4 receptor promoter. J Neurosci. 6 Aug 2003;23(18):7143–54.

    PubMed  CAS  Google Scholar 

  33. Wolak ML, DeJoseph MR, Cator AD, Mokashi AS, Brownfield MS, Urban JH. Comparative distribution of neuropeptide Y Y1 and Y5 receptors in the rat brain by using immunohistochemistry. J Comp Neurol. 22 Sept 2003;464(3):285–311.

    Article  PubMed  CAS  Google Scholar 

  34. Balthasar N, Dalgaard LT, Lee CE, et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell. 4 Nov 2005;123(3):493–505.

    Article  PubMed  CAS  Google Scholar 

  35. Singru PS, Sanchez E, Fekete C, Lechan RM. Importance of melanocortin signaling in refeeding-induced neuronal activation and satiety. Endocrinology. Feb 2007;148(2):638–46.

    Article  PubMed  CAS  Google Scholar 

  36. Sawchenko PE, Swanson LW. Immunohistochemical identification of neurons in the paraventricular nucleus of the hypothalamus that project to the medulla or to the spinal cord in the rat. J Comp Neurol. 1 Mar 1982;205(3): 260–72.

    Article  PubMed  CAS  Google Scholar 

  37. Haynes WG, Morgan DA, Djalali A, Sivitz WI, Mark AL. Interactions between the melanocortin system and leptin in control of sympathetic nerve traffic. Hypertension. Jan 1999;33(1 Pt 2):542–47.

    Article  PubMed  CAS  Google Scholar 

  38. Bamshad M, Aoki VT, Adkison MG, Warren WS, Bartness TJ. Central nervous system origins of the sympathetic nervous system outflow to white adipose tissue. Am J Physiol. Jul 1998;275(1 Pt 2):R291–9.

    PubMed  CAS  Google Scholar 

  39. Elmquist JK. Hypothalamic pathways underlying the endocrine, autonomic, and behavioral effects of leptin. Int J Obes Relat Metab Disord. 2001 Dec;25(Suppl 5):S78–82.

    Article  PubMed  CAS  Google Scholar 

  40. Scott MM, Lachey JL, Sternson SM, et al. Leptin targets in the mouse brain. J Comp Neurol. 10 Jun 2009;514(5): 518–32.

    Article  PubMed  CAS  Google Scholar 

  41. Bellinger LL, Bernardis LL. The dorsomedial hypothalamic nucleus and its role in ingestive behavior and body weight regulation: lessons learned from lesioning studies. Physiol Behav. Jul 2002;76(3):431–42.

    Article  PubMed  CAS  Google Scholar 

  42. Evans SA, Messina MM, Knight WD, Parsons AD, Overton JM. Long-Evans and Sprague-Dawley rats exhibit divergent responses to refeeding after caloric restriction. Am J Physiol Regul Integr Comp Physiol. Jun 2005;288(6): R1468–76.

    Article  PubMed  CAS  Google Scholar 

  43. Singru PS, Fekete C, Lechan RM. Neuroanatomical evidence for participation of the hypothalamic dorsomedial nucleus (DMN) in regulation of the hypothalamic paraventricular nucleus (PVN) by alpha-melanocyte stimulating hormone. Brain Res. 7 Dec 2005;1064(1–2):42–51.

    Article  PubMed  CAS  Google Scholar 

  44. Oldfield BJ, Giles ME, Watson A, Anderson C, Colvill LM, McKinley MJ. The neurochemical characterisation of hypothalamic pathways projecting polysynaptically to brown adipose tissue in the rat. Neuroscience. 2002;110(3): 515–26.

    Article  PubMed  CAS  Google Scholar 

  45. Dimicco JA, Zaretsky DV. The dorsomedial hypothalamus: a new player in thermoregulation. Am J Physiol Regul Integr Comp Physiol. Jan 2007;292(1):R47–63.

