Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The regulation of food intake by the gut-brain axis: implications for obesity

Abstract

Our understanding of the regulation of appetite has improved considerably over the last few decades. Recent work, stimulated by efforts aimed at curbing the current obesity epidemic, has unravelled some of the complex pathways regulating energy homeostasis. Key factors to this progress have been the discovery of leptin and the neuronal circuitry involved in mediating its effects, as well as the identification of gut hormones that have important physiological roles relating to energy homeostasis. Despite these advances in research, there are currently no effective treatments for the growing problem of obesity. In this article, we summarise the regulatory pathways controlling appetite with a special focus on gut hormones. We detail how recent findings have contributed to our knowledge regarding the pathogenesis and treatment of common obesity. A number of barriers still need to be overcome to develop safe and effective anti-obesity treatments. We outline problems highlighted by historical failures and discuss the potential of augmenting natural satiety signals, such as gut hormones, to treat obesity.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  1. Brobeck JR . Mechanism of the development of obesity in animals with hypothalamic lesions. Physiol Rev 1946; 26: 541–559.

    CAS  PubMed  Google Scholar 

  2. Speakman JR, Levitsky DA, Allison DB, Bray MS, de Castro JM, Clegg DJ et al. Set points, settling points and some alternative models: theoretical options to understand how genes and environments combine to regulate body adiposity. Dis Model Mech 2011; 4: 733–745.

    PubMed  PubMed Central  Google Scholar 

  3. Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG . Central nervous system control of food intake. Nature 2000; 404: 661–671.

    Article  CAS  PubMed  Google Scholar 

  4. Berthoud HR . Homeostatic and non-homeostatic pathways involved in the control of food intake and energy balance. Obesity (Silver Spring) 2006; 14 (Suppl 5): 197S–200S.

    Google Scholar 

  5. Beck B . KO's and organisation of peptidergic feeding behavior mechanisms. Neurosci Biobehav Rev 2001; 25: 143–158.

    CAS  PubMed  Google Scholar 

  6. Schwartz MW . Central nervous system regulation of food intake. Obesity (Silver Spring) 2006; 14 (Suppl 1): 1S–8S.

    CAS  Google Scholar 

  7. Hussain SS, Bloom SR . The pharmacological treatment and management of obesity. Postgrad Med 2011; 123: 34–44.

    PubMed  Google Scholar 

  8. Konner AC, Klockener T, Bruning JC . Control of energy homeostasis by insulin and leptin: targeting the arcuate nucleus and beyond. Physiol Behav 2009; 97: 632–638.

    PubMed  Google Scholar 

  9. Broadwell RD, Brightman MW . Entry of peroxidase into neurons of the central and peripheral nervous systems from extracerebral and cerebral blood. J Comp Neurol 1976; 166: 257–283.

    CAS  PubMed  Google Scholar 

  10. Peruzzo B, Pastor FE, Blazquez JL, Schobitz K, Pelaez B, Amat P et al. A second look at the barriers of the medial basal hypothalamus. Exp Brain Res 2000; 132: 10–26.

    CAS  PubMed  Google Scholar 

  11. Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS . Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev 1999; 20: 68–100.

    CAS  PubMed  Google Scholar 

  12. Bouret SG, Draper SJ, Simerly RB . Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. J Neurosci 2004; 24: 2797–2805.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Cone RD, Cowley MA, Butler AA, Fan W, Marks DL, Low MJ . The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis. Int J Obes Relat Metab Disord 2001; 25 (Suppl 5): S63–S67.

    CAS  PubMed  Google Scholar 

  14. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998; 92: 573–585.

    CAS  PubMed  Google Scholar 

  15. Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, Cullen MJ et al. A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 1996; 380: 243–247.

    CAS  PubMed  Google Scholar 

  16. Rossi M, Choi SJ, O'Shea D, Miyoshi T, Ghatei MA, Bloom SR . Melanin-concentrating hormone acutely stimulates feeding, but chronic administration has no effect on body weight. Endocrinology 1997; 138: 351–355.

