Gut-Brain Cross-Talk in Metabolic Control

Cell

Volumn 168, Issue 5, 2017, Pages 758-774

  Clemmensen, Christoffer ^a,b   Müller, Timo D ^a,b   Woods, Stephen C ^c   Berthoud, Hans Rudolf ^d   Seeley, Randy J ^e   Tschöp, Matthias H ^a,b  

^a Institute for Diabetes and Obesity   (United Kingdom)

^b TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^c UNIVERSITY OF CINCINNATI   (United States)

^d PENNINGTON BIOMEDICAL RESEARCH CENTER   (United States)

^e UNIVERSITY OF MICHIGAN   (United States)

Author keywords

appetite; bariatric surgery; brain; diabetes; energy balance; gut; metabolic syndrome; obesity; pharmacology; satiety

Indexed keywords

AMYLIN; BILE ACID; CANNABINOID 1 RECEPTOR; CHOLECYSTOKININ; FIBROBLAST GROWTH FACTOR 19; FIBROBLAST GROWTH FACTOR 21; GHRELIN; GLUCAGON; GLUCAGON LIKE PEPTIDE 1; LEPTIN; MELANOCORTIN; NEUROTENSIN; PEPTIDE YY; THYROID HORMONE;

ADAPTATION; APPETITE; ARCUATE NUCLEUS; BARIATRIC SURGERY; BODY WEIGHT; BRAIN FUNCTION; COMORBIDITY; DESENSITIZATION; DIET INDUCED OBESITY; ENERGY BALANCE; ENERGY METABOLISM; ENTEROENDOCRINE CELL; EPIGENETICS; FEEDING BEHAVIOR; GASTROINTESTINAL TRACT; GASTROINTESTINAL TRACT FUNCTION; GUT BRAIN CROSS TALK; HOMEOSTASIS; HORMONE ACTION; HUMAN; INHERITANCE; INTESTINE FLORA; INTESTINE FUNCTION; INTESTINE INNERVATION; LEAN BODY WEIGHT; LIFESTYLE; LIVER FUNCTION; METABOLIC DISORDER; METABOLIC REGULATION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PANCREAS FUNCTION; PERSONALIZED MEDICINE; POLYPHARMACY; PRIORITY JOURNAL; REVIEW; REWARD; RHOMBENCEPHALON; SATIETY; SENSORY NERVE; STOMACH FUNCTION; ANATOMY AND HISTOLOGY; ANIMAL; BRAIN; FOOD INTAKE; INNERVATION; NERVE TRACT; PHYSIOLOGY; PLEASURE;

ANIMALS; APPETITE REGULATION; BRAIN; ENERGY METABOLISM; GASTROINTESTINAL TRACT; HOMEOSTASIS; HUMANS; NEURAL PATHWAYS; PLEASURE; SATIATION;

EID: 85014047655     PISSN: 00928674     EISSN: 10974172     Source Type: Journal    
DOI: 10.1016/j.cell.2017.01.025     Document Type: Review

References (207)

