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Regulation of energy balance by a gut–brain axis and involvement of the gut microbiota

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Abstract

Despite significant progress in understanding the homeostatic regulation of energy balance, successful therapeutic options for curbing obesity remain elusive. One potential target for the treatment of obesity is via manipulation of the gut–brain axis, a complex bidirectional communication system that is crucial in maintaining energy homeostasis. Indeed, ingested nutrients induce secretion of gut peptides that act either via paracrine signaling through vagal and non-vagal neuronal relays, or in an endocrine fashion via entry into circulation, to ultimately signal to the central nervous system where appropriate responses are generated. We review here the current hypotheses of nutrient sensing mechanisms of enteroendocrine cells, including the release of gut peptides, mainly cholecystokinin, glucagon-like peptide-1, and peptide YY, and subsequent gut-to-brain signaling pathways promoting a reduction of food intake and an increase in energy expenditure. Furthermore, this review highlights recent research suggesting this energy regulating gut–brain axis can be influenced by gut microbiota, potentially contributing to the development of obesity.

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Abbreviations

AgRP:

Agouti-related protein

AEA:

Anadamide

ARC:

Arcuate nucleus

BAT:

Brown adipose tissue

BDNF:

Brain-derived neurotrophic factor

CB1 :

Cannabinoid receptor 1

CCK:

Cholecystokinin

CCK-1R:

CCK-1 receptor

CNS:

Central nervous system

DVC:

Dorsal vagal complex

ENS:

Enteric nervous system

EEC:

Enteroendocrine cell

GI:

Gastrointestinal

GF:

Germ free

GLP-1:

Glucagon-like peptide 1

GLP-1R:

GLP-1 receptor

GPR:

G-coupled protein receptor

IP:

Intraperitoneal

KO:

Knockout

LPS:

Lipopolysaccharide

NPY:

Neuropeptide Y

NTS:

Nucleus tractus solitarius

OTU:

Operational taxonomic unit

OXM:

Oxyntomodulin

PVN:

Paraventricular nucleus

PYY:

Peptide YY

TLR:

Toll-like receptor

Y2R:

Y2 receptor

References

  1. Duca FA, Bauer PV, Hamr SC, Lam TK (2015) Glucoregulatory relevance of small intestinal nutrient sensing in physiology, bariatric surgery, and pharmacology. Cell Metab 22:367–380

    Article  CAS  PubMed  Google Scholar 

  2. Mayer EA (2011) Gut feelings: the emerging biology of gut–brain communication. Nat Rev Neurosci 12:453–466

    Article  CAS  PubMed  Google Scholar 

  3. Hamr SC, Wang B, Swartz TD, Duca FA (2015) Does nutrient sensing determine how we “see” food? Curr Diab Rep 15:604

    Article  PubMed  Google Scholar 

  4. Psichas A, Reimann F, Gribble FM (2015) Gut chemosensing mechanisms. J Clin Invest 125:908–917

    Article  PubMed  Google Scholar 

  5. Habib AM, Richards P, Cairns LS, Rogers GJ, Bannon CA, Parker HE, Morley TC, Yeo GS, Reimann F, Gribble FM (2012) Overlap of endocrine hormone expression in the mouse intestine revealed by transcriptional profiling and flow cytometry. Endocrinology 153:3054–3065

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Berthoud HR, Kressel M, Raybould HE, Neuhuber WL (1995) Vagal sensors in the rat duodenal mucosa: distribution and structure as revealed by in vivo DiI-tracing. Anat Embryol (Berl) 191:203–212

    Article  CAS  Google Scholar 

  7. Prechtl JC, Powley TL (1990) The fiber composition of the abdominal vagus of the rat. Anat Embryol (Berl) 181:101–115

    Article  CAS  Google Scholar 

  8. Dockray GJ (2013) Enteroendocrine cell signalling via the vagus nerve. Curr Opin Pharmacol 13:954–958

    Article  CAS  PubMed  Google Scholar 

  9. Amato A, Cinci L, Rotondo A, Serio R, Faussone-Pellegrini MS, Vannucchi MG, Mule F (2010) Peripheral motor action of glucagon-like peptide-1 through enteric neuronal receptors. Neurogastroenterol Motil 22:664-e203

    Article  PubMed  CAS  Google Scholar 

  10. Patterson LM, Zheng H, Berthoud HR (2002) Vagal afferents innervating the gastrointestinal tract and CCKA-receptor immunoreactivity. Anat Rec 266:10–20

    Article  PubMed  Google Scholar 

  11. Richards P, Parker HE, Adriaenssens AE, Hodgson JM, Cork SC, Trapp S, Gribble FM, Reimann F (2014) Identification and characterization of GLP-1 receptor-expressing cells using a new transgenic mouse model. Diabetes 63:1224–1233

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Costa M, Brookes SJ, Hennig GW (2000) Anatomy and physiology of the enteric nervous system. Gut 47(Suppl 4):iv15–iv19 (discussion iv26)

    PubMed Central  PubMed  Google Scholar 

  13. Sayegh AI, Covasa M, Ritter RC (2004) Intestinal infusions of oleate and glucose activate distinct enteric neurons in the rat. Auton Neurosci 115:54–63

    Article  CAS  PubMed  Google Scholar 

  14. Ritter RC (2011) A tale of two endings: modulation of satiation by NMDA receptors on or near central and peripheral vagal afferent terminals. Physiol Behav 105:94–99

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Norgren R (1978) Projections from the nucleus of the solitary tract in the rat. Neuroscience 3:207–218

    Article  CAS  PubMed  Google Scholar 

  16. Craig AD (1996) An ascending general homeostatic afferent pathway originating in lamina I. Prog Brain Res 107:225–242

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  18. Zittel TT, De Giorgio R, Sternini C, Raybould HE (1994) Fos protein expression in the nucleus of the solitary tract in response to intestinal nutrients in awake rats. Brain Res 663:266–270

    Article  CAS  PubMed  Google Scholar 

  19. Campos CA, Shiina H, Silvas M, Page S, Ritter RC (2013) Vagal afferent NMDA receptors modulate CCK-induced reduction of food intake through synapsin I phosphorylation in adult male rats. Endocrinology 154:2613–2625

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Babic T, Townsend RL, Patterson LM, Sutton GM, Zheng H, Berthoud HR (2009) Phenotype of neurons in the nucleus of the solitary tract that express CCK-induced activation of the ERK signaling pathway. Am J Physiol Regul Integr Comp Physiol 296:R845–R854

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Sutton GM, Duos B, Patterson LM, Berthoud HR (2005) Melanocortinergic modulation of cholecystokinin-induced suppression of feeding through extracellular signal-regulated kinase signaling in rat solitary nucleus. Endocrinology 146:3739–3747

    Article  CAS  PubMed  Google Scholar 

  22. Seeley RJ, Grill HJ, Kaplan JM (1994) Neurological dissociation of gastrointestinal and metabolic contributions to meal size control. Behav Neurosci 108:347–352

    Article  CAS  PubMed  Google Scholar 

  23. Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA, Dakin CL, Wren AM, Brynes AE, Low MJ, Ghatei MA, Cone RD, Bloom SR (2002) Gut hormone PYY(3–36) physiologically inhibits food intake. Nature 418:650–654

    Article  CAS  PubMed  Google Scholar 

  24. Vincent KM, Sharp JW, Raybould HE (2011) Intestinal glucose-induced calcium-calmodulin kinase signaling in the gut–brain axis in awake rats. Neurogastroenterol Motil 23:e282–e293

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Davis JD, Smith GP (1990) Learning to sham feed: behavioral adjustments to loss of physiological postingestional stimuli. Am J Physiol 259:R1228–R1235