    CAS  PubMed  Google Scholar 

  17. Xu B, Goulding EH, Zang K, Cepoi D, Cone RD, Jones KR et al. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci 2003; 6: 736–742.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Dhillon H, Zigman JM, Ye C, Lee CE, McGovern RA, Tang V et al. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 2006; 49: 191–203.

    CAS  PubMed  Google Scholar 

  19. Lam TK, Schwartz GJ, Rossetti L . Hypothalamic sensing of fatty acids. Nat Neurosci 2005; 8: 579–584.

    CAS  PubMed  Google Scholar 

  20. Jordan SD, Konner AC, Bruning JC . Sensing the fuels: glucose and lipid signaling in the CNS controlling energy homeostasis. Cell Mol Life Sci 2010; 67: 3255–3273.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Levin BE, Magnan C, Dunn-Meynell A, Le Foll C . Metabolic sensing and the brain: who, what, where, and how? Endocrinology 2011; 152: 2552–2557.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Grill HJ, Kaplan JM . The neuroanatomical axis for control of energy balance. Front Neuroendocrinol 2002; 23: 2–40.

    CAS  PubMed  Google Scholar 

  23. Blevins JE, Baskin DG . Hypothalamic-brainstem circuits controlling eating. Forum Nutr 2010; 63: 133–140.

    CAS  PubMed  Google Scholar 

  24. Grill HJ, Schwartz MW, Kaplan JM, Foxhall JS, Breininger J, Baskin DG . Evidence that the caudal brainstem is a target for the inhibitory effect of leptin on food intake. Endocrinology 2002; 143: 239–246.

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  26. Chaudhri O, Small C, Bloom S . Gastrointestinal hormones regulating appetite. Philos Trans R Soc Lond B Biol Sci 2006; 361: 1187–1209.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Schwartz GJ . The role of gastrointestinal vagal afferents in the control of food intake: current prospects. Nutrition 2000; 16: 866–873.

    CAS  PubMed  Google Scholar 

  28. Price CJ, Hoyda TD, Ferguson AV . The area postrema: a brain monitor and integrator of systemic autonomic state. Neuroscientist 2008; 14: 182–194.

    PubMed  Google Scholar 

  29. Ter Horst GJ, de Boer P, Luiten PG, van Willigen JD . Ascending projections from the solitary tract nucleus to the hypothalamus. A Phaseolus vulgaris lectin tracing study in the rat. Neuroscience 1989; 31: 785–797.

    CAS  PubMed  Google Scholar 

  30. ter Horst GJ, Luiten PG, Kuipers F . Descending pathways from hypothalamus to dorsal motor vagus and ambiguus nuclei in the rat. J Auton Nerv Syst 1984; 11: 59–75.

    CAS  PubMed  Google Scholar 

  31. Grijalva CV, Novin D . The role of the hypothalamus and dorsal vagal complex in gastrointestinal function and pathophysiology. Ann NY Acad Sci 1990; 597: 207–222.

    CAS  PubMed  Google Scholar 

  32. Grill HJ, Skibicka KP, Hayes MR . Imaging obesity: fMRI, food reward, and feeding. Cell Metab 2007; 6: 423–425.

    CAS  PubMed  Google Scholar 

  33. De Silva A, Salem V, Long CJ, Makwana A, Newbould RD, Rabiner EA et al. The gut hormones PYY(3-36) and GLP-1(7-36 amide) reduce food intake and modulate brain activity in appetite centers in humans. Cell Metab 2011; 14: 700–706.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Page KA, Seo D, Belfort-DeAguiar R, Lacadie C, Dzuira J, Naik S et al. Circulating glucose levels modulate neural control of desire for high-calorie foods in humans. J Clin Invest 2011; 121: 4161–4169.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Velloso LA, Schwartz MW . Altered hypothalamic function in diet-induced obesity. Int J Obes (Lond) 2011; 35: 1455–1465.

    CAS  Google Scholar 

  36. Raben A, Astrup A . Leptin is influenced both by predisposition to obesity and diet composition. Int J Obes Relat Metab Disord 2000; 24: 450–459.