1. Abizaid, A., Liu, Z.W., Andrews, Z.B., Shanabrough, M., Borok, E., Elsworth, J.D., Roth, R.H., Sleeman, M.W., Picciotto, M.R., Tschöp, M.H., et al. Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J. Clin. Invest. 116 (2006), 3229–3239.
2. Aiello, L., Wheeler, P., The expensive-tissue hypothesis: the brain and the digestive system in human and primate evolution. Curr. Anthropol. 36 (1995), 199–221.
3. Barrera, J.G., Sandoval, D.A., D'Alessio, D.A., Seeley, R.J., GLP-1 and energy balance: an integrated model of short-term and long-term control. Nat. Rev. Endocrinol. 7 (2011), 507–516.
4. Batterham, R.L., ffytche, D.H., Rosenthal, J.M., Zelaya, F.O., Barker, G.J., Withers, D.J., Williams, S.C., PYY modulation of cortical and hypothalamic brain areas predicts feeding behaviour in humans. Nature 450 (2007), 106–109.
5. Baxter, J.D., Webb, P., Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes. Nat. Rev. Drug Discov. 8 (2009), 308–320.
6. Berthoud, H.R., Vagal and hormonal gut-brain communication: from satiation to satisfaction. Neurogastroenterol. Motil. 20:Suppl 1 (2008), 64–72.
7. Berthoud, H.R., The vagus nerve, food intake and obesity. Regul. Pept. 149 (2008), 15–25.
8. Berthoud, H.R., Morrison, C., The brain, appetite, and obesity. Annu. Rev. Psychol. 59 (2008), 55–92.
9. Berthoud, H.R., Neuhuber, W.L., Functional and chemical anatomy of the afferent vagal system. Auton. Neurosci. 85 (2000), 1–17.
10. Berthoud, H.R., Patterson, L.M., Anatomical relationship between vagal afferent fibers and CCK-immunoreactive entero-endocrine cells in the rat small intestinal mucosa. Acta Anat. (Basel) 156 (1996), 123–131.
11. Berthoud, H.R., Powley, T.L., Vagal afferent innervation of the rat fundic stomach: morphological characterization of the gastric tension receptor. J. Comp. Neurol. 319 (1992), 261–276.
12. Berthoud, H.R., Kressel, M., Raybould, H.E., Neuhuber, W.L., Vagal sensors in the rat duodenal mucosa: distribution and structure as revealed by in vivo DiI-tracing. Anat. Embryol. (Berl.) 191 (1995), 203–212.
13. Berthoud, H.R., Patterson, L.M., Neumann, F., Neuhuber, W.L., Distribution and structure of vagal afferent intraganglionic laminar endings (IGLEs) in the rat gastrointestinal tract. Anat. Embryol. (Berl.) 195 (1997), 183–191.
14. Blackshaw, L.A., Grundy, D., Effects of cholecystokinin (CCK-8) on two classes of gastroduodenal vagal afferent fibre. J. Auton. Nerv. Syst. 31 (1990), 191–201.
15. Branco, T., Tozer, A., Magnus, C.J., Sugino, K., Tanaka, S., Lee, A.K., Wood, J.N., Sternson, S.M., Near-Perfect Synaptic Integration by Nav1.7 in Hypothalamic Neurons Regulates Body Weight. Cell 165 (2016), 1749–1761.
16. Brandsma, E., Houben, T., Fu, J., Shiri-Sverdlov, R., Hofker, M.H., The immunity-diet-microbiota axis in the development of metabolic syndrome. Curr. Opin. Lipidol. 26 (2015), 73–81.
17. Bray, G.A., Effect of caloric restriction on energy expenditure in obese patients. Lancet 2 (1969), 397–398.
18. Brennan, I.M., Feltrin, K.L., Horowitz, M., Smout, A.J., Meyer, J.H., Wishart, J., Feinle-Bisset, C., Evaluation of interactions between CCK and GLP-1 in their effects on appetite, energy intake, and antropyloroduodenal motility in healthy men. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288 (2005), R1477–R1485.
19. Brobeck, J.R., Mechanism of the development of obesity in animals with hypothalamic lesions. Physiol. Rev. 26 (1946), 541–559.
20. Broeders, E.P., Nascimento, E.B., Havekes, B., Brans, B., Roumans, K.H., Tailleux, A., Schaart, G., Kouach, M., Charton, J., Deprez, B., et al. The bile acid chenodeoxycholic acid increases human brown adipose tissue activity. Cell Metab. 22 (2015), 418–426.
21. Cabanac, M., Johnson, K.G., Analysis of a conflict between palatability and cold exposure in rats. Physiol. Behav. 31 (1983), 249–253.
22. Cani, P.D., Delzenne, N.M., The role of the gut microbiota in energy metabolism and metabolic disease. Curr. Pharm. Des. 15 (2009), 1546–1558.
23. Cegla, J., Troke, R.C., Jones, B., Tharakan, G., Kenkre, J., McCullough, K.A., Lim, C.T., Parvizi, N., Hussein, M., Chambers, E.S., et al. Coinfusion of low-dose GLP-1 and glucagon in man results in a reduction in food intake. Diabetes 63 (2014), 3711–3720.
24. Celio, A.C., Pories, W.J., A History of Bariatric Surgery: The Maturation of a Medical Discipline. Surg. Clin. North Am. 96 (2016), 655–667.
25. Chakravarthy, M.V., Booth, F.W., Eating, exercise, and “thrifty” genotypes: connecting the dots toward an evolutionary understanding of modern chronic diseases. J. Appl. Physiol. 96 (2004), 3–10.
26. Chambers, A.P., Jessen, L., Ryan, K.K., Sisley, S., Wilson-Pérez, H.E., Stefater, M.A., Gaitonde, S.G., Sorrell, J.E., Toure, M., Berger, J., et al. Weight-independent changes in blood glucose homeostasis after gastric bypass or vertical sleeve gastrectomy in rats. Gastroenterology 141 (2011), 950–958.
27. Chambers, A.P., Kirchner, H., Wilson-Perez, H.E., Willency, J.A., Hale, J.E., Gaylinn, B.D., Thorner, M.O., Pfluger, P.T., Gutierrez, J.A., Tschop, M.H., et al. The effects of vertical sleeve gastrectomy in rodents are ghrelin independent. Gastroenterology 144 (2013), 50–52.
28. Chan, J.L., Mun, E.C., Stoyneva, V., Mantzoros, C.S., Goldfine, A.B., Peptide YY levels are elevated after gastric bypass surgery. Obesity (Silver Spring) 14 (2006), 194–198.
29. Chen, K.Y., Muniyappa, R., Abel, B.S., Mullins, K.P., Staker, P., Brychta, R.J., Zhao, X., Ring, M., Psota, T.L., Cone, R.D., et al. RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals. J. Clin. Endocrinol. Metab. 100 (2015), 1639–1645.
30. Clemmensen, C., Chabenne, J., Finan, B., Sullivan, L., Fischer, K., Küchler, D., Sehrer, L., Ograjsek, T., Hofmann, S.M., Schriever, S.C., et al. GLP-1/glucagon coagonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet. Diabetes 63 (2014), 1422–1427.
31. Clemmensen, C., Finan, B., Fischer, K., Tom, R.Z., Legutko, B., Sehrer, L., Heine, D., Grassl, N., Meyer, C.W., Henderson, B., et al. Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice. EMBO Mol. Med. 7 (2015), 288–298.