    CAS  PubMed  Google Scholar 

  26. Phillips RJ, Powley TL (1996) Gastric volume rather than nutrient content inhibits food intake. Am J Physiol 271:R766–R769

    CAS  PubMed  Google Scholar 

  27. Raybould HE, Gschossman JM, Ennes H, Lembo T, Mayer EA (1999) Involvement of stretch-sensitive calcium flux in mechanical transduction in visceral afferents. J Auton Nerv Syst 75:1–6

    Article  CAS  PubMed  Google Scholar 

  28. Raybould HE, Gayton RJ, Dockray GJ (1985) CNS effects of circulating CCK8: involvement of brainstem neurones responding to gastric distension. Brain Res 342:187–190

    Article  CAS  PubMed  Google Scholar 

  29. Cooke AR, Clark ED (1976) Effect of first part of duodenum on gastric emptying in dogs: response to acid, fat, glucose, and neural blockade. Gastroenterology 70:550–555

    CAS  PubMed  Google Scholar 

  30. Talsania T, Anini Y, Siu S, Drucker DJ, Brubaker PL (2005) Peripheral exendin-4 and peptide YY(3–36) synergistically reduce food intake through different mechanisms in mice. Endocrinology 146:3748–3756

    Article  CAS  PubMed  Google Scholar 

  31. Wickbom J, Herrington MK, Permert J, Jansson A, Arnelo U (2008) Gastric emptying in response to IAPP and CCK in rats with subdiaphragmatic afferent vagotomy. Regul Pept 148:21–25

    Article  CAS  PubMed  Google Scholar 

  32. Imeryuz N, Yegen BC, Bozkurt A, Coskun T, Villanueva-Penacarrillo ML, Ulusoy NB (1997) Glucagon-like peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms. Am J Physiol 273:G920–G927

    CAS  PubMed  Google Scholar 

  33. Reidelberger RD, Kalogeris TJ, Leung PM, Mendel VE (1983) Postgastric satiety in the sham-feeding rat. Am J Physiol 244:R872–R881

    CAS  PubMed  Google Scholar 

  34. Gibbs J, Maddison SP, Rolls ET (1981) Satiety role of the small intestine examined in sham-feeding rhesus monkeys. J Comp Physiol Psychol 95:1003–1015

    Article  CAS  PubMed  Google Scholar 

  35. Yox DP, Ritter RC (1988) Capsaicin attenuates suppression of sham feeding induced by intestinal nutrients. Am J Physiol 255:R569–R574

    CAS  PubMed  Google Scholar 

  36. Yox DP, Stokesberry H, Ritter RC (1991) Vagotomy attenuates suppression of sham feeding induced by intestinal nutrients. Am J Physiol 260:R503–R508

    CAS  PubMed  Google Scholar 

  37. Sclafani A, Ackroff K, Schwartz GJ (2003) Selective effects of vagal deafferentation and celiac-superior mesenteric ganglionectomy on the reinforcing and satiating action of intestinal nutrients. Physiol Behav 78:285–294

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  39. Cote CD, Zadeh-Tahmasebi M, Rasmussen BA, Duca FA, Lam TK (2014) Hormonal signaling in the gut. J Biol Chem 289:11642–11649

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Moriarty P, Dimaline R, Thompson DG, Dockray GJ (1997) Characterization of cholecystokinin A and cholecystokinin B receptors expressed by vagal afferent neurons. Neuroscience 79:905–913

    Article  CAS  PubMed  Google Scholar 

  41. Brenner L, Ritter RC (1995) Peptide cholesystokinin receptor antagonist increases food intake in rats. Appetite 24:1–9

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  43. Rinaman L (2003) Hindbrain noradrenergic lesions attenuate anorexia and alter central cFos expression in rats after gastric viscerosensory stimulation. J Neurosci 23:10084–10092

    CAS  PubMed  Google Scholar 

  44. Lechan RM, Fekete C (2006) The TRH neuron: a hypothalamic integrator of energy metabolism. Prog Brain Res 153:209–235

    Article  CAS  PubMed  Google Scholar 

  45. Brenner L, Yox DP, Ritter RC (1993) Suppression of sham feeding by intraintestinal nutrients is not correlated with plasma cholecystokinin elevation. Am J Physiol 264:R972–R976

    CAS  PubMed  Google Scholar 

  46. Liddle RA, Green GM, Conrad CK, Williams JA (1986) Proteins but not amino acids, carbohydrates, or fats stimulate cholecystokinin secretion in the rat. Am J Physiol 251:G243–G248

    CAS  PubMed  Google Scholar 

  47. Della-Fera MA, Baile CA (1980) CCK-octapeptide injected in CSF decreases meal size and daily food intake in sheep. Peptides 1:51–54

    Article  CAS  PubMed  Google Scholar 

  48. Schick RR, Stevens CW, Yaksh TL, Go VL (1988) Chronic intraventricular administration of cholecystokinin octapeptide (CCK-8) suppresses feeding in rats. Brain Res 448:294–298

    Article  CAS  PubMed  Google Scholar 

  49. Lo CC, Davidson WS, Hibbard SK, Georgievsky M, Lee A, Tso P, Woods SC (2014) Intraperitoneal CCK and fourth-intraventricular Apo AIV require both peripheral and NTS CCK1R to reduce food intake in male rats. Endocrinology 155:1700–1707

    Article  PubMed Central  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  51. Blevins JE, Hamel FG, Fairbairn E, Stanley BG, Reidelberger RD (2000) Effects of paraventricular nucleus injection of CCK-8 on plasma CCK-8 levels in rats. Brain Res 860:11–20

    Article  CAS  PubMed  Google Scholar 

  52. Beinfeld MC (2001) An introduction to neuronal cholecystokinin. Peptides 22:1197–1200

    Article  CAS  PubMed  Google Scholar 

  53. Sayegh AI (2013) The role of cholecystokinin receptors in the short-term control of food intake. Prog Mol Biol Transl Sci 114:277–316

    Article  CAS  PubMed  Google Scholar 

  54. Calingasan N, Ritter S, Ritter R, Brenner L (1992) Low-dose near-celiac arterial cholecystokinin suppresses food intake in rats. Am J Physiol 263:R572–R577

    CAS  PubMed  Google Scholar 

  55. Cox JE, McCown SM, Bridges JM, Tyler WJ (1996) Inhibition of sucrose intake by continuous celiac, superior mesenteric, and intravenous CCK-8 infusions. Am J Physiol 270:R319–R325

    CAS  PubMed  Google Scholar 

  56. Duca FA, Yue JT (2014) Fatty acid sensing in the gut and the hypothalamus: in vivo and in vitro perspectives. Mol Cell Endocrinol 397:23–33

    Article  CAS  PubMed  Google Scholar 

  57. Dube PE, Brubaker PL (2004) Nutrient, neural and endocrine control of glucagon-like peptide secretion. Horm Metab Res 36:755–760

    Article  CAS  PubMed  Google Scholar 

  58. Steinert RE, Beglinger C, Langhans W (2015) Intestinal GLP-1 and satiation-from man to rodents and back. Int J Obes (Lond). [Epub ahead of print]

  59. Elliott RM, Morgan LM, Tredger JA, Deacon S, Wright J, Marks V (1993) Glucagon-like peptide-1 (7–36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post-prandial and 24-h secretion patterns. J Endocrinol 138:159–166

    Article  CAS  PubMed  Google Scholar 

  60. Roberge JN, Brubaker PL (1993) Regulation of intestinal proglucagon-derived peptide secretion by glucose-dependent insulinotropic peptide in a novel enteroendocrine loop. Endocrinology 133:233–240