    CAS  PubMed  Google Scholar 

  37. Murphy KG, Bloom SR . Gut hormones and the regulation of energy homeostasis. Nature 2006; 444: 854–859.

    CAS  PubMed  Google Scholar 

  38. Rolls ET . Brain mechanisms underlying flavour and appetite. Philos Trans R Soc Lond B Biol Sci 2006; 361: 1123–1136.

    PubMed  PubMed Central  Google Scholar 

  39. Schwartz GJ . Brainstem integrative function in the central nervous system control of food intake. Forum Nutr 2010; 63: 141–151.

    CAS  PubMed  Google Scholar 

  40. Gibbs J, Young RC, Smith GP . Cholecystokinin decreases food intake in rats. J Comp Physiol Psychol 1973; 84: 488–495.

    CAS  PubMed  Google Scholar 

  41. Kissileff HR, Pi-Sunyer FX, Thornton J, Smith GP . C-terminal octapeptide of cholecystokinin decreases food intake in man. Am J Clin Nutr 1981; 34: 154–160.

    CAS  PubMed  Google Scholar 

  42. Buffa R, Solcia E, Go VL . Immunohistochemical identification of the cholecystokinin cell in the intestinal mucosa. Gastroenterology 1976; 70: 528–532.

    CAS  PubMed  Google Scholar 

  43. Liddle RA, Goldfine ID, Rosen MS, Taplitz RA, Williams JA . Cholecystokinin bioactivity in human plasma. Molecular forms, responses to feeding, and relationship to gallbladder contraction. J Clin Invest 1985; 75: 1144–1152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rehfeld JF, Bungaard JR, Friis-Hansen L, Goetze JP . On the tissue-specific processing of procholecystokinin in the brain and gut--a short review. J Physiol Pharmacol 2003; 54 (Suppl 4): 73–79.

    PubMed  Google Scholar 

  45. Moran TH, Ameglio PJ, Schwartz GJ, McHugh PR . Blockade of type A, not type B, CCK receptors attenuates satiety actions of exogenous and endogenous CCK. Am J Physiol 1992; 262 (1 Pt 2): R46–R50.

    CAS  PubMed  Google Scholar 

  46. Zittel TT, Glatzle J, Kreis ME, Starlinger M, Eichner M, Raybould HE et al. C-fos protein expression in the nucleus of the solitary tract correlates with cholecystokinin dose injected and food intake in rats. Brain Res 1999; 846: 1–11.

    CAS  PubMed  Google Scholar 

  47. Blevins JE, Stanley BG, Reidelberger RD . Brain regions where cholecystokinin suppresses feeding in rats. Brain Res 2000; 860: 1–10.

    CAS  PubMed  Google Scholar 

  48. Moran TH, Katz LF, Plata-Salaman CR, Schwartz GJ . Disordered food intake and obesity in rats lacking cholecystokinin A receptors. Am J Physiol 1998; 274 (3 Pt 2): R618–R625.

    CAS  PubMed  Google Scholar 

  49. Kopin AS, Mathes WF, McBride EW, Nguyen M, Al-Haider W, Schmitz F et al. The cholecystokinin-A receptor mediates inhibition of food intake yet is not essential for the maintenance of body weight. J Clin Invest 1999; 103: 383–391.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Crawley JN, Beinfeld MC . Rapid development of tolerance to the behavioural actions of cholecystokinin. Nature 1983; 302: 703–706.

    CAS  PubMed  Google Scholar 

  51. West DB, Fey D, Woods SC . Cholecystokinin persistently suppresses meal size but not food intake in free-feeding rats. Am J Physiol 1984; 246 (5 Pt 2): R776–R787.

    CAS  PubMed  Google Scholar 

  52. West DB, Greenwood MR, Sullivan AC, Prescod L, Marzullo LR, Triscari J . Infusion of cholecystokinin between meals into free-feeding rats fails to prolong the intermeal interval. Physiol Behav 1987; 39: 111–115.