    Article  PubMed  CAS  Google Scholar 

  46. Cypess AM, Lehman S, Williams G, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 9 Apr 2009;360(15):1509–17.

    Article  PubMed  CAS  Google Scholar 

  47. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 9 Apr 2009;360(15):1500–8.

    Article  PubMed  Google Scholar 

  48. Jezek P. Possible physiological roles of mitochondrial uncoupling proteins–UCPn. Int J Biochem Cell Biol. Oct 2002;34(10):1190–206.

    Article  PubMed  CAS  Google Scholar 

  49. Sivitz WI, Fink BD, Donohoue PA. Fasting and leptin modulate adipose and muscle uncoupling protein: divergent effects between messenger ribonucleic acid and protein expression. Endocrinology. Apr 1999;140(4):1511–9.

    Article  PubMed  CAS  Google Scholar 

  50. Hetherington AW, Ranson SW. The relation of various hypothalamic lesions to adiposity in the rat. J Comp Neurol. 1942 1942;76:475–99.

    Article  Google Scholar 

  51. Dhillon H, Zigman JM, Ye C, et al. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron. 19 Jan 2006;49(2):191–203.

    Article  PubMed  CAS  Google Scholar 

  52. Bingham NC, Anderson KK, Reuter AL, Stallings NR, Parker KL. Selective loss of leptin receptors in the ventromedial hypothalamic nucleus results in increased adiposity and a metabolic syndrome. Endocrinology. May 2008;149(5):2138–48.

    Article  PubMed  CAS  Google Scholar 

  53. Komori T, Morikawa Y, Nanjo K, Senba E. Induction of brain-derived neurotrophic factor by leptin in the ventromedial hypothalamus. Neuroscience. 2006;139(3):1107–15.

    Article  PubMed  CAS  Google Scholar 

  54. Lebrun B, Bariohay B, Moyse E, Jean A. Brain-derived neurotrophic factor (BDNF) and food intake regulation: a minireview. Auton Neurosci. Jun 2006;30(126–127):30–38.

    Article  CAS  Google Scholar 

  55. Yeo GS, Connie Hung CC, Rochford J, et al. A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat Neurosci. Nov 2004;7(11):1187–9.

    Article  PubMed  CAS  Google Scholar 

  56. Xu B, Goulding EH, Zang K, et al. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci. Jul 2003;6(7):736–42.

    Article  PubMed  CAS  Google Scholar 

  57. Elias CF, Saper CB, Maratos-Flier E, et al. Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. J Comp Neurol. 28 Dec 1998;402(4):442–59.

    Article  PubMed  CAS  Google Scholar 

  58. Qu D, Ludwig DS, Gammeltoft S, et al. A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature. 21 Mar 1996;380(6571):243–7.

    Article  PubMed  CAS  Google Scholar 

  59. Sakurai T. Roles of orexins in regulation of feeding and wakefulness. NeuroReport. 12 Jun 2002;13(8):987–95.

    Article  PubMed  CAS  Google Scholar 

  60. Georgescu D, Sears RM, Hommel JD, et al. The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance. J Neurosci. 16 Mar 2005;25(11):2933–40.

    Article  PubMed  CAS  Google Scholar 

  61. Harris GC, Wimmer M, Aston-Jones G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature. 22 Sept 2005;437(7058):556–9.

    Article  PubMed  CAS  Google Scholar 

  62. Krowicki ZK, Burmeister MA, Berthoud HR, Scullion RT, Fuchs K, Hornby PJ. Orexins in rat dorsal motor nucleus of the vagus potently stimulate gastric motor function. Am J Physiol Gastrointest Liver Physiol. Aug 2002;283(2): G465–72.

    PubMed  CAS  Google Scholar 

  63. Fulton S, Pissios P, Manchon RP, et al. Leptin regulation of the mesoaccumbens dopamine pathway. Neuron. 21 Sept 2006;51(6):811–22.

    Article  PubMed  CAS  Google Scholar 

  64. Leinninger GM, Jo YH, Leshan RL, et al. Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding. Cell Metab. Aug 2009;10(2):89–98.

