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Peripheral Serotonin: a New Player in Systemic Energy Homeostasis
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  • Journal title : Molecules and Cells
  • Volume 38, Issue 12,  2015, pp.1023-1028
  • Publisher : Korea Society for Molecular and Cellular Biology
  • DOI : 10.14348/molcells.2015.0258
 Title & Authors
Peripheral Serotonin: a New Player in Systemic Energy Homeostasis
Namkung, Jun; Kim, Hail; Park, Sangkyu;
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Whole body energy balance is achieved through the coordinated regulation of energy intake and energy expenditure in various tissues including liver, muscle and adipose tissues. A positive energy imbalance by excessive energy intake or insufficient energy expenditure results in obesity and related metabolic diseases. Although there have been many obesity treatment trials aimed at the reduction of energy intake, these strategies have achieved only limited success because of their associated adverse effects. An ancient neurotransmitter, serotonin is among those traditional pharmacological targets for anti-obesity treatment because it exhibits strong anorectic effect in the brain. However, recent studies suggest the new functions of peripheral serotonin in energy homeostasis ranging from the endocrine regulation by gut-derived serotonin to the autocrine/paracrine regulation by adipocyte-derived serotonin. Here, we discuss the role of serotonin in the regulation of energy homeostasis and introduce peripheral serotonin as a possible target for anti-obesity treatment.
adipose tissue;energy homeostasis;obesity;tryptophan hydroxylase;serotonin;
 Cited by
Regulation of Systemic Energy Homeostasis by Peripheral Serotonin,;;;;

Journal of mucopolysaccharidosis and rare disease, 2016. vol.2. 2, pp.43-45 crossref(new window)
Health and disease, an orchestra of three players: Serotonin, orexins, and nitric oxide, Journal of Neuroscience Research, 2017, 95, 10, 1891  crossref(new windwow)
Increased Serotonin Signaling Contributes to the Warburg Effect in Pancreatic Tumor Cells Under Metabolic Stress and Promotes Growth of Pancreatic Tumors in Mice, Gastroenterology, 2017, 153, 1, 277  crossref(new windwow)
Profiling of the circadian metabolome in thioacetamide-induced liver cirrhosis in mice, Hepatology Communications, 2017, 1, 7, 704  crossref(new windwow)
Microbiota-derived tryptophan indoles increase after gastric bypass surgery and reduce intestinal permeability in vitro and in vivo, Neurogastroenterology & Motility, 2017, e13178  crossref(new windwow)
Quantitative profiling of neurotransmitter abnormalities in brain, cerebrospinal fluid, and serum of experimental diabetic encephalopathy male rat, Journal of Neuroscience Research, 2017  crossref(new windwow)
How important is tryptophan in human health?, Critical Reviews in Food Science and Nutrition, 2017, 1  crossref(new windwow)
Dietary overload lithium decreases the adipogenesis in abdominal adipose tissue of broiler chickens, Environmental Toxicology and Pharmacology, 2017, 49, 163  crossref(new windwow)
5-HT Drives Mortality in Sepsis Induced by Cecal Ligation and Puncture in Mice, Mediators of Inflammation, 2017, 2017, 1  crossref(new windwow)
The Diverse Metabolic Roles of Peripheral Serotonin, Endocrinology, 2017, 158, 5, 1049  crossref(new windwow)
The drug transporter OAT3 (SLC22A8) and endogenous metabolite communication via the gut–liver–kidney axis, Journal of Biological Chemistry, 2017, 292, 38, 15789  crossref(new windwow)
β-cell serotonin production is associated with female sex, old age, and diabetes-free condition, Biochemical and Biophysical Research Communications, 2017  crossref(new windwow)
Serotoninergic and Circadian Systems: Driving Mammary Gland Development and Function, Frontiers in Physiology, 2016, 7  crossref(new windwow)
Dysbiosis of Gut Microbiota Associated with Clinical Parameters in Polycystic Ovary Syndrome, Frontiers in Microbiology, 2017, 8  crossref(new windwow)
Serotonergic Control of Metabolic Homeostasis, Frontiers in Cellular Neuroscience, 2017, 11  crossref(new windwow)
Regulation of Systemic Energy Homeostasis by Peripheral Serotonin, Journal of mucopolysaccharidosis and rare disease, 2016, 2, 2, 43  crossref(new windwow)
Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2AReceptor, Journal of Biological Chemistry, 2016, 291, 38, 20210  crossref(new windwow)
Looking Beyond the 5-HTTLPR Polymorphism: Genetic and Epigenetic Layers of Regulation Affecting the Serotonin Transporter Gene Expression, Molecular Neurobiology, 2016  crossref(new windwow)
Alenina, N., Kikic, D., Todiras, M., Mosienko, V., Qadri, F., Plehm, R., Boye, P., Vilianovitch, L., Sohr, R., Tenner, K., et al. (2009). Growth retardation and altered autonomic control in mice lacking brain serotonin. Proc. Natl. Acad. Sci. USA 106, 10332-10337. crossref(new window)