32. Clemmensen, C., Müller, T.D., Finan, B., Tschöp, M.H., DiMarchi, R., Current and Emerging Treatment Options in Diabetes Care. Handb. Exp. Pharmacol. 233 (2016), 437–459.
33. Coleman, D.L., Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 9 (1973), 294–298.
34. Coleman, D.L., Hummel, K.P., Effects of parabiosis of normal with genetically diabetic mice. Am. J. Physiol. 217 (1969), 1298–1304.
35. Colquitt, J.L., Pickett, K., Loveman, E., Frampton, G.K., Surgery for weight loss in adults. Cochrane Database Syst. Rev.(8), 2014, CD003641.
36. Cummings, D.E., Weigle, D.S., Frayo, R.S., Breen, P.A., Ma, M.K., Dellinger, E.P., Purnell, J.Q., Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N. Engl. J. Med. 346 (2002), 1623–1630.
37. Cynthia, K., Musonius Rufus. 2010, Lectures and Sayings. CreateSpace Independent Publishing Platform.
38. D'Agostino, G., Lyons, D.J., Cristiano, C., Burke, L.K., Madara, J.C., Campbell, J.N., Garcia, A.P., Land, B.B., Lowell, B.B., Dileone, R.J., Heisler, L.K., Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit. eLife, 5, 2016, e12225.
39. Day, J.W., Ottaway, N., Patterson, J.T., Gelfanov, V., Smiley, D., Gidda, J., Findeisen, H., Bruemmer, D., Drucker, D.J., Chaudhary, N., et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat. Chem. Biol. 5 (2009), 749–757.
40. de Jonge, L., Bray, G.A., The thermic effect of food and obesity: a critical review. Obes. Res. 5 (1997), 622–631.
41. de Lartigue, G., Ronveaux, C.C., Raybould, H.E., Vagal plasticity the key to obesity. Mol. Metab. 3 (2014), 855–856.
42. De Silva, A., Salem, V., Long, C.J., Makwana, A., Newbould, R.D., Rabiner, E.A., Ghatei, M.A., Bloom, S.R., Matthews, P.M., Beaver, J.D., Dhillo, W.S., 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. 14 (2011), 700–706.
43. Degirolamo, C., Rainaldi, S., Bovenga, F., Murzilli, S., Moschetta, A., Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr-Fgf15 axis in mice. Cell Rep. 7 (2014), 12–18.
44. Di Angelantonio, E., Bhupathiraju, ShN., Wormser, D., Gao, P., Kaptoge, S., Berrington de Gonzalez, A., Cairns, B.J., Huxley, R., Jackson, ChL., Joshy, G., et al., Global BMI Mortality Collaboration. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet 388 (2016), 776–786.
45. Dickson, S.L., Shirazi, R.H., Hansson, C., Bergquist, F., Nissbrandt, H., Skibicka, K.P., The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors. J. Neurosci. 32 (2012), 4812–4820.
46. Dirksen, C., Jørgensen, N.B., Bojsen-Møller, K.N., Kielgast, U., Jacobsen, S.H., Clausen, T.R., Worm, D., Hartmann, B., Rehfeld, J.F., Damgaard, M., et al. Gut hormones, early dumping and resting energy expenditure in patients with good and poor weight loss response after Roux-en-Y gastric bypass. Int. J. Obes. 37 (2013), 1452–1459.
47. Dossat, A.M., Lilly, N., Kay, K., Williams, D.L., Glucagon-like peptide 1 receptors in nucleus accumbens affect food intake. J. Neurosci. 31 (2011), 14453–14457.
48. Dunn, J.P., Cowan, R.L., Volkow, N.D., Feurer, I.D., Li, R., Williams, D.B., Kessler, R.M., Abumrad, N.N., Decreased dopamine type 2 receptor availability after bariatric surgery: preliminary findings. Brain Res. 1350 (2010), 123–130.
49. Ernst, B., Thurnheer, M., Wilms, B., Schultes, B., Differential changes in dietary habits after gastric bypass versus gastric banding operations. Obes. Surg. 19 (2009), 274–280.
50. Falkén, Y., Hellström, P.M., Holst, J.J., Näslund, E., Changes in glucose homeostasis after Roux-en-Y gastric bypass surgery for obesity at day three, two months, and one year after surgery: role of gut peptides. J. Clin. Endocrinol. Metab. 96 (2011), 2227–2235.
51. Fang, S., Suh, J.M., Reilly, S.M., Yu, E., Osborn, O., Lackey, D., Yoshihara, E., Perino, A., Jacinto, S., Lukasheva, Y., et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat. Med. 21 (2015), 159–165.
52. Fani, L., Bak, S., Delhanty, P., van Rossum, E.F., van den Akker, E.L., The melanocortin-4 receptor as target for obesity treatment: a systematic review of emerging pharmacological therapeutic options. Int. J. Obes. 38 (2014), 163–169.
53. Farooqi, I.S., Keogh, J.M., Yeo, G.S., Lank, E.J., Cheetham, T., O'Rahilly, S., Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N. Engl. J. Med. 348 (2003), 1085–1095.
54. Farooqi, I.S., Bullmore, E., Keogh, J., Gillard, J., O'Rahilly, S., Fletcher, P.C., Leptin regulates striatal regions and human eating behavior. Science, 317, 2007, 1355.
55. Figlewicz, D.P., Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat: Historical perspective. Brain Res. 1645 (2016), 68–70.
56. Finan, B., Yang, B., Ottaway, N., Stemmer, K., Müller, T.D., Yi, C.X., Habegger, K., Schriever, S.C., García-Cáceres, C., Kabra, D.G., et al. Targeted estrogen delivery reverses the metabolic syndrome. Nat. Med. 18 (2012), 1847–1856.
57. Finan, B., Ma, T., Ottaway, N., Müller, T.D., Habegger, K.M., Heppner, K.M., Kirchner, H., Holland, J., Hembree, J., Raver, C., et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci. Transl. Med., 5, 2013, 209ra151.
58. Finan, B., Clemmensen, C., Müller, T.D., Emerging opportunities for the treatment of metabolic diseases: Glucagon-like peptide-1 based multi-agonists. Mol. Cell. Endocrinol. 418 (2015), 42–54.
59. Finan, B., Yang, B., Ottaway, N., Smiley, D.L., Ma, T., Clemmensen, C., Chabenne, J., Zhang, L., Habegger, K.M., Fischer, K., et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat. Med. 21 (2015), 27–36.
60. Finan, B., Clemmensen, C., Zhu, Z., Stemmer, K., Gauthier, K., Muller, L., De Angelis, M., Moreth, K., Neff, F., Perez-Tilve, D., et al. Chemical hybridization of glucagon and thyroid hormone optimizes therapeutic impact for metabolic disease. Cell 167 (2016), 843–857.
61. Finan, B., Müller, T.D., Clemmensen, C., Perez-Tilve, D., DiMarchi, R.D., Tschöp, M.H., Reappraisal of GIP pharmacology for metabolic diseases. Trends Mol. Med. 22 (2016), 359–376.
62. Fosgerau, K., Jessen, L., Lind Tolborg, J., Østerlund, T., Schæffer Larsen, K., Rolsted, K., Brorson, M., Jelsing, J., Skovlund Ryge Neerup, T., The novel GLP-1-gastrin dual agonist, ZP3022, increases β-cell mass and prevents diabetes in db/db mice. Diabetes Obes. Metab. 15 (2013), 62–71.
