Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis

Nature Medicine

Volumn 21, Issue 2, 2015, Pages 166-172

  Crane, Justin D ^a   Palanivel, Rengasamy ^a,b   Mottillo, Emilio P ^a   Bujak, Adam L ^a   Wang, Huaqing ^a,b   Ford, Rebecca J ^a   Collins, Andrew ^a   Blümer, Regje M ^a   Fullerton, Morgan D ^a   Yabut, Julian M ^a   Kim, Janice J ^a,b   Ghia, Jean Eric ^b   Hamza, Shereen M ^c   Morrison, Katherine M ^a   Schertzer, Jonathan D ^a   Dyck, Jason R B ^c   Khan, Waliul I ^a,b   Steinberg, Gregory R ^a  

^a MCMASTER UNIVERSITY   (Canada)

^b MCMASTER UNIVERSITY   (Canada)

^c UNIVERSITY OF ALBERTA   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

INSULIN; SEROTONIN; TRYPTOPHAN HYDROXYLASE; TRYPTOPHAN HYDROXYLASE 2; UNCOUPLING PROTEIN 1; ION CHANNEL; MITOCHONDRIAL PROTEIN; MITOCHONDRIAL UNCOUPLING PROTEIN; TPH1 PROTEIN, MOUSE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BROWN ADIPOCYTE; BROWN ADIPOSE TISSUE; CONTROLLED STUDY; DISEASE ASSOCIATION; DRUG EFFECT; ENERGY EXPENDITURE; ENZYME INHIBITION; ENZYME POLYMORPHISM; GENE DELETION; IN VITRO STUDY; INSULIN RESISTANCE; LIPID DIET; MALE; MOUSE; NONALCOHOLIC FATTY LIVER; NONHUMAN; OBESITY; PRIORITY JOURNAL; PROTEIN DEFICIENCY; THERMOGENESIS; ANIMAL; ANTAGONISTS AND INHIBITORS; BIOSYNTHESIS; DRUG EFFECTS; ENERGY METABOLISM; GENETICS; KNOCKOUT MOUSE; METABOLISM;

ADIPOSE TISSUE, BROWN; ANIMALS; DIET, HIGH-FAT; ENERGY METABOLISM; INSULIN RESISTANCE; ION CHANNELS; MICE; MICE, KNOCKOUT; MITOCHONDRIAL PROTEINS; NON-ALCOHOLIC FATTY LIVER DISEASE; OBESITY; SEROTONIN; THERMOGENESIS; TRYPTOPHAN HYDROXYLASE;

EID: 84923212941     PISSN: 10788956     EISSN: 1546170X     Source Type: Journal    
DOI: 10.1038/nm.3766     Document Type: Article

References (49)