    CAS  PubMed  Google Scholar 

  61. Roberge JN, Gronau KA, Brubaker PL (1996) Gastrin-releasing peptide is a novel mediator of proximal nutrient-induced proglucagon-derived peptide secretion from the distal gut. Endocrinology 137:2383–2388

    CAS  PubMed  Google Scholar 

  62. Theodorakis MJ, Carlson O, Michopoulos S, Doyle ME, Juhaszova M, Petraki K, Egan JM (2006) Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP. Am J Physiol Endocrinol Metab 290:E550–E559

    Article  CAS  PubMed  Google Scholar 

  63. Svendsen B, Pedersen J, Albrechtsen NJ, Hartmann B, Torang S, Rehfeld JF, Poulsen SS, Holst JJ (2015) An analysis of cosecretion and coexpression of gut hormones from male rat proximal and distal small intestine. Endocrinology 156:847–857

    Article  CAS  PubMed  Google Scholar 

  64. Hayes MR, De Jonghe BC, Kanoski SE (2010) Role of the glucagon-like-peptide-1 receptor in the control of energy balance. Physiol Behav 100:503–510

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Williams DL (2009) Minireview: finding the sweet spot: peripheral versus central glucagon-like peptide 1 action in feeding and glucose homeostasis. Endocrinology 150:2997–3001

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Holst JJ (2007) The physiology of glucagon-like peptide 1. Physiol Rev 87:1409–1439

    Article  CAS  PubMed  Google Scholar 

  67. Nakagawa A, Satake H, Nakabayashi H, Nishizawa M, Furuya K, Nakano S, Kigoshi T, Nakayama K, Uchida K (2004) Receptor gene expression of glucagon-like peptide-1, but not glucose-dependent insulinotropic polypeptide, in rat nodose ganglion cells. Auton Neurosci 110:36–43

    Article  CAS  PubMed  Google Scholar 

  68. Kakei M, Yada T, Nakagawa A, Nakabayashi H (2002) Glucagon-like peptide-1 evokes action potentials and increases cytosolic Ca2+ in rat nodose ganglion neurons. Auton Neurosci 102:39–44

    Article  CAS  PubMed  Google Scholar 

  69. Abbott CR, Monteiro M, Small CJ, Sajedi A, Smith KL, Parkinson JR, Ghatei MA, Bloom SR (2005) The inhibitory effects of peripheral administration of peptide YY(3–36) and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal-brainstem-hypothalamic pathway. Brain Res 1044:127–131

    Article  CAS  PubMed  Google Scholar 

  70. Hayes MR, Kanoski SE, De Jonghe BC, Leichner TM, Alhadeff AL, Fortin SM, Arnold M, Langhans W, Grill HJ (2011) The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon-like-peptide-1. Am J Physiol Regul Integr Comp Physiol 301:R1479–R1485

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Ruttimann EB, Arnold M, Hillebrand JJ, Geary N, Langhans W (2009) Intrameal hepatic portal and intraperitoneal infusions of glucagon-like peptide-1 reduce spontaneous meal size in the rat via different mechanisms. Endocrinology 150:1174–1181

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Zhang J, Ritter RC (2012) Circulating GLP-1 and CCK-8 reduce food intake by capsaicin-insensitive, nonvagal mechanisms. Am J Physiol Regul Integr Comp Physiol 302:R264–R273

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. D’Alessio D, Lu W, Sun W, Zheng S, Yang Q, Seeley R, Woods SC, Tso P (2007) Fasting and postprandial concentrations of GLP-1 in intestinal lymph and portal plasma: evidence for selective release of GLP-1 in the lymph system. Am J Physiol Regul Integr Comp Physiol 293:R2163–R2169

    Article  PubMed  CAS  Google Scholar 

  74. Ohlsson L, Kohan AB, Tso P, Ahren B (2014) GLP-1 released to the mesenteric lymph duct in mice: effects of glucose and fat. Regul Pept 189:40–45

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Kohan A, Yoder S, Tso P (2010) Lymphatics in intestinal transport of nutrients and gastrointestinal hormones. Ann N Y Acad Sci 1207(Suppl 1):E44–E51

    Article  PubMed  Google Scholar 

  76. Larsen PJ, Tang-Christensen M, Holst JJ, Orskov C (1997) Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem. Neuroscience 77:257–270

    Article  CAS  PubMed  Google Scholar 

  77. Campos RV, Lee YC, Drucker DJ (1994) Divergent tissue-specific and developmental expression of receptors for glucagon and glucagon-like peptide-1 in the mouse. Endocrinology 134:2156–2164

    CAS  PubMed  Google Scholar 

  78. Turton MD, O’Shea D, Gunn I, Beak SA, Edwards CM, Meeran K, Choi SJ, Taylor GM, Heath MM, Lambert PD, Wilding JP, Smith DM, Ghatei MA, Herbert J, Bloom SR (1996) A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379:69–72

    Article  CAS  PubMed  Google Scholar 

  79. Tang-Christensen M, Larsen PJ, Goke R, Fink-Jensen A, Jessop DS, Moller M, Sheikh SP (1996) Central administration of GLP-1-(7–36) amide inhibits food and water intake in rats. Am J Physiol 271:R848–R856

    CAS  PubMed  Google Scholar 

  80. Williams DL, Baskin DG, Schwartz MW (2009) Evidence that intestinal glucagon-like peptide-1 plays a physiological role in satiety. Endocrinology 150:1680–1687

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Grill HJ, Hayes MR (2009) The nucleus tractus solitarius: a portal for visceral afferent signal processing, energy status assessment and integration of their combined effects on food intake. Int J Obes (Lond) 33(Suppl 1):S11–S15

    Article  CAS  Google Scholar 

  82. Plamboeck A, Veedfald S, Deacon CF, Hartmann B, Wettergren A, Svendsen LB, Meisner S, Hovendal C, Vilsboll T, Knop FK, Holst JJ (2013) The effect of exogenous GLP-1 on food intake is lost in male truncally vagotomized subjects with pyloroplasty. Am J Physiol Gastrointest Liver Physiol 304:G1117–G1127

    Article  CAS  PubMed  Google Scholar 

  83. Kanoski SE, Fortin SM, Arnold M, Grill HJ, Hayes MR (2011) Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, liraglutide and exendin-4. Endocrinology 152:3103–3112

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Pedersen-Bjergaard U, Host U, Kelbaek H, Schifter S, Rehfeld JF, Faber J, Christensen NJ (1996) Influence of meal composition on postprandial peripheral plasma concentrations of vasoactive peptides in man. Scand J Clin Lab Invest 56:497–503

    Article  CAS  PubMed  Google Scholar 

  85. Batterham RL, Heffron H, Kapoor S, Chivers JE, Chandarana K, Herzog H, Le Roux CW, Thomas EL, Bell JD, Withers DJ (2006) Critical role for peptide YY in protein-mediated satiation and body-weight regulation. Cell Metab 4:223–233

    Article  CAS  PubMed  Google Scholar 

  86. Rozengurt N, Wu SV, Chen MC, Huang C, Sternini C, Rozengurt E (2006) Colocalization of the alpha-subunit of gustducin with PYY and GLP-1 in L cells of human colon. Am J Physiol Gastrointest Liver Physiol 291:G792–G802

    Article  CAS  PubMed  Google Scholar 

  87. Fu-Cheng X, Anini Y, Chariot J, Castex N, Galmiche JP, Roze C (1997) Mechanisms of peptide YY release induced by an intraduodenal meal in rats: neural regulation by proximal gut. Pflugers Arch 433:571–579