63. Frank, S., Wilms, B., Veit, R., Ernst, B., Thurnheer, M., Kullmann, S., Fritsche, A., Birbaumer, N., Preissl, H., Schultes, B., Altered brain activity in severely obese women may recover after Roux-en Y gastric bypass surgery. Int. J. Obes. 38 (2014), 341–348.
64. Fulton, S., Pissios, P., Manchon, R.P., Stiles, L., Frank, L., Pothos, E.N., Maratos-Flier, E., Flier, J.S., Leptin regulation of the mesoaccumbens dopamine pathway. Neuron 51 (2006), 811–822.
65. Furness, J.B., The enteric nervous system and neurogastroenterology. Nat. Rev. Gastroenterol. Hepatol. 9 (2012), 286–294.
66. García-Cáceres, C., Quarta, C., Varela, L., Gao, Y., Gruber, T., Legutko, B., Jastroch, M., Johansson, P., Ninkovic, J., Yi, C.X., et al. Astrocytic insulin signaling couples brain glucose uptake with nutrient availability. Cell 166 (2016), 867–880.
67. Gautron, L., Elmquist, J.K., Williams, K.W., Neural control of energy balance: translating circuits to therapies. Cell 161 (2015), 133–145.
68. Gerhard, G.S., Styer, A.M., Wood, G.C., Roesch, S.L., Petrick, A.T., Gabrielsen, J., Strodel, W.E., Still, C.D., Argyropoulos, G., A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass. Diabetes Care 36 (2013), 1859–1864.
69. Gibbs, J., Young, R.C., Smith, G.P., Cholecystokinin elicits satiety in rats with open gastric fistulas. Nature 245 (1973), 323–325.
70. Grayson, B.E., Schneider, K.M., Woods, S.C., Seeley, R.J., Improved rodent maternal metabolism but reduced intrauterine growth after vertical sleeve gastrectomy. Sci. Transl. Med., 5, 2013, 199ra112.
71. Green, E.D., Maffei, M., Braden, V.V., Proenca, R., DeSilva, U., Zhang, Y., Chua, S.C. Jr., Leibel, R.L., Weissenbach, J., Friedman, J.M., The human obese (OB) gene: RNA expression pattern and mapping on the physical, cytogenetic, and genetic maps of chromosome 7. Genome Res. 5 (1995), 5–12.
72. Gribble, F.M., The gut endocrine system as a coordinator of postprandial nutrient homoeostasis. Proc. Nutr. Soc. 71 (2012), 456–462.
73. Gribble, F.M., Reimann, F., Enteroendocrine cells: chemosensors in the intestinal epithelium. Annu. Rev. Physiol. 78 (2016), 277–299.
74. Grill, H.J., Hayes, M.R., Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance. Cell Metab. 16 (2012), 296–309.
75. Grunddal, K.V., Ratner, C.F., Svendsen, B., Sommer, F., Engelstoft, M.S., Madsen, A.N., Pedersen, J., Nøhr, M.K., Egerod, K.L., Nawrocki, A.R., et al. Neurotensin is coexpressed, coreleased, and acts together with GLP-1 and PYY in enteroendocrine control of metabolism. Endocrinology 157 (2016), 176–194.
76. Gutzwiller, J.P., Degen, L., Matzinger, D., Prestin, S., Beglinger, C., Interaction between GLP-1 and CCK-33 in inhibiting food intake and appetite in men. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287 (2004), R562–R567.
77. Habegger, K.M., Heppner, K.M., Geary, N., Bartness, T.J., DiMarchi, R., Tschöp, M.H., The metabolic actions of glucagon revisited. Nat. Rev. Endocrinol. 6 (2010), 689–697.
78. Habegger, K.M., Stemmer, K., Cheng, C., Müller, T.D., Heppner, K.M., Ottaway, N., Holland, J., Hembree, J.L., Smiley, D., Gelfanov, V., et al. Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes 62 (2013), 1453–1463.
79. Hamilton, M.K., Boudry, G., Lemay, D.G., Raybould, H.E., Changes in intestinal barrier function and gut microbiota in high-fat diet-fed rats are dynamic and region dependent. Am. J. Physiol. Gastrointest. Liver Physiol. 308 (2015), G840–G851.
80. Han, W., Tellez, L.A., Niu, J., Medina, S., Ferreira, T.L., Zhang, X., Su, J., Tong, J., Schwartz, G.J., van den Pol, A., de Araujo, I.E., Striatal dopamine links gastrointestinal rerouting to altered sweet appetite. Cell Metab. 23 (2016), 103–112.
81. Hasler, W.L., Methods of gastric electrical stimulation and pacing: a review of their benefits and mechanisms of action in gastroparesis and obesity. Neurogastroenterol. Motil. 21 (2009), 229–243.
82. Henry, F.E., Sugino, K., Tozer, A., Branco, T., Sternson, S.M., Cell type-specific transcriptomics of hypothalamic energy-sensing neuron responses to weight-loss. eLife, 4, 2015, 10.7554/eLife.09800.
83. Herbert, H., Saper, C.B., Cholecystokinin-, galanin-, and corticotropin-releasing factor-like immunoreactive projections from the nucleus of the solitary tract to the parabrachial nucleus in the rat. J. Comp. Neurol. 293 (1990), 581–598.
84. Hervey, G.R., The effects of lesions in the hypothalamus in parabiotic rats. J. Physiol. 145 (1959), 336–352.
85. Heymsfield, S.B., Greenberg, A.S., Fujioka, K., Dixon, R.M., Kushner, R., Hunt, T., Lubina, J.A., Patane, J., Self, B., Hunt, P., McCamish, M., Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282 (1999), 1568–1575.
86. Holt, J.A., Luo, G., Billin, A.N., Bisi, J., McNeill, Y.Y., Kozarsky, K.F., Donahee, M., Wang, D.Y., Mansfield, T.A., Kliewer, S.A., et al. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev. 17 (2003), 1581–1591.
87. Huszar, D., Lynch, C.A., Fairchild-Huntress, V., Dunmore, J.H., Fang, Q., Berkemeier, L.R., Gu, W., Kesterson, R.A., Boston, B.A., Cone, R.D., et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88 (1997), 131–141.
88. Huypens, P., Sass, S., Wu, M., Dyckhoff, D., Tschöp, M., Theis, F., Marschall, S., Hrabě de Angelis, M., Beckers, J., Epigenetic germline inheritance of diet-induced obesity and insulin resistance. Nat. Genet. 48 (2016), 497–499.
89. Ikramuddin, S., Blackstone, R.P., Brancatisano, A., Toouli, J., Shah, S.N., Wolfe, B.M., Fujioka, K., Maher, J.W., Swain, J., Que, F.G., et al. Effect of reversible intermittent intra-abdominal vagal nerve blockade on morbid obesity: the ReCharge randomized clinical trial. JAMA 312 (2014), 915–922.
90. Inagaki, T., Choi, M., Moschetta, A., Peng, L., Cummins, C.L., McDonald, J.G., Luo, G., Jones, S.A., Goodwin, B., Richardson, J.A., et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2 (2005), 217–225.
91. Jacobsen, S.H., Olesen, S.C., Dirksen, C., Jørgensen, N.B., Bojsen-Møller, K.N., Kielgast, U., Worm, D., Almdal, T., Naver, L.S., Hvolris, L.E., et al. Changes in gastrointestinal hormone responses, insulin sensitivity, and beta-cell function within 2 weeks after gastric bypass in non-diabetic subjects. Obes. Surg. 22 (2012), 1084–1096.