Arase, K., Sakaguchi, T., and Bray, G.A. (1988). Effect of fenfluramine on sympathetic firing rate. Pharmacol. Biochem. Behav. 29, 675-680. crossref(new window)

Bertrand, R.L., Senadheera, S., Markus, I., Liu, L., Howitt, L., Chen, H., Murphy, T.V., Sandow, S.L., and Bertrand, P.P. (2011). A Western diet increases serotonin availability in rat small intestine. Endocrinology 152, 36-47. crossref(new window)

Bouwknecht, J.A., van der Gugten, J., Hijzen, T.H., Maes, R.A., Hen, R., and Olivier, B. (2001). Male and female 5-HT(1B) receptor knockout mice have higher body weights than wildtypes. Physiol. Behav. 74, 507-516. crossref(new window)

Brand, T., and Anderson, G.M. (2011). The measurement of plateletpoor plasma serotonin: a systematic review of prior reports and recommendations for improved analysis. Clin. Chem. 57, 1376-1386. crossref(new window)

Breisch, S.T., Zemlan, F.P., and Hoebel, B.G. (1976). Hyperphagia and obesity following serotonin depletion by intraventricular pchlorophenylalanine. Science 192, 382-385. crossref(new window)

Collins, S., Yehuda-Shnaidman, E., and Wang, H. (2010). Positive and negative control of Ucp1 gene transcription and the role of [beta]-adrenergic signaling networks. Int. J. Obes. 34, S28-S33. crossref(new window)

Colman, E., Golden, J., Roberts, M., Egan, A., Weaver, J., and Rosebraugh, C. (2012). The FDA's assessment of two drugs for chronic weight management. N Eng. J. Med. 367, 1577-1579. crossref(new window)

Crane, J.D., Palanivel, R., Mottillo, E.P., Bujak, A.L., Wang, H., Ford, R.J., Collins, A., Blumer, R.M., Fullerton, M.D., Yabut, J.M., et al. (2015). Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis. Nat. Med. 21, 166-172. crossref(new window)

Feldman, J.M. (1988). Effect of the monoamine oxidase inhibitors clorgyline and pargyline on the hyperphagia of obese mice. Behav. Brain Res. 29, 147-158. crossref(new window)

Gershon, M.D., and Ross, L.L. (1966). Location of sites of 5-hydroxytryptamine storage and metabolism by radioautography. J. Physiol. 186, 477-492. crossref(new window)

Gershon, M.D., and Tack, J. (2007). The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 132, 397-414. crossref(new window)

Gres, S., Canteiro, S., Mercader, J., and Carpene, C. (2013). Oxidation of high doses of serotonin favors lipid accumulation in mouse and human fat cells. Mol. Nutr. Food Res. 57, 1089-1099. crossref(new window)

Gutknecht, L., Araragi, N., Merker, S., Waider, J., Sommerlandt, F.M., Mlinar, B., Baccini, G., Mayer, U., Proft, F., Hamon, M., et al. (2012). Impacts of brain serotonin deficiency following Tph2 inactivation on development and raphe neuron serotonergic specification. PLoS One 7, e43157. crossref(new window)