    Article  CAS  PubMed  Google Scholar 

  88. Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, Ghatei MA, Bloom SR (2003) Inhibition of food intake in obese subjects by peptide YY3–36. N Engl J Med 349:941–948

    Article  CAS  PubMed  Google Scholar 

  89. Koda S, Date Y, Murakami N, Shimbara T, Hanada T, Toshinai K, Niijima A, Furuya M, Inomata N, Osuye K, Nakazato M (2005) The role of the vagal nerve in peripheral PYY3–36-induced feeding reduction in rats. Endocrinology 146:2369–2375

    Article  CAS  PubMed  Google Scholar 

  90. Halatchev IG, Cone RD (2005) Peripheral administration of PYY(3–36) produces conditioned taste aversion in mice. Cell Metab 1:159–168

    Article  CAS  PubMed  Google Scholar 

  91. Sainsbury A, Schwarzer C, Couzens M, Fetissov S, Furtinger S, Jenkins A, Cox HM, Sperk G, Hokfelt T, Herzog H (2002) Important role of hypothalamic Y2 receptors in body weight regulation revealed in conditional knockout mice. Proc Natl Acad Sci USA 99:8938–8943

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Broberger C, Landry M, Wong H, Walsh JN, Hokfelt T (1997) Subtypes Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in pro-opiomelanocortin- and neuropeptide-Y-containing neurons of the rat hypothalamic arcuate nucleus. Neuroendocrinology 66:393–408

    Article  CAS  PubMed  Google Scholar 

  93. King PJ, Williams G, Doods H, Widdowson PS (2000) Effect of a selective neuropeptide Y Y(2) receptor antagonist, BIIE0246 on neuropeptide Y release. Eur J Pharmacol 396:R1–R3

    Article  CAS  PubMed  Google Scholar 

  94. Li Y, Wu XY, Zhu JX, Owyang C (2001) Intestinal serotonin acts as paracrine substance to mediate pancreatic secretion stimulated by luminal factors. Am J Physiol Gastrointest Liver Physiol 281:G916–G923

    CAS  PubMed  Google Scholar 

  95. Li B, Shao D, Luo Y, Wang P, Liu C, Zhang X, Cui R (2015) Role of 5-HT3 receptor on food intake in fed and fasted mice. PLoS One 10:e0121473

    Article  PubMed Central  PubMed  Google Scholar 

  96. Halford JC, Lawton CL, Blundell JE (1997) The 5-HT2 receptor agonist MK-212 reduces food intake and increases resting but prevents the behavioural satiety sequence. Pharmacol Biochem Behav 56:41–46

    Article  CAS  PubMed  Google Scholar 

  97. Savastano DM, Hayes MR, Covasa M (2007) Serotonin-type 3 receptors mediate intestinal lipid-induced satiation and Fos-like immunoreactivity in the dorsal hindbrain. Am J Physiol Regul Integr Comp Physiol 292:R1063–R1070

    Article  CAS  PubMed  Google Scholar 

  98. Crane JD, Palanivel R, Mottillo EP, Bujak AL, Wang H, Ford RJ, Collins A, Blumer RM, Fullerton MD, Yabut JM, Kim JJ, Ghia JE, Hamza SM, Morrison KM, Schertzer JD, Dyck JR, Khan WI, Steinberg GR (2015) Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis. Nat Med 21:166–172

    Article  CAS  PubMed  Google Scholar 

  99. Fujimoto K, Cardelli JA, Tso P (1992) Increased apolipoprotein A-IV in rat mesenteric lymph after lipid meal acts as a physiological signal for satiation. Am J Physiol 262:G1002–G1006

    CAS  PubMed  Google Scholar 

  100. Sakata Y, Fujimoto K, Ogata S, Koyama T, Fukagawa K, Sakai T, Tso P (1996) Postabsorptive factors are important for satiation in rats after a lipid meal. Am J Physiol 271:G438–G442

    CAS  PubMed  Google Scholar 

  101. Raybould HE, Meyer JH, Tabrizi Y, Liddle RA, Tso P (1998) Inhibition of gastric emptying in response to intestinal lipid is dependent on chylomicron formation. Am J Physiol 274:R1834–R1838

    CAS  PubMed  Google Scholar 

  102. Lo CC, Langhans W, Georgievsky M, Arnold M, Caldwell JL, Cheng S, Liu M, Woods SC, Tso P (2012) Apolipoprotein AIV requires cholecystokinin and vagal nerves to suppress food intake. Endocrinology 153:5857–5865

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  103. Williams CM, Rogers PJ, Kirkham TC (1998) Hyperphagia in pre-fed rats following oral delta9-THC. Physiol Behav 65:343–346

    Article  CAS  PubMed  Google Scholar 

  104. Christopoulou FD, Kiortsis DN (2011) An overview of the metabolic effects of rimonabant in randomized controlled trials: potential for other cannabinoid 1 receptor blockers in obesity. J Clin Pharm Ther 36:10–18

    Article  CAS  PubMed  Google Scholar 

  105. Paulino G, Barbier de la Serre C, Knotts TA, Oort PJ, Newman JW, Adams SH, Raybould HE (2009) Increased expression of receptors for orexigenic factors in nodose ganglion of diet-induced obese rats. Am J Physiol Endocrinol Metab 296:E898–E903

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  106. Gomez R, Navarro M, Ferrer B, Trigo JM, Bilbao A, Del Arco I, Cippitelli A, Nava F, Piomelli D, Rodriguez de Fonseca F (2002) A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J Neurosci 22:9612–9617

    CAS  PubMed  Google Scholar 

  107. Kentish SJ, Page AJ (2015) The role of gastrointestinal vagal afferent fibres in obesity. J Physiol 593:775–786

    Article  CAS  PubMed  Google Scholar 

  108. Fioravanti B, De Felice M, Stucky CL, Medler KA, Luo MC, Gardell LR, Ibrahim M, Malan TP Jr, Yamamura HI, Ossipov MH, King T, Lai J, Porreca F, Vanderah TW (2008) Constitutive activity at the cannabinoid CB1 receptor is required for behavioral response to noxious chemical stimulation of TRPV1: antinociceptive actions of CB1 inverse agonists. J Neurosci 28:11593–11602

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  109. Barbara G, Wang B, Stanghellini V, de Giorgio R, Cremon C, Di Nardo G, Trevisani M, Campi B, Geppetti P, Tonini M, Bunnett NW, Grundy D, Corinaldesi R (2007) Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome. Gastroenterology 132:26–37

    Article  CAS  PubMed  Google Scholar 

  110. Watkins LR, Maier SF, Goehler LE (1995) Cytokine-to-brain communication: a review & analysis of alternative mechanisms. Life Sci 57:1011–1026

    Article  CAS  PubMed  Google Scholar 

  111. McDermott JR, Leslie FC, D’Amato M, Thompson DG, Grencis RK, McLaughlin JT (2006) Immune control of food intake: enteroendocrine cells are regulated by CD4+ T lymphocytes during small intestinal inflammation. Gut 55:492–497

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  112. Everard A, Lazarevic V, Derrien M, Girard M, Muccioli GG, Neyrinck AM, Possemiers S, Van Holle A, Francois P, de Vos WM, Delzenne NM, Schrenzel J, Cani PD (2011) Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes 60:2775–2786

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  113. Bucinskaite V, Kurosawa M, Miyasaka K, Funakoshi A, Lundeberg T (1997) Interleukin-1beta sensitizes the response of the gastric vagal afferent to cholecystokinin in rat. Neurosci Lett 229:33–36