1. Qiu, Y. et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157, 1292-1308 (2014).
2. Shabalina, I.G. et al. UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic. Cell Reports 5, 1196-1203 (2013).
3. Cypess, A.M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509-1517 (2009).
4. Ouellet, V. et al. Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans. J. Clin. Endocrinol. Metab. 96, 192-199 (2011).
5. Saito, M. et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58, 1526-1531 (2009).
6. Berger, M., Gray, J.A. & Roth, B.L. The expanded biology of serotonin. Annu. Rev. Med. 60, 355-366 (2009).
7. Khan, W.I. & Ghia, J.E. Gut hormones: emerging role in immune activation and inflammation. Clin. Exp. Immunol. 161, 19-27 (2010).
8. Walther, D.J. et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299, 76 (2003).
9. Kim, H.-J. et al. Metabolomic analysis of livers and serum from high-fat diet induced obese mice. J. Proteome Res. 10, 722-731 (2011).
10. Kwak, S.H. et al. Association of variations in TPH1 and HTR2B with gestational weight gain and measures of obesity. Obesity (Silver Spring) 20, 233-238 (2012).
11. Tecott, L.H. Serotonin and the orchestration of energy balance. Cell Metab. 6, 352-361 (2007).
12. Alenina, N. et al. Growth retardation and altered autonomic control in mice lacking brain serotonin. Proc. Natl. Acad. Sci. USA 106, 10332-10337 (2009).
13. Sumara, G., Sumara, O., Kim, J.K. & Karsenty, G. Gut-derived serotonin is a multifunctional determinant to fasting adaptation. Cell Metab. 16, 588-600 (2012).
14. Ghia, J.E. et al. Serotonin has a key role in pathogenesis of experimental colitis. Gastroenterology 137, 1649-1660 (2009).
15. Paulmann, N. et al. Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation. PLoS Biol. 7, e1000229 (2009).
16. Li, Z. et al. Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons. J. Neurosci. 31, 8998-9009 (2011).
17. Uldry, M. et al. Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab. 3, 333-341 (2006).
18. Liu, Q. et al. Discovery and characterization of novel tryptophan hydroxylase inhibitors that selectively inhibit serotonin synthesis in the gastrointestinal tract. J. Pharmacol. Exp. Ther. 325, 47-55 (2008).
19. Yadav, V.K. et al. Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis. Nat. Med. 16, 308-312 (2010).
20. Cohen, P. et al. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell 156, 304-316 (2014).
21. Schulz, T.J. et al. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature 495, 379-383 (2013).
22. Feldmann, H.M., Golozoubova, V., Cannon, B. & Nedergaard, J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab. 9, 203-209 (2009).
23. Rapport, M.M., Green, A.A. & Page, I.H. Serum vasoconstrictor, serotonin; isolation and characterization. J. Biol. Chem. 176, 1243-1251 (1948).
24. Hodges, M.R. et al. Defects in breathing and thermoregulation in mice with near-complete absence of central serotonin neurons. J. Neurosci. 28, 2495-2505 (2008).
25. Breum, L., Rasmussen, M.H., Hilsted, J. & Fernstrom, J.D. Twenty-four-hour plasma tryptophan concentrations and ratios are below normal in obese subjects and are not normalized by substantial weight reduction. Am. J. Clin. Nutr. 77, 1112-1118 (2003).
26. Bertrand, R.L. et al. A Western diet increases serotonin availability in rat small intestine. Endocrinology 152, 36-47 (2011).
27. Sullo, A., Brizzi, G. & Maffulli, N. Chronic peripheral administration of serotonin inhibits thyroid function in the rat. Muscles Ligaments Tendons J. 1, 48-50 (2011).
28. Srinivasan, S. et al. Serotonin regulates C. elegans fat and feeding through independent molecular mechanisms. Cell Metab. 7, 533-544 (2008).
29. Ducy, P. & Karsenty, G. The two faces of serotonin in bone biology. J. Cell Biol. 191, 7-13 (2010).
30. Watts, S.W., Morrison, S.F., Davis, R.P. & Barman, S.M. Serotonin and blood pressure regulation. Pharmacol. Rev. 64, 359-388 (2012).
31. Gustafsson, B.I. et al. Long-term serotonin administration induces heart valve disease in rats. Circulation 111, 1517-1522 (2005).
32. Stunes, A.K. et al. Adipocytes express a functional system for serotonin synthesis, reuptake and receptor activation. Diabetes Obes. Metab. 13, 551-558 (2011).
33. Asghari, R., Lung, M.S.Y., Pilowsky, P.M. & Connor, M. Sex differences in the expression of serotonin-synthesizing enzymes in mouse trigeminal ganglia. Neuroscience 199, 429-437 (2011).
34. Kinoshita, M. et al. Regulation of adipocyte differentiation by activation of serotonin (5-HT) receptors 5-HT2AR and 5-HT2CR and involvement of microRNA-448-mediated repression of KLF5. Mol. Endocrinol. 24, 1978-1987 (2010).
35. Timmons, J.A. et al. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proc. Natl. Acad. Sci. USA 104, 4401-4406 (2007).
36. Nichols, D.E. & Nichols, C.D. Serotonin receptors. Chem. Rev. 108, 1614-1641 (2008).
37. Izikki, M. et al. Tryptophan hydroxylase 1 knockout and tryptophan hydroxylase 2 polymorphism: effects on hypoxic pulmonary hypertension in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 293, L1045-L1052 (2007).
38. Serra, F., LeFeuvre, R.A., Slater, D., Palou, A. & Rothwell, N.J. Thermogenic actions of tryptophan in the rat are mediated independently of 5-HT. Brain Res. 578, 327-334 (1992).
39. Kiefer, F.W. et al. Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue. Nat. Med. 18, 918-925 (2012).
40. Roberts, L.D. et al. ?-Aminoisobutyric acid induces browning of white fat and hepatic ?-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab. 19, 96-108 (2014).
41. Côté, F. et al. Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function. Proc. Natl. Acad. Sci. USA 100, 13525-13530 (2003).
42. O'Neill, H.M. et al. AMP-activated protein kinase (AMPK) ?1?2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. Proc. Natl. Acad. Sci. USA 108, 16092-16097 (2011).
43. Crane, J.D., Mottillo, E.P., Farncombe, T.H., Morrison, K.M. & Steinberg, G.R. A standardized infrared imaging technique that specifically detects UCP1-mediated thermogenesis in vivo. Mol. Metab. 3, 490-494 (2014).
44. Steinberg, G.R. et al. Whole body deletion of AMP-activated protein kinase ?2 reduces muscle AMPK activity and exercise capacity. J. Biol. Chem. 285, 37198-37209 (2010).
45. Watt, M.J. et al. CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Nat. Med. 12, 541-548 (2006).
46. Cui, Y. et al. Lrp5 functions in bone to regulate bone mass. Nat. Med. 17, 684-691 (2011).
47. Galic, S. et al. Hematopoietic AMPK ?1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. J. Clin. Invest. 121, 4903-4915 (2011).
48. Jorgensen, S.B. et al. Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity. Diabetes 62, 56-64 (2013).
49. Ohno, H., Shinoda, K., Spiegelman, B.M. & Kajimura, S. PPAR? agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab. 15, 395-404 (2012).