    Article  PubMed  CAS  Google Scholar 

  65. Kelley AE, Berridge KC. The neuroscience of natural rewards: relevance to addictive drugs. J Neurosci. 1 May 2002;22(9):3306–11.

    PubMed  CAS  Google Scholar 

  66. Farooqi IS, Bullmore E, Keogh J, Gillard J, O’Rahilly S, Fletcher PC. Leptin regulates striatal regions and human eating behavior. Science. 7 Sept 2007;317(5843):1355.

    Article  PubMed  CAS  Google Scholar 

  67. Lechan RM. The dilemma of the nonthyroidal illness syndrome. Acta Biomed. Dec 2008;79(3):165–71.

    PubMed  CAS  Google Scholar 

  68. Rosenbaum M, Murphy EM, Heymsfield SB, Matthews DE, Leibel RL. Low dose leptin administration reverses effects of sustained weight-reduction on energy expenditure and circulating concentrations of thyroid hormones. J Clin Endocrinol Metab. May 2002;87(5):2391–4.

    Article  PubMed  CAS  Google Scholar 

  69. Silva JE. The thermogenic effect of thyroid hormone and its clinical implications. Ann Intern Med. 5 Aug 2003;139(3):205–13.

    PubMed  CAS  Google Scholar 

  70. Ribeiro MO, Carvalho SD, Schultz JJ, et al. Thyroid hormone–sympathetic interaction and adaptive thermogenesis are thyroid hormone receptor isoform–specific. J Clin Invest. Jul 2001;108(1):97–105.

    PubMed  CAS  Google Scholar 

  71. Collin A, Cassy S, Buyse J, Decuypere E, Damon M. Potential involvement of mammalian and avian uncoupling proteins in the thermogenic effect of thyroid hormones. Domest Anim Endocrinol. Jul 2005;29(1):78–87.

    Article  PubMed  CAS  Google Scholar 

  72. Fekete C, Lechan RM. Negative feedback regulation of hypophysiotropic thyrotropin-releasing hormone (TRH) synthesizing neurons: role of neuronal afferents and type 2 deiodinase. Front Neuroendocrinol. Aug–Sept 2007;28 (2–3):97–114.

    Article  PubMed  CAS  Google Scholar 

  73. Lechan RM, Fekete C. Role of melanocortin signaling in the regulation of the hypothalamic-pituitary-thyroid (HPT) axis. Peptides. Feb 2006;27(2):310–25.

    Article  PubMed  CAS  Google Scholar 

  74. Sarkar S, Legradi G, Lechan RM. Intracerebroventricular administration of alpha-melanocyte stimulating hormone increases phosphorylation of CREB in TRH- and CRH-producing neurons of the hypothalamic paraventricular nucleus. Brain Res. 26 Jul 2002;945(1):50–59.

    Article  PubMed  CAS  Google Scholar 

  75. Harris M, Aschkenasi C, Elias CF, et al. Transcriptional regulation of the thyrotropin-releasing hormone gene by leptin and melanocortin signaling. J Clin Invest. Jan 2001;107(1):111–20.

    Article  PubMed  CAS  Google Scholar 

  76. Fekete C, Kelly J, Mihaly E, et al. Neuropeptide Y has a central inhibitory action on the hypothalamic-pituitary-thyroid axis. Endocrinology. Jun 2001;142(6):2606–13.

    Article  PubMed  CAS  Google Scholar 

  77. Fekete C, Marks DL, Sarkar S, et al. Effect of Agouti-related protein (Agrp) in regulation of the Hypothalamic-pituitary-thyroid (Hpt) axis in the Mc4-R Ko mouse. Endocrinology. 15 Jul 2004;145(11):4816–21.

    Google Scholar 

  78. Sarkar S, Lechan RM. Central administration of neuropeptide Y reduces alpha-melanocyte-stimulating hormone-induced cyclic adenosine 5′-monophosphate response element binding protein (CREB) phosphorylation in pro-thyrotropin-releasing hormone neurons and increases CREB phosphorylation in corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus. Endocrinology. Jan 2003;144(1):281–91.