    Article  CAS  PubMed  Google Scholar 

  114. Gaige S, Abou E, Abysique A, Bouvier M (2004) Effects of interactions between interleukin-1 beta and leptin on cat intestinal vagal mechanoreceptors. J Physiol 555:297–310

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  115. Pavlov VA, Tracey KJ (2012) The vagus nerve and the inflammatory reflex—linking immunity and metabolism. Nat Rev Endocrinol 8:743–754

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  116. Ravussin E, Lillioja S, Knowler WC, Christin L, Freymond D, Abbott WG, Boyce V, Howard BV, Bogardus C (1988) Reduced rate of energy expenditure as a risk factor for body-weight gain. N Engl J Med 318:467–472

    Article  CAS  PubMed  Google Scholar 

  117. Griffiths M, Payne PR, Stunkard AJ, Rivers JP, Cox M (1990) Metabolic rate and physical development in children at risk of obesity. Lancet 336:76–78

    Article  CAS  PubMed  Google Scholar 

  118. Christiansen E, Garby L (2002) Prediction of body weight changes caused by changes in energy balance. Eur J Clin Invest 32:826–830

    Article  CAS  PubMed  Google Scholar 

  119. Westerterp KR (2004) Diet induced thermogenesis. Nutr Metab (Lond) 1:5

    Article  CAS  Google Scholar 

  120. Lowell BB, Spiegelman BM (2000) Towards a molecular understanding of adaptive thermogenesis. Nature 404:652–660

    CAS  PubMed  Google Scholar 

  121. Hwa JJ, Ghibaudi L, Williams P, Witten MB, Tedesco R, Strader CD (1998) Differential effects of intracerebroventricular glucagon-like peptide-1 on feeding and energy expenditure regulation. Peptides 19:869–875

    Article  CAS  PubMed  Google Scholar 

  122. Dakin CL, Small CJ, Park AJ, Seth A, Ghatei MA, Bloom SR (2002) Repeated ICV administration of oxyntomodulin causes a greater reduction in body weight gain than in pair-fed rats. Am J Physiol Endocrinol Metab 283:E1173–E1177

    Article  CAS  PubMed  Google Scholar 

  123. Sloth B, Holst JJ, Flint A, Gregersen NT, Astrup A (2007) 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 292:E1062–E1068

    Article  CAS  PubMed  Google Scholar 

  124. Blouet C, Schwartz GJ (2012) Duodenal lipid sensing activates vagal afferents to regulate non-shivering brown fat thermogenesis in rats. PLoS One 7:e51898

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  125. Lockie SH, Heppner KM, Chaudhary N, Chabenne JR, Morgan DA, Veyrat-Durebex C, Ananthakrishnan G, Rohner-Jeanrenaud F, Drucker DJ, DiMarchi R, Rahmouni K, Oldfield BJ, Tschop MH, Perez-Tilve D (2012) Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling. Diabetes 61:2753–2762

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  126. Fang S, Suh JM, Reilly SM, Yu E, Osborn O, Lackey D, Yoshihara E, Perino A, Jacinto S, Lukasheva Y, Atkins AR, Khvat A, Schnabl B, Yu RT, Brenner DA, Coulter S, Liddle C, Schoonjans K, Olefsky JM, Saltiel AR, Downes M, Evans RM (2015) Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 21:159–165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Berteus Forslund H, Lindroos AK, Sjostrom L, Lissner L (2002) Meal patterns and obesity in Swedish women-a simple instrument describing usual meal types, frequency and temporal distribution. Eur J Clin Nutr 56:740–747

    Article  CAS  PubMed  Google Scholar 

  128. Berg C, Lappas G, Wolk A, Strandhagen E, Toren K, Rosengren A, Thelle D, Lissner L (2009) Eating patterns and portion size associated with obesity in a Swedish population. Appetite 52:21–26

    Article  PubMed  Google Scholar 

  129. Papadimitriou MA, Krzemien AA, Hahn PM, Van Vugt DA (2007) Peptide YY(3–36)-induced inhibition of food intake in female monkeys. Brain Res 1175:60–65

    Article  CAS  PubMed  Google Scholar 

  130. Orskov C, Rabenhoj L, Wettergren A, Kofod H, Holst JJ (1994) Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans. Diabetes 43:535–539

    Article  CAS  PubMed  Google Scholar 

  131. Baranowska B, Radzikowska M, Wasilewska-Dziubinska E, Roguski K, Borowiec M (2000) Disturbed release of gastrointestinal peptides in anorexia nervosa and in obesity. Diabetes Obes Metab 2:99–103

    Article  CAS  PubMed  Google Scholar 

  132. Xu J, McNearney TA, Chen JD (2011) Impaired postprandial releases/syntheses of ghrelin and PYY(3–36) and blunted responses to exogenous ghrelin and PYY(3–36) in a rodent model of diet-induced obesity. J Gastroenterol Hepatol 26:700–705

    Article  CAS  PubMed  Google Scholar 

  133. Duca FA, Sakar Y, Covasa M (2013) Combination of obesity and high-fat feeding diminishes sensitivity to GLP-1R agonist exendin-4. Diabetes 62:2410–2415

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  134. Covasa M, Ritter RC (1998) Rats maintained on high-fat diets exhibit reduced satiety in response to CCK and bombesin. Peptides 19:1407–1415

    Article  CAS  PubMed  Google Scholar 

  135. Donovan MJ, Paulino G, Raybould HE (2009) Activation of hindbrain neurons in response to gastrointestinal lipid is attenuated by high fat, high energy diets in mice prone to diet-induced obesity. Brain Res 1248:136–140

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  136. Daly DM, Park SJ, Valinsky WC, Beyak MJ (2011) Impaired intestinal afferent nerve satiety signalling and vagal afferent excitability in diet induced obesity in the mouse. J Physiol 589:2857–2870

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  137. Duca FA, Covasa M (2012) Current and emerging concepts on the role of peripheral signals in the control of food intake and development of obesity. Br J Nutr 108:778–793

    Article  CAS  PubMed  Google Scholar 

  138. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI (2007) The human microbiome project. Nature 449:804–810

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  139. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Zheng H, Xie Y, Tap J, Lepage P, Bertalan M, Batto JM, Hansen T, Le Paslier D, Linneberg A, Nielsen HB, Pelletier E, Renault P, Sicheritz-Ponten T, Turner K, Zhu H, Yu C, Li S, Jian M, Zhou Y, Li Y, Zhang X, Li S, Qin N, Yang H, Wang J, Brunak S, Dore J, Guarner F, Kristiansen K, Pedersen O, Parkhill J, Weissenbach J, Meta HITC, Bork P, Ehrlich SD, Wang J (2010) A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464:59–65

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  140. Wostmann BS, Larkin C, Moriarty A, Bruckner-Kardoss E (1983) Dietary intake, energy metabolism, and excretory losses of adult male germfree Wistar rats. Lab Anim Sci 33:46–50

    CAS  PubMed  Google Scholar 

  141. Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI (2004) The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 101:15718–15723

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  142. Backhed F, Manchester JK, Semenkovich CF, Gordon JI (2007) Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci USA 104:979–984

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  143. Hoverstad T, Midtvedt T (1986) Short-chain fatty acids in germfree mice and rats. J Nutr 116:1772–1776

    CAS  PubMed  Google Scholar 

  144. Al-Asmakh M, Zadjali F (2015) Use of germ-free animal models in microbiota-related research. J Microbiol Biotechnol 25:1583–1588

    Article  PubMed  Google Scholar 

  145. Smith K, McCoy KD, Macpherson AJ (2007) Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin Immunol 19:59–69

    Article  CAS  PubMed  Google Scholar 

  146. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA, Biddinger SB, Dutton RJ, Turnbaugh PJ (2014) Diet rapidly and reproducibly alters the human gut microbiome. Nature 505:559–563