    CAS  PubMed  Google Scholar 

  53. Kojima M, Kangawa K . Ghrelin: structure and function. Physiol Rev 2005; 85: 495–522.

    CAS  PubMed  Google Scholar 

  54. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K . Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656–660.

    CAS  PubMed  Google Scholar 

  55. Patterson M, Bloom SR, Gardiner JV . Ghrelin and appetite control in humans-Potential application in the treatment of obesity. Peptides 2011; 32: 2290–2294.

    CAS  PubMed  Google Scholar 

  56. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS . A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 2001; 50: 1714–1719.

    CAS  PubMed  Google Scholar 

  57. Tschop M, Wawarta R, Riepl RL, Friedrich S, Bidlingmaier M, Landgraf R et al. Post-prandial decrease of circulating human ghrelin levels. J Endocrinol Invest 2001; 24: RC19–RC21.

    CAS  PubMed  Google Scholar 

  58. Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T et al. Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J Clin Endocrinol Metab 2001; 86: 4753–4758.

    CAS  PubMed  Google Scholar 

  59. Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 2001; 86: 5992.

    CAS  PubMed  Google Scholar 

  60. Wren AM, Small CJ, Abbott CR, Dhillo WS, Seal LJ, Cohen MA et al. Ghrelin causes hyperphagia and obesity in rats. Diabetes 2001; 50: 2540–2547.

    CAS  PubMed  Google Scholar 

  61. Castaneda TR, Tong J, Datta R, Culler M, Tschop MH . Ghrelin in the regulation of body weight and metabolism. Front Neuroendocrinol 2010; 31: 44–60.

    CAS  PubMed  Google Scholar 

  62. Lawrence CB, Snape AC, Baudoin FM, Luckman SM . Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers. Endocrinology 2002; 143: 155–162.

    CAS  PubMed  Google Scholar 

  63. Chuang JC, Perello M, Sakata I, Osborne-Lawrence S, Savitt JM, Lutter M et al. Ghrelin mediates stress-induced food-reward behavior in mice. J Clin Invest 2011; 121: 2684–2692.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML . Circulating ghrelin levels are decreased in human obesity. Diabetes 2001; 50: 707–709.

    CAS  PubMed  Google Scholar 

  65. Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002; 346: 1623–1630.

    PubMed  Google Scholar 

  66. Gardiner JV, Campbell D, Patterson M, Kent A, Ghatei MA, Bloom SR et al. The hyperphagic effect of ghrelin is inhibited in mice by a diet high in fat. Gastroenterology 2010; 138: 2468–2476, 2476.e1.

    CAS  PubMed  Google Scholar 

  67. Adrian TE, Ferri GL, Bacarese-Hamilton AJ, Fuessl HS, Polak JM, Bloom SR . Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 1985; 89: 1070–1077.

    CAS  PubMed  Google Scholar 

  68. Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS et al. Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med 2003; 349: 941–948.

    CAS  PubMed  Google Scholar 

  69. Batterham RL, Heffron H, Kapoor S, Chivers JE, Chandarana K, Herzog H et al. Critical role for peptide YY in protein-mediated satiation and body-weight regulation. Cell Metab 2006; 4: 223–233.

    CAS  PubMed  Google Scholar 

  70. Vincent RP, le Roux CW . Changes in gut hormones after bariatric surgery. Clin Endocrinol (Oxf) 2008; 69: 173–179.

    CAS  Google Scholar 

  71. Chandarana K, Gelegen C, Karra E, Choudhury AI, Drew ME, Fauveau V et al. Diet and gastrointestinal bypass-induced weight loss: the roles of ghrelin and peptide YY. Diabetes 2011; 60: 810–818.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Vrang N, Madsen AN, Tang-Christensen M, Hansen G, Larsen PJ . PYY(3-36) reduces food intake and body weight and improves insulin sensitivity in rodent models of diet-induced obesity. Am J Physiol Regul Integr Comp Physiol 2006; 291: R367–R375.

    CAS  PubMed  Google Scholar 

  73. Degen L, Oesch S, Casanova M, Graf S, Ketterer S, Drewe J et al. Effect of peptide YY3-36 on food intake in humans. Gastroenterology 2005; 129: 1430–1436.