Halford, J.C.G., and Blundell, J.E. (1996). The 5-HT1B receptor agonist CP-94,253 reduces food intake and preserves the behavioural satiety sequence. Physiol. Behav. 60, 933-939. crossref(new window)

Hannon, J., and Hoyer, D. (2008). Molecular biology of 5-HT receptors. Behav. Brain Res. 195, 198-213. crossref(new window)

Haub, S., Ritze, Y., Ladel, I., Saum, K., Hubert, A., Spruss, A., Trautwein, C., and Bischoff, S.C. (2011). Serotonin receptor type 3 antagonists improve obesity-associated fatty liver disease in mice. J. Pharmacol. Exp. Ther. 339, 790-798. crossref(new window)

Heal, D.J., Aspley, S., Prow, M.R., Jackson, H.C., Martin, K.F., and Cheetham, S.C. (1998). Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine. Int. J. Obes. Relat. Metab. Disord. 22 Suppl 1, S18-28; discussion S29.

Heisler, L.K., Kanarek, R.B., and Gerstein, A. (1997). Fluoxetine decreases fat and protein intakes but not carbohydrate intake in male rats. Pharmacol. Biochem. Behav. 58, 767-773. crossref(new window)

Heisler, L.K., Cowley, M.A., Tecott, L.H., Fan, W., Low, M.J., Smart, J.L., Rubinstein, M., Tatro, J.B., Marcus, J.N., Holstege, H., et al. (2002). Activation of central melanocortin pathways by fenfluramine. Science 297, 609-611. crossref(new window)

Kennett, G.A., and Curzon, G. (1988). Evidence that hypophagia induced by mCPP and TFMPP requires 5-HT1C and 5-HT1B receptors; hypophagia induced by RU 24969 only requires 5-HT1B receptors. Psychopharmacology (Berl) 96, 93-100. crossref(new window)

Keszthelyi, D., Troost, F.J., and Masclee, A.A.M. (2009). Understanding the role of tryptophan and serotonin metabolism in gastrointestinal function. Neurogastroenterol. Motil. 21, 1239-1249. crossref(new window)

Kim, H., Toyofuku, Y., Lynn, F.C., Chak, E., Uchida, T., Mizukami, H., Fujitani, Y., Kawamori, R., Miyatsuka, T., Kosaka, Y., et al. (2010). Serotonin regulates pancreatic beta cell mass during pregnancy. Nat. Med. 16, 804-808. crossref(new window)

Kim, H.J., Kim, J.H., Noh, S., Hur, H.J., Sung, M.J., Hwang, J.T., Park, J.H., Yang, H.J., Kim, M.S., Kwon, D.Y., et al. (2011). Metabolomic analysis of livers and serum from high-fat diet induced obese mice. J. Proteome Res. 10, 722-731. crossref(new window)

Kim, K., Oh, C.M., Ohara-Imaizumi, M., Park, S., Namkung, J., Yadav, V.K., Tamarina, N.A., Roe, M.W., Philipson, L.H., Karsenty, G., et al. (2015). Functional role of serotonin in insulin secretion in a diet-induced insulin-resistant state. Endocrinology 156, 444-452. crossref(new window)

Kinoshita, M., Ono, K., Horie, T., Nagao, K., Nishi, H., Kuwabara, Y., Takanabe-Mori, R., Hasegawa, K., Kita, T., and Kimura, T. (2010). 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. crossref(new window)

Lam, D.D., and Heisler, L.K. (2007). Serotonin and energy balance: molecular mechanisms and implications for type 2 diabetes. Exp. Rev. Mol. Med. 9, 1-24.