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  147. Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI (2009) The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med 1:6ra14

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  148. Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI (2005) Obesity alters gut microbial ecology. Proc Natl Acad Sci USA 102:11070–11075

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  149. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI (2009) A core gut microbiome in obese and lean twins. Nature 457:480–484

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  150. Furet JP, Kong LC, Tap J, Poitou C, Basdevant A, Bouillot JL, Mariat D, Corthier G, Dore J, Henegar C, Rizkalla S, Clement K (2010) Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes 59:3049–3057

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  151. Ley RE, Turnbaugh PJ, Klein S, Gordon JI (2006) Microbial ecology: human gut microbes associated with obesity. Nature 444:1022–1023

    Article  CAS  PubMed  Google Scholar 

  152. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI (2006) An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444:1027–1031

    Article  PubMed  Google Scholar 

  153. Duncan SH, Lobley GE, Holtrop G, Ince J, Johnstone AM, Louis P, Flint HJ (2008) Human colonic microbiota associated with diet, obesity and weight loss. Int J Obes (Lond) 32:1720–1724

    Article  CAS  Google Scholar 

  154. Zhang H, DiBaise JK, Zuccolo A, Kudrna D, Braidotti M, Yu Y, Parameswaran P, Crowell MD, Wing R, Rittmann BE, Krajmalnik-Brown R (2009) Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci USA 106:2365–2370

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  155. Duca FA, Sakar Y, Lepage P, Devime F, Langelier B, Dore J, Covasa M (2014) Replication of obesity and associated signaling pathways through transfer of microbiota from obese-prone rats. Diabetes 63:1624–1636

    Article  CAS  PubMed  Google Scholar 

  156. Murphy EF, Cotter PD, Healy S, Marques TM, O’Sullivan O, Fouhy F, Clarke SF, O’Toole PW, Quigley EM, Stanton C, Ross PR, O’Doherty RM, Shanahan F (2010) Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models. Gut 59:1635–1642

    Article  CAS  PubMed  Google Scholar 

  157. Tims S, Derom C, Jonkers DM, Vlietinck R, Saris WH, Kleerebezem M, de Vos WM, Zoetendal EG (2013) Microbiota conservation and BMI signatures in adult monozygotic twins. ISME J 7:707–717

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  158. Everard A, Cani PD (2013) Diabetes, obesity and gut microbiota. Best Pract Res Clin Gastroenterol 27:73–83

    Article  CAS  PubMed  Google Scholar 

  159. Reimann F, Tolhurst G, Gribble FM (2012) G-protein-coupled receptors in intestinal chemosensation. Cell Metab 15:421–431

    Article  CAS  PubMed  Google Scholar 

  160. Samuel BS, Shaito A, Motoike T, Rey FE, Backhed F, Manchester JK, Hammer RE, Williams SC, Crowley J, Yanagisawa M, Gordon JI (2008) Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc Natl Acad Sci USA 105:16767–16772

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  161. Schwiertz A, Taras D, Schafer K, Beijer S, Bos NA, Donus C, Hardt PD (2010) Microbiota and SCFA in lean and overweight healthy subjects. Obesity (Silver Spring) 18:190–195

    Article  Google Scholar 

  162. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS, Mackay F, Artis D, Xavier RJ, Teixeira MM, Mackay CR (2009) Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461:1282–1286

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  163. Fernandes J, Su W, Rahat-Rozenbloom S, Wolever TM, Comelli EM (2014) Adiposity, gut microbiota and faecal short chain fatty acids are linked in adult humans. Nutr Diabetes 4:e121

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  164. Fava F, Gitau R, Griffin BA, Gibson GR, Tuohy KM, Lovegrove JA (2013) The type and quantity of dietary fat and carbohydrate alter faecal microbiome and short-chain fatty acid excretion in a metabolic syndrome ‘at-risk’ population. Int J Obes (Lond) 37:216–223

    Article  CAS  Google Scholar 

  165. Pan XD, Chen FQ, Wu TX, Tang HG, Zhao ZY (2009) Prebiotic oligosaccharides change the concentrations of short-chain fatty acids and the microbial population of mouse bowel. J Zhejiang Univ Sci B 10:258–263

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  166. Liou AP, Paziuk M, Luevano JM Jr, Machineni S, Turnbaugh PJ, Kaplan LM (2013) Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Transl Med 5:178ra141

    Article  CAS  Google Scholar 

  167. Cani PD, Daubioul CA, Reusens B, Remacle C, Catillon G, Delzenne NM (2005) Involvement of endogenous glucagon-like peptide-1(7–36) amide on glycaemia-lowering effect of oligofructose in streptozotocin-treated rats. J Endocrinol 185:457–465

    Article  CAS  PubMed  Google Scholar 

  168. Chambers ES, Viardot A, Psichas A, Morrison DJ, Murphy KG, Zac-Varghese SE, MacDougall K, Preston T, Tedford C, Finlayson GS, Blundell JE, Bell JD, Thomas EL, Mt-Isa S, Ashby D, Gibson GR, Kolida S, Dhillo WS, Bloom SR, Morley W, Clegg S, Frost G (2015) Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut 64:1744–1754

    Article  PubMed Central  PubMed  Google Scholar 

  169. den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud DJ, Bakker BM (2013) The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res 54:2325–2340

    Article  CAS  Google Scholar 

  170. Lin HV, Frassetto A, Kowalik EJ Jr, Nawrocki AR, Lu MM, Kosinski JR, Hubert JA, Szeto D, Yao X, Forrest G, Marsh DJ (2012) Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS One 7:e35240

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  171. Puddu A, Sanguineti R, Montecucco F, Viviani GL (2014) Evidence for the gut microbiota short-chain fatty acids as key pathophysiological molecules improving diabetes. Mediators Inflamm 2014:162021

    PubMed Central  PubMed  Google Scholar 

  172. Gao Z, Yin J, Zhang J, Ward RE, Martin RJ, Lefevre M, Cefalu WT, Ye J (2009) Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 58:1509–1517

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  173. Frost G, Sleeth ML, Sahuri-Arisoylu M, Lizarbe B, Cerdan S, Brody L, Anastasovska J, Ghourab S, Hankir M, Zhang S, Carling D, Swann JR, Gibson G, Viardot A, Morrison D, Louise Thomas E, Bell JD (2014) The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat Commun 5:3611

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  174. Freeland KR, Wolever TM (2010) Acute effects of intravenous and rectal acetate on glucagon-like peptide-1, peptide YY, ghrelin, adiponectin and tumour necrosis factor-alpha. Br J Nutr 103:460–466

    Article  CAS  PubMed  Google Scholar 

  175. Le Poul E, Loison C, Struyf S, Springael JY, Lannoy V, Decobecq ME, Brezillon S, Dupriez V, Vassart G, Van Damme J, Parmentier M, Detheux M (2003) Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem 278:25481–25489

    Article  PubMed  CAS  Google Scholar 

  176. Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, Muir AI, Wigglesworth MJ, Kinghorn I, Fraser NJ, Pike NB, Strum JC, Steplewski KM, Murdock PR, Holder JC, Marshall FH, Szekeres PG, Wilson S, Ignar DM, Foord SM, Wise A, Dowell SJ (2003) The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem 278:11312–11319

    Article  CAS  PubMed  Google Scholar 

  177. Kasubuchi M, Hasegawa S, Hiramatsu T, Ichimura A, Kimura I (2015) Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation. Nutrients 7:2839–2849