    CAS  PubMed  Google Scholar 

  74. Sloth B, Holst JJ, Flint A, Gregersen NT, Astrup A . Effects of PYY1-36 and PYY3-36 on appetite, energy intake, energy expenditure, glucose and fat metabolism in obese and lean subjects. Am J Physiol Endocrinol Metab 2007; 292: E1062–E1068.

    CAS  PubMed  Google Scholar 

  75. Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA, Dakin CL et al. Gut hormone PYY(3-36) physiologically inhibits food intake. Nature 2002; 418: 650–654.

    CAS  PubMed  Google Scholar 

  76. Michel MC, Beck-Sickinger A, Cox H, Doods HN, Herzog H, Larhammar D et al. XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. Pharmacol Rev 1998; 50: 143–150.

    CAS  PubMed  Google Scholar 

  77. Schmidt PT, Naslund E, Gryback P, Jacobsson H, Holst JJ, Hilsted L et al. A role for pancreatic polypeptide in the regulation of gastric emptying and short-term metabolic control. J Clin Endocrinol Metab 2005; 90: 5241–5246.

    CAS  PubMed  Google Scholar 

  78. Asakawa A, Inui A, Ueno N, Fujimiya M, Fujino MA, Kasuga M . Mouse pancreatic polypeptide modulates food intake, while not influencing anxiety in mice. Peptides 1999; 20: 1445–1448.

    CAS  PubMed  Google Scholar 

  79. Batterham RL, Le Roux CW, Cohen MA, Park AJ, Ellis SM, Patterson M et al. Pancreatic polypeptide reduces appetite and food intake in humans. J Clin Endocrinol Metab 2003; 88: 3989–3992.

    CAS  PubMed  Google Scholar 

  80. Hankir MK, Parkinson JR, Minnion JS, Addison ML, Bloom SR, Bell JD . Peptide YY 3-36 and pancreatic polypeptide differentially regulate hypothalamic neuronal activity in mice in vivo as measured by manganese-enhanced magnetic resonance imaging. J Neuroendocrinol 2011; 23: 371–380.

    CAS  PubMed  Google Scholar 

  81. Dhanvantari S, Seidah NG, Brubaker PL . Role of prohormone convertases in the tissue-specific processing of proglucagon. Mol Endocrinol 1996; 10: 342–355.

    CAS  PubMed  Google Scholar 

  82. Herrmann C, Goke R, Richter G, Fehmann HC, Arnold R, Goke B . Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients. Digestion 1995; 56: 117–126.

    CAS  PubMed  Google Scholar 

  83. Rocca AS, Brubaker PL . Role of the vagus nerve in mediating proximal nutrient-induced glucagon-like peptide-1 secretion. Endocrinology 1999; 140: 1687–1694.

    CAS  PubMed  Google Scholar 

  84. Chu ZL, Carroll C, Alfonso J, Gutierrez V, He H, Lucman A et al. A role for intestinal endocrine cell-expressed g protein-coupled receptor 119 in glycemic control by enhancing glucagon-like Peptide-1 and glucose-dependent insulinotropic Peptide release. Endocrinology 2008; 149: 2038–2047.

    CAS  PubMed  Google Scholar 

  85. Kreymann B, Williams G, Ghatei MA, Bloom SR . Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet 1987; 2: 1300–1304.

    CAS  PubMed  Google Scholar 

  86. Drucker DJ . The biology of incretin hormones. Cell Metab 2006; 3: 153–165.

    CAS  PubMed  Google Scholar 

  87. Parkinson JR, Chaudhri OB, Kuo YT, Field BC, Herlihy AH, Dhillo WS et al. Differential patterns of neuronal activation in the brainstem and hypothalamus following peripheral injection of GLP-1, oxyntomodulin and lithium chloride in mice detected by manganese-enhanced magnetic resonance imaging (MEMRI). Neuroimage 2009; 44: 1022–1031.

    PubMed  Google Scholar 

  88. Eng J, Kleinman WA, Singh L, Singh G, Raufman JP . Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 1992; 267: 7402–7405.