    Article  PubMed  CAS  Google Scholar 

  79. Lechan RM, Hollenberg A, Fekete C. Hypothalamic-pituitary-thyroid axis: organization, neural/endocrine control of TRH. In: Squire LR, editor. Encyclopedia of neuroscience. 3rd ed. Oxford: Academic Press; 2009. pp. 75–87.

    Chapter  Google Scholar 

  80. Coppola A, Liu ZW, Andrews ZB, et al. A central thermogenic-like mechanism in feeding regulation: an interplay between arcuate nucleus T3 and UCP2. Cell Metab. Jan 2007;5(1):21–33.

    Article  PubMed  CAS  Google Scholar 

  81. Coppola A, Meli R, Diano S. Inverse shift in circulating corticosterone and leptin levels elevates hypothalamic deiodinase type 2 in fasted rats. Endocrinology. Jun 2005;146(6):2827–33.

    Article  PubMed  CAS  Google Scholar 

  82. Lechan RM, Fekete C. Infundibular tanycytes as modulators of neuroendocrine function: hypothetical role in the regulation of the thyroid and gonadal axis. Acta Biomed. 2007;78(Suppl 1):84–98.

    PubMed  Google Scholar 

  83. Ishii S, Kamegai J, Tamura H, Shimizu T, Sugihara H, Oikawa S. Hypothalamic neuropeptide Y/Y1 receptor pathway activated by a reduction in circulating leptin, but not by an increase in circulating ghrelin, contributes to hyperphagia associated with triiodothyronine-induced thyrotoxicosis. Neuroendocrinology. Dec 2003;78(6):321–30.

    Article  PubMed  CAS  Google Scholar 

  84. Kong WM, Martin NM, Smith KL, et al. Triiodothyronine stimulates food intake via the hypothalamic ventromedial nucleus independent of changes in energy expenditure. Endocrinology. Nov 2004;145(11):5252–8.

    Article  PubMed  CAS  Google Scholar 

  85. Niswender KD, Baskin DG, Schwartz MW. Insulin and its evolving partnership with leptin in the hypothalamic control of energy homeostasis. Trends Endocrinol Metab. Oct 2004;15(8):362–9.

    PubMed  CAS  Google Scholar 

  86. McGowan MK, Andrews KM, Grossman SP. Chronic intrahypothalamic infusions of insulin or insulin antibodies alter body weight and food intake in the rat. Physiol Behav. Apr 1992;51(4):753–66.

    Article  PubMed  CAS  Google Scholar 

  87. Obici S, Feng Z, Karkanias G, Baskin DG, Rossetti L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci. Jun 2002;5(6):566–72.

    Article  PubMed  CAS  Google Scholar 

  88. Bruning JC, Gautam D, Burks DJ, et al. Role of brain insulin receptor in control of body weight and reproduction. Science. 22 Sept 2000;289(5487):2122–5.

    Article  PubMed  CAS  Google Scholar 

  89. de Luca C, Kowalski TJ, Zhang Y, et al. Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. J Clin Invest. Dec 2005;115(12):3484–93.

    Article  PubMed  CAS  Google Scholar 

  90. Figlewicz DP, Benoit SC. Insulin, leptin, and food reward: update 2008. Am J Physiol Regul Integr Comp Physiol. Jan 2009;296(1):R9–19.

    Article  PubMed  CAS  Google Scholar 

  91. Figlewicz DP, Evans SB, Murphy J, Hoen M, Baskin DG. Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat. Brain Res. 21 Feb 2003;964(1):107–15.

    Article  PubMed  CAS  Google Scholar 

  92. Kadowaki T, Yamauchi T, Kubota N. The physiological and pathophysiological role of adiponectin and adiponectin receptors in the peripheral tissues and CNS. FEBS Lett. 9 Jan 2008;582(1):74–80.