92. Jansen, P.L., van Werven, J., Aarts, E., Berends, F., Janssen, I., Stoker, J., Schaap, F.G., Alterations of hormonally active fibroblast growth factors after Roux-en-Y gastric bypass surgery. Dig. Dis. 29 (2011), 48–51.
93. Jiang, C., Xie, C., Lv, Y., Li, J., Krausz, K.W., Shi, J., Brocker, C.N., Desai, D., Amin, S.G., Bisson, W.H., et al. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat. Commun., 6, 2015, 10166.
94. Kawamata, Y., Fujii, R., Hosoya, M., Harada, M., Yoshida, H., Miwa, M., Fukusumi, S., Habata, Y., Itoh, T., Shintani, Y., et al. A G protein-coupled receptor responsive to bile acids. J. Biol. Chem. 278 (2003), 9435–9440.
95. Kennedy, G.C., The role of depot fat in the hypothalamic control of food intake in the rat. Proc. R. Soc. Lond. B Biol. Sci. 140 (1953), 578–596.
96. Kennedy, G.C., Food intake, energy balance and growth. Br. Med. Bull. 22 (1966), 216–220.
97. Kenny, P.J., Reward mechanisms in obesity: new insights and future directions. Neuron 69 (2011), 664–679.
98. Kharitonenkov, A., DiMarchi, R., FGF21 Revolutions: Recent Advances Illuminating FGF21 Biology and Medicinal Properties. Trends Endocrinol. Metab. 26 (2015), 608–617.
99. Kievit, P., Halem, H., Marks, D.L., Dong, J.Z., Glavas, M.M., Sinnayah, P., Pranger, L., Cowley, M.A., Grove, K.L., Culler, M.D., Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes 62 (2013), 490–497.
100. Koch, M., Varela, L., Kim, J.G., Kim, J.D., Hernández-Nuño, F., Simonds, S.E., Castorena, C.M., Vianna, C.R., Elmquist, J.K., Morozov, Y.M., et al. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519 (2015), 45–50.
101. Kohli, R., Setchell, K.D., Kirby, M., Myronovych, A., Ryan, K.K., Ibrahim, S.H., Berger, J., Smith, K., Toure, M., Woods, S.C., Seeley, R.J., A surgical model in male obese rats uncovers protective effects of bile acids post-bariatric surgery. Endocrinology 154 (2013), 2341–2351.
102. Korner, J., Bessler, M., Inabnet, W., Taveras, C., Holst, J.J., Exaggerated glucagon-like peptide-1 and blunted glucose-dependent insulinotropic peptide secretion are associated with Roux-en-Y gastric bypass but not adjustable gastric banding. Surg. Obes. Relat. Dis. 3 (2007), 597–601.
103. Krashes, M.J., Lowell, B.B., Garfield, A.S., Melanocortin-4 receptor-regulated energy homeostasis. Nat. Neurosci. 19 (2016), 206–219.
104. Kühnen, P., Clément, K., Wiegand, S., Blankenstein, O., Gottesdiener, K., Martini, L.L., Mai, K., Blume-Peytavi, U., Grüters, A., Krude, H., Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist. N. Engl. J. Med. 375 (2016), 240–246.
105. Larsen, P.J., Tang-Christensen, M., Holst, J.J., Orskov, C., Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem. Neuroscience 77 (1997), 257–270.
106. le Roux, C.W., Bueter, M., The physiology of altered eating behaviour after Roux-en-Y gastric bypass. Exp. Physiol. 99 (2014), 1128–1132.
107. Leibel, R.L., Rosenbaum, M., Hirsch, J., Changes in energy expenditure resulting from altered body weight. N. Engl. J. Med. 332 (1995), 621–628.
108. Leonard, W.R., Snodgrass, J.J., Robertson, M.L., Effects of brain evolution on human nutrition and metabolism. Annu. Rev. Nutr. 27 (2007), 311–327.
109. Liu, J., Lee, J., Salazar Hernandez, M.A., Mazitschek, R., Ozcan, U., Treatment of obesity with celastrol. Cell 161 (2015), 999–1011.
110. Locke, A.E., Kahali, B., Berndt, S.I., Justice, A.E., Pers, T.H., Day, F.R., Powell, C., Vedantam, S., Buchkovich, M.L., Yang, J., et al. LifeLines Cohort Study ADIPOGen Consortium AGEN-BMI Working Group CARDIOGRAMplusC4D Consortium CKDGen Consortium GLGC ICBP MAGIC Investigators MuTHER Consortium MIGen Consortium PAGE Consortium ReproGen Consortium GENIE Consortium, International Endogene Consortium. Genetic studies of body mass index yield new insights for obesity biology. Nature 518 (2015), 197–206.
111. Lucas, F., Sclafani, A., Flavor preferences conditioned by intragastric fat infusions in rats. Physiol. Behav. 46 (1989), 403–412.
112. Lynch, L., Hogan, A.E., Duquette, D., Lester, C., Banks, A., LeClair, K., Cohen, D.E., Ghosh, A., Lu, B., Corrigan, M., et al. iNKT cells induce FGF21 for thermogenesis and are required for maximal weight loss in GLP1 therapy. Cell Metab. 24 (2016), 510–519.
113. Madara, J.L., Functional morphology of epithelium of the small intestine. Handbook of Physiology: The Gastrointestinal System, Intestinal Absorption and Secretion, 2011, Wiley-Blackwell.
114. Madsbad, S., Dirksen, C., Holst, J.J., Mechanisms of changes in glucose metabolism and bodyweight after bariatric surgery. Lancet Diabetes Endocrinol. 2 (2014), 152–164.
115. Maffei, M., Fei, H., Lee, G.H., Dani, C., Leroy, P., Zhang, Y., Proenca, R., Negrel, R., Ailhaud, G., Friedman, J.M., Increased expression in adipocytes of ob RNA in mice with lesions of the hypothalamus and with mutations at the db locus. Proc. Natl. Acad. Sci. USA 92 (1995), 6957–6960.
116. Makaronidis, J.M., Batterham, R.L., Potential mechanisms mediating sustained weight loss following Roux-en-Y gastric bypass and sleeve gastrectomy. Endocrinol. Metab. Clin. North Am. 45 (2016), 539–552.
117. McGavigan, A.K., Garibay, D., Henseler, Z.M., Chen, J., Bettaieb, A., Haj, F.G., Ley, R.E., Chouinard, M.L., Cummings, B.P., TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice. Gut 66 (2017), 226–234.
118. Mikkelsen, K.H., Frost, M., Bahl, M.I., Licht, T.R., Jensen, U.S., Rosenberg, J., Pedersen, O., Hansen, T., Rehfeld, J.F., Holst, J.J., et al. Effect of antibiotics on gut microbiota, gut hormones and glucose metabolism. PLoS ONE, 10, 2015, e0142352.
119. Mingrone, G., Panunzi, S., De Gaetano, A., Guidone, C., Iaconelli, A., Nanni, G., Castagneto, M., Bornstein, S., Rubino, F., Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial. Lancet 386 (2015), 964–973.
120. Morton, G.J., Matsen, M.E., Bracy, D.P., Meek, T.H., Nguyen, H.T., Stefanovski, D., Bergman, R.N., Wasserman, D.H., Schwartz, M.W., FGF19 action in the brain induces insulin-independent glucose lowering. J. Clin. Invest. 123 (2013), 4799–4808.