    CAS  PubMed  Google Scholar 

  89. Shyangdan DS, Royle P, Clar C, Sharma P, Waugh N, Snaith A . Glucagon-like peptide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev 2011. CD006423.

  90. Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean ME et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond) 2011; e-pub ahead of print 16 August 2011; doi:10.1038/ijo.2011.158.

    PubMed  Google Scholar 

  91. Vilsboll T, Christensen M, Junker AE, Knop FK, Gluud LL . Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ 2012; 344: d7771.

    PubMed  PubMed Central  Google Scholar 

  92. Arakawa M, Mita T, Azuma K, Ebato C, Goto H, Nomiyama T et al. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes 2010; 59: 1030–1037.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Jin SL, Han VK, Simmons JG, Towle AC, Lauder JM, Lund PK . Distribution of glucagonlike peptide I (GLP-I), glucagon, and glicentin in the rat brain: an immunocytochemical study. J Comp Neurol 1988; 271: 519–532.

    CAS  PubMed  Google Scholar 

  94. Le Quellec A, Kervran A, Blache P, Ciurana AJ, Bataille D . Oxyntomodulin-like immunoreactivity: diurnal profile of a new potential enterogastrone. J Clin Endocrinol Metab 1992; 74: 1405–1409.

    CAS  PubMed  Google Scholar 

  95. Baggio LL, Huang Q, Brown TJ, Drucker DJ . Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology 2004; 127: 546–558.

    CAS  PubMed  Google Scholar 

  96. Schjoldager B, Mortensen PE, Myhre J, Christiansen J, Holst JJ . Oxyntomodulin from distal gut. Role in regulation of gastric and pancreatic functions. Dig Dis Sci 1989; 34: 1411–1419.

    CAS  PubMed  Google Scholar 

  97. Wynne K, Park AJ, Small CJ, Meeran K, Ghatei MA, Frost GS et al. Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomised controlled trial. Int J Obes (Lond) 2006; 30: 1729–1736.

    CAS  Google Scholar 

  98. Chaudhri OB, Parkinson JR, Kuo YT, Druce MR, Herlihy AH, Bell JD et al. Differential hypothalamic neuronal activation following peripheral injection of GLP-1 and oxyntomodulin in mice detected by manganese-enhanced magnetic resonance imaging. Biochem Biophys Res Commun 2006; 350: 298–306.

    CAS  PubMed  Google Scholar 

  99. Dakin CL, Small CJ, Batterham RL, Neary NM, Cohen MA, Patterson M et al. Peripheral oxyntomodulin reduces food intake and body weight gain in rats. Endocrinology 2004; 145: 2687–2695.

    CAS  PubMed  Google Scholar 

  100. Svoboda M, Tastenoy M, Vertongen P, Robberecht P . Relative quantitative analysis of glucagon receptor mRNA in rat tissues. Mol Cell Endocrinol 1994; 105: 131–137.

    CAS  PubMed  Google Scholar 

  101. Woods SC, Lutz TA, Geary N, Langhans W . Pancreatic signals controlling food intake; insulin, glucagon and amylin. Philos Trans R Soc Lond B Biol Sci 2006; 361: 1219–1235.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Schulman JL, Carleton JL, Whitney G, Whitehorn JC . Effect of glucagon on food intake and body weight in man. J Appl Physiol 1957; 11: 419–421.

    CAS  PubMed  Google Scholar 

  103. de Castro JM, Paullin SK, DeLugas GM . Insulin and glucagon as determinants of body weight set point and microregulation in rats. J Comp Physiol Psychol 1978; 92: 571–579.

    CAS  PubMed  Google Scholar 

  104. Langhans W, Zeiger U, Scharrer E, Geary N . Stimulation of feeding in rats by intraperitoneal injection of antibodies to glucagon. Science 1982; 218: 894–896.