Lam, D.D., Przydzial, M.J., Ridley, S.H., Yeo, G.S.H., Rochford, J.J., O'Rahilly, S., and Heisler, L.K. (2008). Serotonin 5-HT2C receptor agonist rromotes hypophagia via downstream activation of melanocortin 4 receptors. Endocrinology 149, 1323-1328. crossref(new window)

Lam, D.D., Garfield, A.S., Marston, O.J., Shaw, J., and Heisler, L.K. (2010). Brain serotonin system in the coordination of food intake and body weight. Pharmacol. Biochem. Behav. 97, 84-91. crossref(new window)

Le Feuvre, R.A., Aisenthal, L., and Rothwell, N.J. (1991). Involvement of corticotrophin releasing factor (CRF) in the thermogenic and anorexic actions of serotonin (5-HT) and related compounds. Brain Res. 555, 245-250. crossref(new window)

Lesurtel, M., Graf, R., Aleil, B., Walther, D.J., Tian, Y., Jochum, W., Gachet, C., Bader, M., and Clavien, P.A. (2006). Platelet-derived serotonin mediates liver regeneration. Science 312, 104-107. crossref(new window)

Martin, C.K., Redman, L.M., Zhang, J., Sanchez, M., Anderson, C.M., Smith, S.R., and Ravussin, E. (2010). Lorcaserin, a 5-HT(2C) receptor agonist, reduces body weight by decreasing energy intake without influencing energy expenditure. J. Clin. Endocrinol. Metab. 96, 837-845.

Matsuda, M., Imaoka, T., Vomachka, A.J., Gudelsky, G.A., Hou, Z., Mistry, M., Bailey, J.P., Nieport, K.M., Walther, D.J., Bader, M., et al. (2004). Serotonin regulates mammary gland development via an autocrine-paracrine loop. Dev. Cell 6, 193-203. crossref(new window)

Merens, W., Willem Van der Does, A.J., and Spinhoven, P. (2007). The effects of serotonin manipulations on emotional information processing and mood. J. Affect. Disord. 103, 43-62. crossref(new window)

Monti, J.M. (2011). Serotonin control of sleep-wake behavior. Sleep Med. Rev. 15, 269-281. crossref(new window)

Moore, M.C., DiCostanzo, C.A., Dardevet, D., Lautz, M., Farmer, B., Neal, D.W., and Cherrington, A.D. (2004). Portal infusion of a selective serotonin reuptake inhibitor enhances hepatic glucose disposal in conscious dogs. Am. J. Physiol. Endocrinol. Metab. 287, E1057-1063. crossref(new window)

Murphy, D.L., and Lesch, K.P. (2008). Targeting the murine serotonin transporter: insights into human neurobiology. Nat. Rev. Neurosci. 9, 85-96.

Nomura, S., Shouzu, A., Omoto, S., Nishikawa, M., and Iwasaka, T. (2005). 5-HT2A receptor antagonist increases circulating adiponectin in patients with type 2 diabetes. Blood Coagul. Fibrinolysis 16, 423-428. crossref(new window)

Nonogaki, K., Strack, A.M., Dallman, M.F., and Tecott, L.H. (1998). Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat. Med. 4, 1152-1156. crossref(new window)

Oh, C.M., Namkung, J., Go, Y., Shong, K.E., Kim, K., Kim, H., Park, B.Y., Lee, H.W., Jeon, Y.H., Song, J., et al. (2015). Regulation of systemic energy homeostasis by serotonin in adipose tissues. Nat. Commun. 6, 6794. crossref(new window)

Ohara-Imaizumi, M., Kim, H., Yoshida, M., Fujiwara, T., Aoyagi, K., Toyofuku, Y., Nakamichi, Y., Nishiwaki, C., Okamura, T., and Uchida, T. (2013). Serotonin regulates glucose-stimulated insulin secretion from pancreatic ${\beta}$ cells during pregnancy. Proc. Natl. Acad. Sci. USA 110, 19420-19425. crossref(new window)

Rothwell, N.J., and Stock, M.J. (1987). Effect of diet and fenfluramine on thermogenesis in the rat: possible involvement of serotonergic mechanisms. Int. J. Obes. 11, 319-324.