    Article  PubMed  CAS  Google Scholar 

  93. Kubota N, Yano W, Kubota T, et al. Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab. Jul 2007;6(1):55–68.

    Article  PubMed  CAS  Google Scholar 

  94. Jayasena CN, Bloom SR. Role of gut hormones in obesity. Endocrinol Metab Clin North Am. Sept 2008;37(3):769–87.

    Article  PubMed  CAS  Google Scholar 

  95. Karra E, Batterham RL. The role of gut hormones in the regulation of body weight and energy homeostasis. Mol Cell Endocrinol. 27 Jun 2009;316(2):120–8.

    Google Scholar 

  96. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 9 Dec 1999;402(6762):656–60.

    Article  PubMed  CAS  Google Scholar 

  97. Nakazato M, Murakami N, Date Y, et al. A role for ghrelin in the central regulation of feeding. Nature. 11 Jan 2001;409(6817):194–8.

    Article  PubMed  CAS  Google Scholar 

  98. Theander-Carrillo C, Wiedmer P, Cettour-Rose P, et al. Ghrelin action in the brain controls adipocyte metabolism. J Clin Invest. Jul 2006;116(7):1983–93.

    Article  PubMed  CAS  Google Scholar 

  99. Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 19 Oct 2000;407(6806):908–13.

    Article  PubMed  CAS  Google Scholar 

  100. Willesen MG, Kristensen P, Romer J. Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology. Nov 1999;70(5):306–16.

    Article  PubMed  CAS  Google Scholar 

  101. Kola B, Hubina E, Tucci SA, et al. Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem. 1 Jul 2005;280(26):25196–201.

    Article  PubMed  CAS  Google Scholar 

  102. Date Y, Shimbara T, Koda S, et al. Peripheral ghrelin transmits orexigenic signals through the noradrenergic pathway from the hindbrain to the hypothalamus. Cell Metab. Oct 2006;4(4):323–31.

    Article  PubMed  CAS  Google Scholar 

  103. Abizaid A, Liu ZW, Andrews ZB, et al. Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J Clin Invest. Dec 2006;116(12):3229–39.

    Article  PubMed  CAS  Google Scholar 

  104. Toshinai K, Date Y, Murakami N, et al. Ghrelin-induced food intake is mediated via the orexin pathway. Endocrinology. Apr 2003;144(4):1506–12.

    Article  PubMed  CAS  Google Scholar 

  105. Zigman JM, Nakano Y, Coppari R, et al. Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Invest. Dec 2005;115(12):3564–72.

    Article  PubMed  CAS  Google Scholar 

  106. Shiiya T, Nakazato M, Mizuta M, et al. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab. Jan 2002;87(1):240–4.

    Article  PubMed  CAS  Google Scholar 

  107. Cummings DE, Weigle DS, Frayo RS, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med. 23 May 2002;346(21):1623–30.

    Article  PubMed  Google Scholar 

  108. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. Feb 2006;27(1):73–100.

    Article  PubMed  CAS  Google Scholar 

  109. Di Marzo V, Ligresti A, Cristino L. The endocannabinoid system as a link between homoeostatic and hedonic pathways involved in energy balance regulation. Int J Obes (Lond). Jun 2009;33(Suppl 2):S18–24.

    Article  CAS  Google Scholar 

  110. Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. Nov 2003;4(11):873–84.

    Article  PubMed  CAS  Google Scholar 

  111. Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev. Jul 2003;83(3):1017–66.

    PubMed  CAS  Google Scholar 

  112. Wittmann G, Deli L, Kallo I, et al. Distribution of type 1 cannabinoid receptor (CB1)-immunoreactive axons in the mouse hypothalamus. J Comp Neurol. 10 Jul 2007;503(2):270–9.

    Article  PubMed  CAS  Google Scholar 

  113. Greenberg I, Kuehnle J, Mendelson JH, Bernstein JG. Effects of marihuana use on body weight and caloric intake in humans. Psychopharmacology (Berl). 26 Aug 1976;49(1):79–84.