    CAS  PubMed  Google Scholar 

  105. Habegger KM, Heppner KM, Geary N, Bartness TJ, DiMarchi R, Tschop MH . The metabolic actions of glucagon revisited. Nat Rev Endocrinol 2010; 6: 689–697.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Pocai A, Carrington PE, Adams JR, Wright M, Eiermann G, Zhu L et al. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 2009; 58: 2258–2266.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Day JW, Ottaway N, Patterson JT, Gelfanov V, Smiley D, Gidda J et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol 2009; 5: 749–757.

    CAS  PubMed  Google Scholar 

  108. Bailey RJ, Walker CS, Ferner AH, Loomes KM, Prijic G, Halim A et al. Pharmacological characterisation of rat amylin receptors: implications for the identification of amylin receptor subtypes. Br J Pharmacol 2011; Oct: 20.

    Google Scholar 

  109. Hollander P, Maggs DG, Ruggles JA, Fineman M, Shen L, Kolterman OG et al. Effect of pramlintide on weight in overweight and obese insulin-treated type 2 diabetes patients. Obes Res 2004; 12: 661–668.

    CAS  PubMed  Google Scholar 

  110. Mustain WC, Rychahou PG, Evers BM . The role of neurotensin in physiologic and pathologic processes. Curr Opin Endocrinol Diabetes Obes 2011; 18: 75–82.

    CAS  PubMed  Google Scholar 

  111. Cui H, Cai F, Belsham DD . Anorexigenic hormones leptin, insulin, and alpha-melanocyte-stimulating hormone directly induce neurotensin (NT) gene expression in novel NT-expressing cell models. J Neurosci 2005; 25: 9497–9506.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Kim ER, Leckstrom A, Mizuno TM . Impaired anorectic effect of leptin in neurotensin receptor 1-deficient mice. Behav Brain Res 2008; 194: 66–71.

    CAS  PubMed  Google Scholar 

  113. Cooke JH, Patterson M, Patel SR, Smith KL, Ghatei MA, Bloom SR et al. Peripheral and central administration of xenin and neurotensin suppress food intake in rodents. Obesity (Silver Spring) 2009; 17: 1135–1143.

    CAS  Google Scholar 

  114. Zhang JV, Ren PG, Avsian-Kretchmer O, Luo CW, Rauch R, Klein C et al. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science 2005; 310: 996–999.

    CAS  PubMed  Google Scholar 

  115. Li JB, Asakawa A, Cheng K, Li Y, Chaolu H, Tsai M et al. Biological effects of obestatin. Endocrine 2011; 39: 205–211.

    CAS  PubMed  Google Scholar 

  116. Damholt AB, Buchan AM, Holst JJ, Kofod H . Proglucagon processing profile in canine L cells expressing endogenous prohormone convertase 1/3 and prohormone convertase 2. Endocrinology 1999; 140: 4800–4808.

    CAS  PubMed  Google Scholar 

  117. Tang-Christensen M, Larsen PJ, Thulesen J, Romer J, Vrang N . The proglucagon-derived peptide, glucagon-like peptide-2, is a neurotransmitter involved in the regulation of food intake. Nat Med 2000; 6: 802–807.

    CAS  PubMed  Google Scholar 

  118. Scott RB, Kirk D, MacNaughton WK, Meddings JB . GLP-2 augments the adaptive response to massive intestinal resection in rat. Am J Physiol 1998; 275 (5 Pt 1): G911–G921.

    CAS  PubMed  Google Scholar 

  119. Schmidt PT, Naslund E, Gryback P, Jacobsson H, Hartmann B, Holst JJ et al. Peripheral administration of GLP-2 to humans has no effect on gastric emptying or satiety. Regul Pept 2003; 116: 21–25.

    CAS  PubMed  Google Scholar 

  120. Wadden TA, Butryn ML, Wilson C . Lifestyle modification for the management of obesity. Gastroenterology 2007; 132: 2226–2238.

    PubMed  Google Scholar 

  121. Alhassan S, Kim S, Bersamin A, King AC, Gardner CD . Dietary adherence and weight loss success among overweight women: results from the A TO Z weight loss study. Int J Obes (Lond) 2008; 32: 985–991.