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  178. Tazoe H, Otomo Y, Karaki S, Kato I, Fukami Y, Terasaki M, Kuwahara A (2009) Expression of short-chain fatty acid receptor GPR41 in the human colon. Biomed Res 30:149–156

    Article  CAS  PubMed  Google Scholar 

  179. Karaki S, Tazoe H, Hayashi H, Kashiwabara H, Tooyama K, Suzuki Y, Kuwahara A (2008) Expression of the short-chain fatty acid receptor, GPR43, in the human colon. J Mol Histol 39:135–142

    Article  CAS  PubMed  Google Scholar 

  180. Karaki S, Mitsui R, Hayashi H, Kato I, Sugiya H, Iwanaga T, Furness JB, Kuwahara A (2006) Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine. Cell Tissue Res 324:353–360

    Article  CAS  PubMed  Google Scholar 

  181. Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM, Diakogiannaki E, Cameron J, Grosse J, Reimann F, Gribble FM (2012) Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61:364–371

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  182. Tang C, Ahmed K, Gille A, Lu S, Grone HJ, Tunaru S, Offermanns S (2015) Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes. Nat Med 21:173–177

    Article  CAS  PubMed  Google Scholar 

  183. Nohr MK, Egerod KL, Christiansen SH, Gille A, Offermanns S, Schwartz TW, Moller M (2015) Expression of the short chain fatty acid receptor GPR41/FFAR3 in autonomic and somatic sensory ganglia. Neuroscience 290:126–137

    Article  CAS  PubMed  Google Scholar 

  184. Nohr MK, Pedersen MH, Gille A, Egerod KL, Engelstoft MS, Husted AS, Sichlau RM, Grunddal KV, Poulsen SS, Han S, Jones RM, Offermanns S, Schwartz TW (2013) GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine cells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes. Endocrinology 154:3552–3564

    Article  PubMed  CAS  Google Scholar 

  185. Duca FA, Swartz TD, Sakar Y, Covasa M (2012) Increased oral detection, but decreased intestinal signaling for fats in mice lacking gut microbiota. PLoS One 7:e39748

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  186. Swartz TD, Duca FA, de Wouters T, Sakar Y, Covasa M (2012) Up-regulation of intestinal type 1 taste receptor 3 and sodium glucose luminal transporter-1 expression and increased sucrose intake in mice lacking gut microbiota. Br J Nutr 107:621–630

    Article  CAS  PubMed  Google Scholar 

  187. Fredborg M, Theil PK, Jensen BB, Purup S (2012) G protein-coupled receptor120 (GPR120) transcription in intestinal epithelial cells is significantly affected by bacteria belonging to the Bacteroides, Proteobacteria, and Firmicutes phyla. J Anim Sci 90(Suppl 4):10–12

    Article  PubMed  Google Scholar 

  188. Dewulf EM, Cani PD, Claus SP, Fuentes S, Puylaert PG, Neyrinck AM, Bindels LB, de Vos WM, Gibson GR, Thissen JP, Delzenne NM (2013) Insight into the prebiotic concept: lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women. Gut 62:1112–1121

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  189. Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, Geurts L, Naslain D, Neyrinck A, Lambert DM, Muccioli GG, Delzenne NM (2009) Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 58:1091–1103

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  190. Neyrinck AM, Van Hee VF, Piront N, De Backer F, Toussaint O, Cani PD, Delzenne NM (2012) Wheat-derived arabinoxylan oligosaccharides with prebiotic effect increase satietogenic gut peptides and reduce metabolic endotoxemia in diet-induced obese mice. Nutr Diabetes 2:e28

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  191. Cani PD, Neyrinck AM, Maton N, Delzenne NM (2005) Oligofructose promotes satiety in rats fed a high-fat diet: involvement of glucagon-like Peptide-1. Obes Res 13:1000–1007

    Article  CAS  PubMed  Google Scholar 

  192. Cani PD, Dewever C, Delzenne NM (2004) Inulin-type fructans modulate gastrointestinal peptides involved in appetite regulation (glucagon-like peptide-1 and ghrelin) in rats. Br J Nutr 92:521–526

    Article  CAS  PubMed  Google Scholar 

  193. Cani PD, Joly E, Horsmans Y, Delzenne NM (2006) Oligofructose promotes satiety in healthy human: a pilot study. Eur J Clin Nutr 60:567–572

    Article  CAS  PubMed  Google Scholar 

  194. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmee E, Cousin B, Sulpice T, Chamontin B, Ferrieres J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56:1761–1772

    Article  CAS  PubMed  Google Scholar 

  195. de La Serre CB, Ellis CL, Lee J, Hartman AL, Rutledge JC, Raybould HE (2010) Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation. Am J Physiol Gastrointest Liver Physiol 299:G440–G448

    Article  CAS  Google Scholar 

  196. Caesar R, Tremaroli V, Kovatcheva-Datchary P, Cani PD, Backhed F (2015) Crosstalk between gut microbiota and dietary lipids aggravates WAT inflammation through TLR signaling. Cell Metab 22:658–668

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  197. Everard A, Geurts L, Caesar R, Van Hul M, Matamoros S, Duparc T, Denis RG, Cochez P, Pierard F, Castel J, Bindels LB, Plovier H, Robine S, Muccioli GG, Renauld JC, Dumoutier L, Delzenne NM, Luquet S, Backhed F, Cani PD (2014) Intestinal epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional status. Nat Commun 5:5648

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  198. Zuo DC, Choi S, Shahi PK, Kim MY, Park CG, Kim YD, Lee J, Chang IY, So I, Jun JY (2013) Inhibition of pacemaker activity in interstitial cells of Cajal by LPS via NF-kappaB and MAP kinase. World J Gastroenterol 19:1210–1218

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  199. Hosoi T, Okuma Y, Matsuda T, Nomura Y (2005) Novel pathway for LPS-induced afferent vagus nerve activation: possible role of nodose ganglion. Auton Neurosci 120:104–107

    Article  CAS  PubMed  Google Scholar 

  200. de Lartigue G, Barbier de la Serre C, Espero E, Lee J, Raybould HE (2011) Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons. Am J Physiol Endocrinol Metab 301:E187–E195

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  201. de La Serre CB, de Lartigue G, Raybould HE (2015) Chronic exposure to low dose bacterial lipopolysaccharide inhibits leptin signaling in vagal afferent neurons. Physiol Behav 139:188–194

    Article  CAS  Google Scholar 

  202. de Lartigue G, Barbier de la Serre C, Espero E, Lee J, Raybould HE (2012) Leptin resistance in vagal afferent neurons inhibits cholecystokinin signaling and satiation in diet induced obese rats. PLoS One 7:e32967

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  203. Diaz Heijtz R, Wang S, Anuar F, Qian Y, Bjorkholm B, Samuelsson A, Hibberd ML, Forssberg H, Pettersson S (2011) Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci USA 108:3047–3052

    Article  PubMed  Google Scholar 

  204. Gareau MG, Wine E, Rodrigues DM, Cho JH, Whary MT, Philpott DJ, Macqueen G, Sherman PM (2011) Bacterial infection causes stress-induced memory dysfunction in mice. Gut 60:307–317

    Article  PubMed  Google Scholar 

  205. Neufeld KM, Kang N, Bienenstock J, Foster JA (2011) Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil 23(255–264):e119

    Google Scholar 

  206. Bercik P, Verdu EF, Foster JA, Macri J, Potter M, Huang X, Malinowski P, Jackson W, Blennerhassett P, Neufeld KA, Lu J, Khan WI, Corthesy-Theulaz I, Cherbut C, Bergonzelli GE, Collins SM (2010) Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology 139(2102–2112):e2101