    CAS  Google Scholar 

  114. Despres JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 17 Nov 2005;353(20):2121–34.

    Article  PubMed  CAS  Google Scholar 

  115. Kola B, Farkas I, Christ-Crain M, et al. The orexigenic effect of ghrelin is mediated through central activation of the endogenous cannabinoid system. PLoS One. 2008;3(3):e1797.

    Article  PubMed  CAS  Google Scholar 

  116. Hentges ST, Low MJ, Williams JT. Differential regulation of synaptic inputs by constitutively released endocannabinoids and exogenous cannabinoids. J Neurosci. 19 Oct 2005;25(42):9746–51.

    Article  PubMed  CAS  Google Scholar 

  117. Anderson-Baker WC, McLaughlin CL, Baile CA. Oral and hypothalamic injections of barbiturates, benzodiazepines and cannabinoids and food intake in rats. Pharmacol Biochem Behav. Nov 1979;11(5):487–91.

    Article  PubMed  CAS  Google Scholar 

  118. Jamshidi N, Taylor DA. Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmacol. Nov 2001;134(6):1151–4.

    Article  PubMed  CAS  Google Scholar 

  119. Verty AN, McGregor IS, Mallet PE. Paraventricular hypothalamic CB(1) cannabinoid receptors are involved in the feeding stimulatory effects of Delta(9)-tetrahydrocannabinol. Neuropharmacology. Dec 2005;49(8):1101–9.

    Article  PubMed  CAS  Google Scholar 

  120. Jo YH, Chen YJ, Chua SC Jr., Talmage DA, Role LW. Integration of endocannabinoid and leptin signaling in an appetite-related neural circuit. Neuron. 22 Dec 2005;48(6):1055–66.

    Article  PubMed  CAS  Google Scholar 

  121. Simiand J, Keane M, Keane PE, Soubrie P. SR 141716, a CB1 cannabinoid receptor antagonist, selectively reduces sweet food intake in marmoset. Behav Pharmacol. Mar 1998;9(2):179–81.

    PubMed  CAS  Google Scholar 

  122. Melis T, Succu S, Sanna F, Boi A, Argiolas A, Melis MR. The cannabinoid antagonist SR 141716A (Rimonabant) reduces the increase of extra-cellular dopamine release in the rat nucleus accumbens induced by a novel high palatable food. Neurosci Lett. 4 Jun 2007;419(3):231–5.

    Article  PubMed  CAS  Google Scholar 

  123. Obici S. Minireview: Molecular targets for obesity therapy in the brain. Endocrinology. Jun 2009;150(6):2512–7.

    Article  PubMed  CAS  Google Scholar 

  124. Ritter S, Dinh TT, Li AJ. Hindbrain catecholamine neurons control multiple glucoregulatory responses. Physiol Behav. 30 Nov 2006;89(4):490–500.

    Article  PubMed  CAS  Google Scholar 

  125. Fekete C, Singru PS, Sanchez E, et al. Differential effects of central leptin, insulin, or glucose administration during fasting on the hypothalamic-pituitary-thyroid axis and feeding-related neurons in the arcuate nucleus. Endocrinology. Jan 2006;147(1):520–9.

    Article  PubMed  CAS  Google Scholar 

  126. Xue B, Kahn BB. AMPK integrates nutrient and hormonal signals to regulate food intake and energy balance through effects in the hypothalamus and peripheral tissues. J Physiol. 1 Jul 2006;574(Pt 1):73–83.

    Article  PubMed  CAS  Google Scholar 

  127. Claret M, Smith MA, Batterham RL, et al. AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J Clin Invest. Aug 2007;117(8):2325–36.

    Article  PubMed  CAS  Google Scholar 

  128. Han SM, Namkoong C, Jang PG, et al. Hypothalamic AMP-activated protein kinase mediates counter-regulatory responses to hypoglycaemia in rats. Diabetologia. Oct 2005;48(10):2170–8.

    Article  PubMed  CAS  Google Scholar 

  129. Mountjoy PD, Rutter GA. Glucose sensing by hypothalamic neurons and pancreatic islet cells: AMPle evidence for common mechanisms? Exp Physiol. Mar 2007;92(2):311–9.