    CAS  Google Scholar 

  122. Johnson PM, Kenny PJ . Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nat Neurosci 2010; 13: 635–641.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Rucker D, Padwal R, Li SK, Curioni C, Lau DC . Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ 2007; 335: 1194–1199.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Richelsen B, Tonstad S, Rossner S, Toubro S, Niskanen L, Madsbad S et al. Effect of orlistat on weight regain and cardiovascular risk factors following a very-low-energy diet in abdominally obese patients: a 3-year randomized, placebo-controlled study. Diabetes Care 2007; 30: 27–32.

    CAS  PubMed  Google Scholar 

  125. Padwal R, Kezouh A, Levine M, Etminan M . Long-term persistence with orlistat and sibutramine in a population-based cohort. Int J Obes (Lond) 2007; 31: 1567–1570.

    CAS  Google Scholar 

  126. Pinder RM, Brogden RN, Sawyer PR, Speight TM, Avery GS . Fenfluramine: a review of its pharmacological properties and therapeutic efficacy in obesity. Drugs 1975; 10: 241–323.

    CAS  PubMed  Google Scholar 

  127. Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997; 337: 581–588.

    CAS  PubMed  Google Scholar 

  128. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S . Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005; 365: 1389–1397.

    CAS  PubMed  Google Scholar 

  129. Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A . Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 2007; 370: 1706–1713.

    CAS  PubMed  Google Scholar 

  130. Torp-Pedersen C, Caterson I, Coutinho W, Finer N, Van Gaal L, Maggioni A et al. Cardiovascular responses to weight management and sibutramine in high-risk subjects: an analysis from the SCOUT trial. Eur Heart J 2007; 28: 2915–2923.

    PubMed  Google Scholar 

  131. James WPT, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP et al. Effect of Sibutramine on Cardiovascular Outcomes in Overweight and Obese Subjects. New Engl J Med 2010; 363: 905–917.

    CAS  PubMed  Google Scholar 

  132. Kokoeva MV, Yin H, Flier JS . Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science 2005; 310: 679–683.

    CAS  PubMed  Google Scholar 

  133. Lambert PD, Anderson KD, Sleeman MW, Wong V, Tan J, Hijarunguru A et al. Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity. Proc Natl Acad Sci USA 2001; 98: 4652–4657.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Ettinger MP, Littlejohn TW, Schwartz SL, Weiss SR, McIlwain HH, Heymsfield SB et al. Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: a randomized, dose-ranging study. JAMA 2003; 289: 1826–1832.

    CAS  PubMed  Google Scholar 

  135. Sjostrom L . Bariatric surgery and reduction in morbidity and mortality: experiences from the SOS study. Int J Obes (Lond) 2008; 32 (Suppl 7): S93–S97.

    Google Scholar 

  136. Powell AG, Apovian CM, Aronne LJ . New drug targets for the treatment of obesity. Clin Pharmacol Ther 2011; 90: 40–51.

    CAS  PubMed  Google Scholar 

  137. Neary NM, Small CJ, Druce MR, Park AJ, Ellis SM, Semjonous NM et al. Peptide YY3-36 and glucagon-like peptide-17-36 inhibit food intake additively. Endocrinology 2005; 146: 5120–5127.

    CAS  PubMed  Google Scholar 

  138. Field BC, Wren AM, Peters V, Baynes KC, Martin NM, Patterson M et al. PYY3-36 and oxyntomodulin can be additive in their effect on food intake in overweight and obese humans. Diabetes 2010; 59: 1635–1639.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

SSH is funded by a Welcome Trust Clinical Research Fellowship. The Section is funded by grants from the MRC, BBSRC, NIHR, an Integrative Mammalian Biology (IMB) Capacity Building Award, an FP7-HEALTH-2009-241592 EuroCHIP grant and is supported by the NIHR Imperial Biomedical Research Centre Funding Scheme.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S R Bloom.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hussain, S., Bloom, S. The regulation of food intake by the gut-brain axis: implications for obesity. Int J Obes 37, 625–633 (2013). https://doi.org/10.1038/ijo.2012.93

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2012.93

Keywords

This article is cited by

Search

Quick links