    Google Scholar 

  207. Steenbergen L, Sellaro R, van Hemert S, Bosch JA, Colzato LS (2015) A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav Immun 48:258–264

    Article  PubMed  Google Scholar 

  208. Ait-Belgnaoui A, Durand H, Cartier C, Chaumaz G, Eutamene H, Ferrier L, Houdeau E, Fioramonti J, Bueno L, Theodorou V (2012) Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats. Psychoneuroendocrinology 37:1885–1895

    Article  CAS  PubMed  Google Scholar 

  209. Schele E, Grahnemo L, Anesten F, Hallen A, Backhed F, Jansson JO (2013) The gut microbiota reduces leptin sensitivity and the expression of the obesity-suppressing neuropeptides proglucagon (Gcg) and brain-derived neurotrophic factor (Bdnf) in the central nervous system. Endocrinology 154:3643–3651

    Article  CAS  PubMed  Google Scholar 

  210. Mumphrey MB, Patterson LM, Zheng H, Berthoud HR (2013) Roux-en-Y gastric bypass surgery increases number but not density of CCK-, GLP-1-, 5-HT-, and neurotensin-expressing enteroendocrine cells in rats. Neurogastroenterol Motil 25:e70–e79

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  211. Madsbad S, Krarup T, Deacon CF, Holst JJ (2008) Glucagon-like peptide receptor agonists and dipeptidyl peptidase-4 inhibitors in the treatment of diabetes: a review of clinical trials. Curr Opin Clin Nutr Metab Care 11:491–499

    Article  CAS  PubMed  Google Scholar 

  212. Irwin N, Montgomery IA, Moffett RC, Flatt PR (2013) Chemical cholecystokinin receptor activation protects against obesity-diabetes in high fat fed mice and has sustainable beneficial effects in genetic ob/ob mice. Biochem Pharmacol 85:81–91

    Article  CAS  PubMed  Google Scholar 

  213. Irwin N, Frizelle P, O’Harte FP, Flatt PR (2013) (pGlu-Gln)-CCK-8[mPEG]: a novel, long-acting, mini-PEGylated cholecystokinin (CCK) agonist that improves metabolic status in dietary-induced diabetes. Biochim Biophys Acta 1830:4009–4016

    Article  CAS  PubMed  Google Scholar 

  214. van Bloemendaal L, IJzerman RG, Ten Kulve JS, Barkhof F, Konrad RJ, Drent ML, Veltman DJ, Diamant M (2014) GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans. Diabetes 63:4186–4196

    Article  PubMed  CAS  Google Scholar 

  215. Yang Y, Moghadam AA, Cordner ZA, Liang NC, Moran TH (2014) Long term exendin-4 treatment reduces food intake and body weight and alters expression of brain homeostatic and reward markers. Endocrinology 155:3473–3483

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  216. Finan B, Yang B, Ottaway N, Smiley DL, Ma T, Clemmensen C, Chabenne J, Zhang L, Habegger KM, Fischer K, Campbell JE, Sandoval D, Seeley RJ, Bleicher K, Uhles S, Riboulet W, Funk J, Hertel C, Belli S, Sebokova E, Conde-Knape K, Konkar A, Drucker DJ, Gelfanov V, Pfluger PT, Muller TD, Perez-Tilve D, DiMarchi RD, Tschop MH (2015) A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med 21:27–36

    Article  CAS  PubMed  Google Scholar 

  217. Osto M, Abegg K, Bueter M, le Roux CW, Cani PD, Lutz TA (2013) Roux-en-Y gastric bypass surgery in rats alters gut microbiota profile along the intestine. Physiol Behav 119:92–96

    Article  CAS  PubMed  Google Scholar 

  218. Casselbrant A, Elias E, Fandriks L, Wallenius V (2015) Expression of tight-junction proteins in human proximal small intestinal mucosa before and after Roux-en-Y gastric bypass surgery. Surg Obes Relat Dis 11:45–53

    Article  PubMed  Google Scholar 

  219. Tremaroli V, Karlsson F, Werling M, Stahlman M, Kovatcheva-Datchary P, Olbers T, Fandriks L, le Roux CW, Nielsen J, Backhed F (2015) Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation. Cell Metab 22:228–238

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  220. Dubos R, Schaedler RW, Costello RL (1963) The effect of antibacterial drugs on the weight of mice. J Exp Med 117:245–257

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  221. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R (2008) Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57:1470–1481

    Article  CAS  PubMed  Google Scholar 

  222. Nobel YR, Cox LM, Kirigin FF, Bokulich NA, Yamanishi S, Teitler I, Chung J, Sohn J, Barber CM, Goldfarb DS, Raju K, Abubucker S, Zhou Y, Ruiz VE, Li H, Mitreva M, Alekseyenko AV, Weinstock GM, Sodergren E, Blaser MJ (2015) Metabolic and metagenomic outcomes from early-life pulsed antibiotic treatment. Nat Commun 6:7486

    Article  PubMed Central  PubMed  Google Scholar 

  223. Cox LM, Yamanishi S, Sohn J, Alekseyenko AV, Leung JM, Cho I, Kim SG, Li H, Gao Z, Mahana D, Zarate Rodriguez JG, Rogers AB, Robine N, Loke P, Blaser MJ (2014) Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 158:705–721

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  224. Cox LM, Blaser MJ (2013) Pathways in microbe-induced obesity. Cell Metab 17:883–894

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  225. Cho I, Yamanishi S, Cox L, Methe BA, Zavadil J, Li K, Gao Z, Mahana D, Raju K, Teitler I, Li H, Alekseyenko AV, Blaser MJ (2012) Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 488:621–626

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  226. Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, Sitaraman SV, Knight R, Ley RE, Gewirtz AT (2010) Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328:228–231

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  227. Tomasik PJ, Sztefko K (2009) The effect of enteral and parenteral feeding on secretion of orexigenic peptides in infants. BMC Gastroenterol 9:92

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  228. De Palma G, Blennerhassett P, Lu J, Deng Y, Park AJ, Green W, Denou E, Silva MA, Santacruz A, Sanz Y, Surette MG, Verdu EF, Collins SM, Bercik P (2015) Microbiota and host determinants of behavioural phenotype in maternally separated mice. Nat Commun 6:7735

    Article  PubMed  CAS  Google Scholar 

  229. Alang N, Kelly CR (2015) Weight gain after fecal microbiota transplantation. Open Forum Infect Dis 2:ofv004

    Article  PubMed Central  PubMed  Google Scholar 

  230. Vrieze A, Van Nood E, Holleman F, Salojarvi J, Kootte RS, Bartelsman JF, Dallinga-Thie GM, Ackermans MT, Serlie MJ, Oozeer R, Derrien M, Druesne A, Van Hylckama Vlieg JE, Bloks VW, Groen AK, Heilig HG, Zoetendal EG, Stroes ES, de Vos WM, Hoekstra JB, Nieuwdorp M (2012) Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143(913–916):e917

    Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Toronto General Research Institute, UHN, Toronto, ON, M5G 1L7, Canada

    Paige V. Bauer, Sophie C. Hamr & Frank A. Duca

  2. Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8, Canada

    Paige V. Bauer & Sophie C. Hamr

  3. MaRS Centre, Toronto Medical Discovery Tower, Room 10-701H, 101 College Street, Toronto, ON, M5G 1L7, Canada

    Frank A. Duca

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  1. Paige V. Bauer
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  2. Sophie C. Hamr
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Bauer, P.V., Hamr, S.C. & Duca, F.A. Regulation of energy balance by a gut–brain axis and involvement of the gut microbiota. Cell. Mol. Life Sci. 73, 737–755 (2016). https://doi.org/10.1007/s00018-015-2083-z

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