121. Müller, T.D., Sullivan, L.M., Habegger, K., Yi, C.X., Kabra, D., Grant, E., Ottaway, N., Krishna, R., Holland, J., Hembree, J., et al. Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21. J. Pept. Sci. 18 (2012), 383–393.
122. Mullur, R., Liu, Y.Y., Brent, G.A., Thyroid hormone regulation of metabolism. Physiol. Rev. 94 (2014), 355–382.
123. Myronovych, A., Kirby, M., Ryan, K.K., Zhang, W., Jha, P., Setchell, K.D., Dexheimer, P.J., Aronow, B., Seeley, R.J., Kohli, R., Vertical sleeve gastrectomy reduces hepatic steatosis while increasing serum bile acids in a weight-loss-independent manner. Obesity (Silver Spring) 22 (2014), 390–400.
124. Näslund, E., Backman, L., Holst, J.J., Theodorsson, E., Hellström, P.M., Importance of small bowel peptides for the improved glucose metabolism 20 years after jejunoileal bypass for obesity. Obes. Surg. 8 (1998), 253–260.
125. Neary, N.M., Small, C.J., Druce, M.R., Park, A.J., Ellis, S.M., Semjonous, N.M., Dakin, C.L., Filipsson, K., Wang, F., Kent, A.S., et al. Peptide YY3-36 and glucagon-like peptide-17-36 inhibit food intake additively. Endocrinology 146 (2005), 5120–5127.
126. Ochner, C.N., Laferrère, B., Afifi, L., Atalayer, D., Geliebter, A., Teixeira, J., Neural responsivity to food cues in fasted and fed states pre and post gastric bypass surgery. Neurosci. Res. 74 (2012), 138–143.
127. Oral, E.A., Simha, V., Ruiz, E., Andewelt, A., Premkumar, A., Snell, P., Wagner, A.J., DePaoli, A.M., Reitman, M.L., Taylor, S.I., et al. Leptin-replacement therapy for lipodystrophy. N. Engl. J. Med. 346 (2002), 570–578.
128. Oswald, K.D., Murdaugh, D.L., King, V.L., Boggiano, M.M., Motivation for palatable food despite consequences in an animal model of binge eating. Int. J. Eat. Disord. 44 (2011), 203–211.
129. Patti, M.E., Houten, S.M., Bianco, A.C., Bernier, R., Larsen, P.R., Holst, J.J., Badman, M.K., Maratos-Flier, E., Mun, E.C., Pihlajamaki, J., et al. Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism. Obesity (Silver Spring) 17 (2009), 1671–1677.
130. Penney, N.C., Kinross, J., Newton, R.C., Purkayastha, S., The role of bile acids in reducing the metabolic complications of obesity after bariatric surgery: a systematic review. Int. J. Obes. 39 (2015), 1565–1574.
131. Perry, R.J., Peng, L., Barry, N.A., Cline, G.W., Zhang, D., Cardone, R.L., Petersen, K.F., Kibbey, R.G., Goodman, A.L., Shulman, G.I., Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome. Nature 534 (2016), 213–217.
132. Pi-Sunyer, F.X., Aronne, L.J., Heshmati, H.M., Devin, J., Rosenstock, J., RIO-North America Study Group. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 295 (2006), 761–775.
133. Pocai, A., Carrington, P.E., Adams, J.R., Wright, M., Eiermann, G., Zhu, L., Du, X., Petrov, A., Lassman, M.E., Jiang, G., et al. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 58 (2009), 2258–2266.
134. Powley, T.L., Spaulding, R.A., Haglof, S.A., Vagal afferent innervation of the proximal gastrointestinal tract mucosa: chemoreceptor and mechanoreceptor architecture. J. Comp. Neurol. 519 (2011), 644–660.
135. Quarta, C., Sánchez-Garrido, M.A., Tschöp, M.H., Clemmensen, C., Renaissance of leptin for obesity therapy. Diabetologia 59 (2016), 920–927.
136. Ramsay, D.S., Woods, S.C., Clarifying the roles of homeostasis and allostasis in physiological regulation. Psychol. Rev. 121 (2014), 225–247.
137. Ratner, C., Skov, L.J., Raida, Z., Bächler, T., Bellmann-Sickert, K., Le Foll, C., Sivertsen, B., Dalbøge, L.S., Hartmann, B., Beck-Sickinger, A.G., et al. Effects of peripheral neurotensin on appetite regulation and its role in gastric bypass surgery. Endocrinology 157 (2016), 3482–3492.
138. Ravinet Trillou, C., Delgorge, C., Menet, C., Arnone, M., Soubrié, P., CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. Int. J. Obes. Relat. Metab. Disord. 28 (2004), 640–648.
139. Rehfeld, J.F., The new biology of gastrointestinal hormones. Physiol. Rev. 78 (1998), 1087–1108.
140. Reijnders, D., Goossens, G.H., Hermes, G.D., Neis, E.P., van der Beek, C.M., Most, J., Holst, J.J., Lenaerts, K., Kootte, R.S., Nieuwdorp, M., et al. Effects of gut microbiota manipulation by antibiotics on host metabolism in obese humans: a randomized double-blind placebo-controlled trial. Cell Metab., 24, 2016, 341.
141. Reimann, F., Tolhurst, G., Gribble, F.M., G-protein-coupled receptors in intestinal chemosensation. Cell Metab. 15 (2012), 421–431.
142. Rising, R., Alger, S., Boyce, V., Seagle, H., Ferraro, R., Fontvieille, A.M., Ravussin, E., Food intake measured by an automated food-selection system: relationship to energy expenditure. Am. J. Clin. Nutr. 55 (1992), 343–349.
143. Romero, F., Nicolau, J., Flores, L., Casamitjana, R., Ibarzabal, A., Lacy, A., Vidal, J., Comparable early changes in gastrointestinal hormones after sleeve gastrectomy and Roux-En-Y gastric bypass surgery for morbidly obese type 2 diabetic subjects. Surg. Endosc. 26 (2012), 2231–2239.
144. Rosenbaum, M., Hirsch, J., Murphy, E., Leibel, R.L., Effects of changes in body weight on carbohydrate metabolism, catecholamine excretion, and thyroid function. Am. J. Clin. Nutr. 71 (2000), 1421–1432.
145. Rubino, F., Nathan, D.M., Eckel, R.H., Schauer, P.R., Alberti, K.G., Zimmet, P.Z., Del Prato, S., Ji, L., Sadikot, S.M., Herman, W.H., et al., Delegates of the 2nd Diabetes Surgery Summit. Metabolic surgery in the treatment algorithm for type 2 diabetes: a joint statement by international diabetes organizations. Diabetes Care 39 (2016), 861–877.
146. Ryan, K.K., Kohli, R., Gutierrez-Aguilar, R., Gaitonde, S.G., Woods, S.C., Seeley, R.J., Fibroblast growth factor-19 action in the brain reduces food intake and body weight and improves glucose tolerance in male rats. Endocrinology 154 (2013), 9–15.
147. Ryan, K.K., Tremaroli, V., Clemmensen, C., Kovatcheva-Datchary, P., Myronovych, A., Karns, R., Wilson-Pérez, H.E., Sandoval, D.A., Kohli, R., Bäckhed, F., Seeley, R.J., FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 509 (2014), 183–188.