Sakaguchi, T., and Bray, G.A. (1989). Effect of norepinephrine, serotonin and tryptophan on the firing rate of sympathetic nerves. Brain Res. 492, 271-280. crossref(new window)

Savelieva, K.V., Zhao, S., Pogorelov, V.M., Rajan, I., Yang, Q., Cullinan, E., and Lanthorn, T.H. (2008). Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants. PLoS One 3, e3301. crossref(new window)

Serretti, A., and Mandelli, L. (2010). Antidepressants and body weight: a comprehensive review and meta-analysis. J. Clin. Psychiatry 71, 1259-1272. crossref(new window)

Sohn, J.W., Elmquist, J.K., and Williams, K.W. (2013). Neuronal circuits that regulate feeding behavior and metabolism. Trends Neurosci. 36, 504-512. crossref(new window)

Sumara, G., Sumara, O., Kim, Jason K., and Karsenty, G. (2012). Gut-derived serotonin is a multifunctional determinant to fasting adaptation. Cell Metab. 16, 588-600. crossref(new window)

Tecott, L.H., Sun, L.M., Akana, S.F., Strack, A.M., Lowenstein, D.H., Dallman, M.F., and Julius, D. (1995). Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 374, 542-546. crossref(new window)

Uchida-Kitajima, S., Yamauchi, T., Takashina, Y., Okada-Iwabu, M., Iwabu, M., Ueki, K., and Kadowaki, T. (2008). 5-Hydroxytryptamine 2A receptor signaling cascade modulates adiponectin and plasminogen activator inhibitor 1 expression in adipose tissue. FEBS Lett. 582, 3037-3044. crossref(new window)

Vickers, S.P., Clifton, P.G., Dourish, C.T., and Tecott, L.H. (1999). Reduced satiating effect of d-fenfluramine in serotonin 5-HT2C receptor mutant mice. Psychopharmacology 143, 309-314. crossref(new window)

Wade, P.R., Chen, J., Jaffe, B., Kassem, I.S., Blakely, R.D., and Gershon, M.D. (1996). Localization and function of a 5-HT transporter in crypt epithelia of the gastrointestinal tract. J. Neurosci. 16, 2352-2364. crossref(new window)

Walther, D.J., and Bader, M. (2003). A unique central tryptophan hydroxylase isoform. Biochem. Pharmacol. 66, 1673-1680. crossref(new window)

Watanabe, H., Akasaka, D., Ogasawara, H., Sato, K., Miyake, M., Saito, K., Takahashi, Y., Kanaya, T., Takakura, I., Hondo, T., et al. (2010). Peripheral serotonin enhances lipid metabolism by accelerating bile acid turnover. Endocrinology 151, 4776-4786. crossref(new window)

Yadav, V.K., Ryu, J.H., Suda, N., Tanaka, K.F., Gingrich, J.A., Schutz, G., Glorieux, F.H., Chiang, C.Y., Zajac, J.D., Insogna, K.L., et al. (2008). Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135, 825-837. crossref(new window)

Yamakawa, J., Takahashi, T., Itoh, T., Kusaka, K., Kawaura, K., Wang, X.Q., and Kanda, T. (2003). A novel serotonin blocker, sarpogrelate, increases circulating adiponectin levels in diabetic patients with arteriosclerosis obliterans. Diabetes Care 26, 2477-2478. crossref(new window)

Young, S.N., and Leyton, M. (2002). The role of serotonin in human mood and social interaction: Insight from altered tryptophan levels. Pharmacol. Biochem. Behav. 71, 857-865. crossref(new window)

Zhang, X., Beaulieu, J.M., Sotnikova, T.D., Gainetdinov, R.R., and Caron, M.G. (2004). Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science 305, 217. crossref(new window)

Zhou, L., Sutton, G.M., Rochford, J.J., Semple, R.K., Lam, D.D., Oksanen, Laura J., Thornton-Jones, Z.D., Clifton, P.G., Yueh, C.-Y., Evans, M.L., et al. (2007). Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways. Cell Metab. 6, 398-405. crossref(new window)