    Article  PubMed  CAS  Google Scholar 

  130. Marty N, Dallaporta M, Thorens B. Brain glucose sensing, counterregulation, and energy homeostasis. Physiology (Bethesda). Aug 2007;22:241–51.

    Article  CAS  Google Scholar 

  131. Lane MD, Wolfgang M, Cha SH, Dai Y. Regulation of food intake and energy expenditure by hypothalamic malonyl-CoA. Int J Obes (Lond). Sept 2008;32(Suppl 4):S49–54.

    Article  CAS  Google Scholar 

  132. Lopez M, Tovar S, Vazquez MJ, Nogueiras R, Senaris R, Dieguez C. Sensing the fat: fatty acid metabolism in the hypothalamus and the melanocortin system. Peptides. Oct 2005;26(10):1753–8.

    Article  PubMed  CAS  Google Scholar 

  133. Hu Z, Dai Y, Prentki M, Chohnan S, Lane MD. A role for hypothalamic malonyl-CoA in the control of food intake. J Biol Chem. 2 Dec 2005;280(48):39681–3.

    Article  PubMed  CAS  Google Scholar 

  134. Choi YH, Fletcher PJ, Anderson GH. Extracellular amino acid profiles in the paraventricular nucleus of the rat hypothalamus are influenced by diet composition. Brain Res. 23 Feb 2001;892(2):320–8.

    Article  PubMed  CAS  Google Scholar 

  135. Blouet C, Jo YH, Li X, Schwartz GJ. Mediobasal hypothalamic leucine sensing regulates food intake through activation of a hypothalamus-brainstem circuit. J Neurosci. 1 Jul 2009;29(26):8302–11.

    Article  PubMed  CAS  Google Scholar 

  136. Cota D, Proulx K, Smith KA, et al. Hypothalamic mTOR signaling regulates food intake. Science. 12 May 2006;312(5775):927–30.

    Article  PubMed  CAS  Google Scholar 

  137. White BD, He B, Dean RG, Martin RJ. Low protein diets increase neuropeptide Y gene expression in the basomedial hypothalamus of rats. J Nutr. Aug 1994;124(8):1152–60.

    PubMed  CAS  Google Scholar 

  138. Morrison CD, Xi X, White CL, Ye J, Martin RJ. Amino acids inhibit Agrp gene expression via an mTOR-dependent mechanism. Am J Physiol Endocrinol Metab. Jul 2007;293(1):E165–71.

    Article  PubMed  CAS  Google Scholar 

  139. Howard JK, Flier JS. Attenuation of leptin and insulin signaling by SOCS proteins. Trends Endocrinol Metab. Nov 2006;17(9):365–71.

    Article  PubMed  CAS  Google Scholar 

  140. Roth JD, Roland BL, Cole RL, et al. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc Natl Acad Sci USA. 20 May 2008;105(20):7257–62.

    Article  PubMed  CAS  Google Scholar 

  141. Ravussin E, Smith SR, Mitchell JA, et al. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity (Silver Spring). 11 Jun 2009;17(9):1736–43.

    Google Scholar 

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Authors and Affiliations

  1. Division of Endocrinology, Diabetes and Metabolism, Department of Neuroscience, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA

    Ronald M. Lechan

  2. Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, 1083, Hungary

    Csaba Fekete

  3. Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, Tufts Medical Medical Center, Boston, MA, USA

    Csaba Fekete

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  1. Ronald M. Lechan
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  2. Csaba Fekete
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  1. Department of Pediatric Endocrinology, and Diabetes, Duke University, DUMC 3080, Durham, 27710, North Carolina, USA

    Michael Freemark

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Lechan, R.M., Fekete, C. (2010). Neuroendocrine and Metabolic Adaptations in the Central Nervous System That Facilitate Weight Regain. In: Freemark, M. (eds) Pediatric Obesity. Contemporary Endocrinology. Humana Press, New York, NY. https://doi.org/10.1007/978-1-60327-874-4_28

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