148. Salehi, M., Prigeon, R.L., D'Alessio, D.A., Gastric bypass surgery enhances glucagon-like peptide 1-stimulated postprandial insulin secretion in humans. Diabetes 60 (2011), 2308–2314.
149. Sánchez-Garrido, M.A., Habegger, K.M., Clemmensen, C., Holleman, C., Müller, T.D., Perez-Tilve, D., Li, P., Agrawal, A.S., Finan, B., Drucker, D.J., et al. Fibroblast activation protein (FAP) as a novel metabolic target. Mol. Metab. 5 (2016), 1015–1024.
150. Sayin, S.I., Wahlström, A., Felin, J., Jäntti, S., Marschall, H.U., Bamberg, K., Angelin, B., Hyötyläinen, T., Orešič, M., Bäckhed, F., Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 17 (2013), 225–235.
151. Scarlett, J.M., Rojas, J.M., Matsen, M.E., Kaiyala, K.J., Stefanovski, D., Bergman, R.N., Nguyen, H.T., Dorfman, M.D., Lantier, L., Wasserman, D.H., et al. Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents. Nat. Med. 22 (2016), 800–806.
152. Schauer, P.R., Bhatt, D.L., Kirwan, J.P., Wolski, K., Brethauer, S.A., Navaneethan, S.D., Aminian, A., Pothier, C.E., Kim, E.S., Nissen, S.E., Kashyap, S.R., STAMPEDE Investigators. Bariatric surgery versus intensive medical therapy for diabetes-3-year outcomes. N. Engl. J. Med. 370 (2014), 2002–2013.
153. Schnorr, S.L., Candela, M., Rampelli, S., Centanni, M., Consolandi, C., Basaglia, G., Turroni, S., Biagi, E., Peano, C., Severgnini, M., et al. Gut microbiome of the Hadza hunter-gatherers. Nat. Commun., 5, 2014, 3654.
154. Scholtz, S., Miras, A.D., Chhina, N., Prechtl, C.G., Sleeth, M.L., Daud, N.M., Ismail, N.A., Durighel, G., Ahmed, A.R., Olbers, T., et al. Obese patients after gastric bypass surgery have lower brain-hedonic responses to food than after gastric banding. Gut 63 (2014), 891–902.
155. Schultes, B., Ernst, B., Wilms, B., Thurnheer, M., Hallschmid, M., Hedonic hunger is increased in severely obese patients and is reduced after gastric bypass surgery. Am. J. Clin. Nutr. 92 (2010), 277–283.
156. Schwartz, M.W., Woods, S.C., Porte, D. Jr., Seeley, R.J., Baskin, D.G., Central nervous system control of food intake. Nature 404 (2000), 661–671.
157. Schwartz, M.W., Woods, S.C., Seeley, R.J., Barsh, G.S., Baskin, D.G., Leibel, R.L., Is the energy homeostasis system inherently biased toward weight gain?. Diabetes 52 (2003), 232–238.
158. Sclafani, A., Oral and postoral determinants of food reward. Physiol. Behav. 81 (2004), 773–779.
159. Sclafani, A., Gut-brain nutrient signaling. Appetition vs. satiation. Appetite 71 (2013), 454–458.
160. Sclafani, A., Ackroff, K., Role of gut nutrient sensing in stimulating appetite and conditioning food preferences. Am. J. Physiol. Regul. Integr. Comp. Physiol. 302 (2012), R1119–R1133.
161. Sclafani, A., Springer, D., Dietary obesity in adult rats: similarities to hypothalamic and human obesity syndromes. Physiol. Behav. 17 (1976), 461–471.
162. Sclafani, A., Ackroff, K., Schwartz, G.J., Selective effects of vagal deafferentation and celiac-superior mesenteric ganglionectomy on the reinforcing and satiating action of intestinal nutrients. Physiol. Behav. 78 (2003), 285–294.
163. Sclafani, A., Zukerman, S., Ackroff, K., GPR40 and GPR120 fatty acid sensors are critical for postoral but not oral mediation of fat preferences in the mouse. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305 (2013), R1490–R1497.
164. Sclafani, A., Touzani, K., Ackroff, K., Ghrelin signaling is not essential for sugar or fat conditioned flavor preferences in mice. Physiol. Behav. 149 (2015), 14–22.
165. Sclafani, A., Koepsell, H., Ackroff, K., SGLT1 sugar transporter/sensor is required for post-oral glucose appetition. Am. J. Physiol. Regul. Integr. Comp. Physiol. 310 (2016), R631–R639.
166. Seeley, R.J., Chambers, A.P., Sandoval, D.A., The role of gut adaptation in the potent effects of multiple bariatric surgeries on obesity and diabetes. Cell Metab. 21 (2015), 369–378.
167. Shin, A.C., Berthoud, H.R., Food reward functions as affected by obesity and bariatric surgery. Int. J. Obes. 35:Suppl 3 (2011), S40–S44.
168. Shin, A.C., Zheng, H., Pistell, P.J., Berthoud, H.R., Roux-en-Y gastric bypass surgery changes food reward in rats. Int. J. Obes. 35 (2011), 642–651.
169. Skibicka, K.P., Hansson, C., Egecioglu, E., Dickson, S.L., Role of ghrelin in food reward: impact of ghrelin on sucrose self-administration and mesolimbic dopamine and acetylcholine receptor gene expression. Addict. Biol. 17 (2012), 95–107.
170. Smith, G.P., The direct and indirect controls of meal size. Neurosci. Biobehav. Rev. 20 (1996), 41–46.
171. Speakman, J.R., If body fatness is under physiological regulation, then how come we have an obesity epidemic?. Physiology (Bethesda) 29 (2014), 88–98.
172. Stanley, S.A., Kelly, L., Latcha, K.N., Schmidt, S.F., Yu, X., Nectow, A.R., Sauer, J., Dyke, J.P., Dordick, J.S., Friedman, J.M., Bidirectional electromagnetic control of the hypothalamus regulates feeding and metabolism. Nature 531 (2016), 647–650.
173. Stearns, A.T., Balakrishnan, A., Radmanesh, A., Ashley, S.W., Rhoads, D.B., Tavakkolizadeh, A., Relative contributions of afferent vagal fibers to resistance to diet-induced obesity. Dig. Dis. Sci. 57 (2012), 1281–1290.
174. Steculorum, S.M., Paeger, L., Bremser, S., Evers, N., Hinze, Y., Idzko, M., Kloppenburg, P., Brüning, J.C., Hypothalamic UDP increases in obesity and promotes feeding via p2y6-dependent activation of AgRP neurons. Cell 162 (2015), 1404–1417.
175. Steele, K.E., Prokopowicz, G.P., Schweitzer, M.A., Magunsuon, T.H., Lidor, A.O., Kuwabawa, H., Kumar, A., Brasic, J., Wong, D.F., Alterations of central dopamine receptors before and after gastric bypass surgery. Obes. Surg. 20 (2010), 369–374.
176. Stefater, M.A., Perez-Tilve, D., Chambers, A.P., Wilson-Perez, H.E., Sandoval, D.A., Berger, J., Toure, M., Tschop, M., Woods, S.C., Seeley, R.J., Sleeve gastrectomy induces loss of weight and fat mass in obese rats, but does not affect leptin sensitivity. Gastroenterology 138 (2010), 2426–2436.
177. Steinert, R.E., Peterli, R., Keller, S., Meyer-Gerspach, A.C., Drewe, J., Peters, T., Beglinger, C., Bile acids and gut peptide secretion after bariatric surgery: a 1-year prospective randomized pilot trial. Obesity (Silver Spring) 21 (2013), E660–E668.
178. Sternson, S.M., Roth, B.L., Chemogenetic tools to interrogate brain functions. Annu. Rev. Neurosci. 37 (2014), 387–407.
179. Suarez-Pinzon, W.L., Power, R.F., Yan, Y., Wasserfall, C., Atkinson, M., Rabinovitch, A., Combination therapy with glucagon-like peptide-1 and gastrin restores normoglycemia in diabetic NOD mice. Diabetes 57 (2008), 3281–3288.
180. Suh, J.M., Jonker, J.W., Ahmadian, M., Goetz, R., Lackey, D., Osborn, O., Huang, Z., Liu, W., Yoshihara, E., van Dijk, T.H., et al. Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature 513 (2014), 436–439.
181. Tamaki, M., Fujitani, Y., Uchida, T., Hirose, T., Kawamori, R., Watada, H., Combination treatment of db/db mice with exendin-4 and gastrin preserves β-cell mass by stimulating β-cell growth and differentiation. J. Diabetes Investig. 1 (2010), 172–183.
182. Tan, T.M., Field, B.C., McCullough, K.A., Troke, R.C., Chambers, E.S., Salem, V., Gonzalez Maffe, J., Baynes, K.C., De Silva, A., Viardot, A., et al. Coadministration of glucagon-like peptide-1 during glucagon infusion in humans results in increased energy expenditure and amelioration of hyperglycemia. Diabetes 62 (2013), 1131–1138.
183. Tan, C.L., Cooke, E.K., Leib, D.E., Lin, Y.C., Daly, G.E., Zimmerman, C.A., Knight, Z.A., Warm-sensitive neurons that control body temperature. Cell 167 (2016), 47–59.
184. Tartaglia, L.A., Dembski, M., Weng, X., Deng, N., Culpepper, J., Devos, R., Richards, G.J., Campfield, L.A., Clark, F.T., Deeds, J., et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 83 (1995), 1263–1271.
185. Teixeira, T.F., Collado, M.C., Ferreira, C.L., Bressan, J., Peluzio, Mdo.C., Potential mechanisms for the emerging link between obesity and increased intestinal permeability. Nutr. Res. 32 (2012), 637–647.
186. Tellez, L.A., Han, W., Zhang, X., Ferreira, T.L., Perez, I.O., Shammah-Lagnado, S.J., van den Pol, A.N., de Araujo, I.E., Separate circuitries encode the hedonic and nutritional values of sugar. Nat. Neurosci. 19 (2016), 465–470.
187. Tichansky, D.S., Glatt, A.R., Madan, A.K., Harper, J., Tokita, K., Boughter, J.D., Decrease in sweet taste in rats after gastric bypass surgery. Surg. Endosc. 25 (2011), 1176–1181.
188. Trevaskis, J.L., Parkes, D.G., Roth, J.D., Insights into amylin-leptin synergy. Trends Endocrinol. Metab. 21 (2010), 473–479.
189. Tschöp, M.H., Finan, B., Clemmensen, C., Gelfanov, V., Perez-Tilve, D., Müller, T.D., DiMarchi, R.D., Unimolecular polypharmacy for treatment of diabetes and obesity. Cell Metab. 24 (2016), 51–62.
190. Udit, S., Gautron, L., Molecular anatomy of the gut-brain axis revealed with transgenic technologies: implications in metabolic research. Front. Neurosci., 7, 2013, 134.
191. Ullrich, J., Ernst, B., Wilms, B., Thurnheer, M., Schultes, B., Roux-en Y gastric bypass surgery reduces hedonic hunger and improves dietary habits in severely obese subjects. Obes. Surg. 23 (2013), 50–55.
192. Unniappan, S., Kieffer, T.J., Leptin extends the anorectic effects of chronic PYY(3-36) administration in ad libitum-fed rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295 (2008), R51–R58.
193. Valdearcos, M., Xu, A.W., Koliwad, S.K., Hypothalamic inflammation in the control of metabolic function. Annu. Rev. Physiol. 77 (2015), 131–160.
194. Wang, H., Chen, J., Hollister, K., Sowers, L.C., Forman, B.M., Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol. Cell 3 (1999), 543–553.
195. Wang, L., Barachina, M.D., Martínez, V., Wei, J.Y., Taché, Y., Synergistic interaction between CCK and leptin to regulate food intake. Regul. Pept. 92 (2000), 79–85.
196. Watanabe, M., Houten, S.M., Mataki, C., Christoffolete, M.A., Kim, B.W., Sato, H., Messaddeq, N., Harney, J.W., Ezaki, O., Kodama, T., et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439 (2006), 484–489.
197. Waterson, M.J., Horvath, T.L., Neuronal regulation of energy homeostasis: beyond the hypothalamus and feeding. Cell Metab. 22 (2015), 962–970.
198. Wilson-Pérez, H.E., Chambers, A.P., Ryan, K.K., Li, B., Sandoval, D.A., Stoffers, D., Drucker, D.J., Pérez-Tilve, D., Seeley, R.J., Vertical sleeve gastrectomy is effective in two genetic mouse models of glucagon-like Peptide 1 receptor deficiency. Diabetes 62 (2013), 2380–2385.
199. Wilson-Pérez, H.E., Chambers, A.P., Sandoval, D.A., Stefater, M.A., Woods, S.C., Benoit, S.C., Seeley, R.J., The effect of vertical sleeve gastrectomy on food choice in rats. Int. J. Obes. 37 (2013), 288–295.
200. Wouterlood, F.G., Bloem, B., Mansvelder, H.D., Luchicchi, A., Deisseroth, K., A fourth generation of neuroanatomical tracing techniques: exploiting the offspring of genetic engineering. J. Neurosci. Methods 235 (2014), 331–348.
201. Wu, Q., Clark, M.S., Palmiter, R.D., Deciphering a neuronal circuit that mediates appetite. Nature 483 (2012), 594–597.
202. Xu, J., Lloyd, D.J., Hale, C., Stanislaus, S., Chen, M., Sivits, G., Vonderfecht, S., Hecht, R., Li, Y.S., Lindberg, R.A., et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 58 (2009), 250–259.
203. Xue, Y., Wang, H., Du, M., Zhu, M.J., Maternal obesity induces gut inflammation and impairs gut epithelial barrier function in nonobese diabetic mice. J. Nutr. Biochem. 25 (2014), 758–764.
204. Yeo, G.S., Farooqi, I.S., Aminian, S., Halsall, D.J., Stanhope, R.G., O'Rahilly, S., A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat. Genet. 20 (1998), 111–112.
205. Zagorodnyuk, V.P., Chen, B.N., Brookes, S.J., Intraganglionic laminar endings are mechano-transduction sites of vagal tension receptors in the guinea-pig stomach. J. Physiol. 534 (2001), 255–268.
206. Zelissen, P.M., Stenlof, K., Lean, M.E., Fogteloo, J., Keulen, E.T., Wilding, J., Finer, N., Rössner, S., Lawrence, E., Fletcher, C., McCamish, M., Author Group. Effect of three treatment schedules of recombinant methionyl human leptin on body weight in obese adults: a randomized, placebo-controlled trial. Diabetes Obes. Metab. 7 (2005), 755–761.
207. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., Friedman, J.M., Positional cloning of the mouse obese gene and its human homologue. Nature 372 (1994), 425–432.