Background Obesity is defined as excessive fat mass and is a major cause of many chronic diseases such as diabetes, cardiovascular disease, and cancer. Increasing energy expenditure and regulating adipose tissue metabolism are important targets for the treatment of obesity. Serotonin (5-hydroxytryptophan [5-HT]) is a monoamine metabolite of the essential amino acid tryptophan. Here, we demonstrated that 5-HT in mature adipocytes regulated energy expenditure and lipid metabolism.
Methods Tryptophan hydroxylase 1 (TPH1) is the rate-limiting enzyme during 5-HT synthesis in non-neural peripheral tissues. We generated adipose tissue-specific Tph1 knockout (Tph1 FKO) mice and adipose tissue-specific serotonin receptor 2A KO (Htr2a FKO) mice and analyzed their phenotypes during high-fat diet (HFD) induced obesity.
Results Tph1 FKO mice fed HFD exhibited reduced lipid accumulation, increased thermogenesis, and resistance to obesity. In addition, Htr2a FKO mice fed HFD showed reduced lipid accumulation in white adipose tissue and resistance to obesity.
Conclusion These data suggest that the inhibition of serotonin signaling might be an effective strategy in obesity.
Citations
Citations to this article as recorded by
Sulforaphane-rich aqueous broccoli seed extract suppresses diet-induced obesity via 5-HT2A/AMPK signaling in mice Yong Jae Jeon, Junkyu Park, Keun-Tae Park, Heejoon Jo, Soohyun Um, Hyeongju Jeong, Kyuho Moon, Seung-Su Lee, Jinbong Park, Ji Hoon Jung, Seong-Gyu Ko, Kyungjin Lee, Woojin Kim Phytomedicine.2026; 153: 157935. CrossRef
TPH1-dependent maternal hyposerotonemia: long-term effects on adult wild-type mouse offspring Françoise Saurini, Carolina Jaliffa, Gwenaëlle Le Pen, Zsolt Csaba, Chantal Joubert, Jacques Callebert, Jean-Marie Launay, Catherine Senamaud-Beaufort, Oumy Seydi, Pierre Gressens, Guilan Vodjdani, Sylvie Berrard, Tania Vitalis Communications Biology.2026;[Epub] CrossRef
Serotonin signaling to regulate energy metabolism: a gut microbiota perspective Guoli Li, Sijing Dong, Chunhao Liu, Jing Yang, Patrick C N Rensen, Yanan Wang Life Metabolism.2025;[Epub] CrossRef
Gut Bacteria-Derived Tryptamine Ameliorates Diet-Induced Obesity and Insulin Resistance in Mice Jongjun Lee, Hye-Rim Jang, Dongjin Lee, Yeonmi Lee, Hui-Young Lee International Journal of Molecular Sciences.2025; 26(3): 1327. CrossRef
Hyperinsulinemia-induced upregulation of adipocyte TPH2 contributes to peripheral serotonin production, metabolic dysfunction, and obesity Brian I. Park, Andrew R. Reeves, Ying Zhu, Robin A. Wilson, Sophia C. Fernandes, Kimberly K. Buhman, Kelli A. Lytle, Michael D. Jensen, Andrew S. Greenberg Journal of Clinical Investigation.2025;[Epub] CrossRef
Differential effects of lithium on metabolic dysfunctions in astrocytes derived from bipolar disorder patients Gyu Hyeon Baek, Dayeon Kim, Geurim Son, Hyunsu Do, Gyu-Bum Yeon, Mahn Jae Lee, Moongi Ji, Ji-Hoon Son, Mingyu Ju, Insook Ahn, Chanhee S. Kang, Haeun Lee, Sungwoo Choi, Jae Myoung Suh, Jinsoo Seo, Fred H. Gage, Man-Jeong Paik, YongKeun Park, Dae-Sung Kim, Molecular Psychiatry.2025; 30(12): 5833. CrossRef
Amino Acid Metabolite Profiling for Predicting and Understanding the Metabolic Effects of Metabolic and Bariatric Surgery Hyeon-Seong Lee, Jaeyoung Kwon, Yeongkeun Kwon Journal of Metabolic and Bariatric Surgery.2025; 14(2): 124. CrossRef
Tryptophan Metabolism in Obesity: Pathways, Mechanisms, and Therapeutic Perspectives Ghazaleh Shimi Current Medical Science.2025; 45(6): 1304. CrossRef
Tryptophan enhances diet-induced improvement of white adipose tissue in obese rats Roman Yanko, Mikhail Levashov Archives of Biological Sciences.2025; 77(4): 323. CrossRef
Linking serotonin homeostasis to gut function: Nutrition, gut microbiota and beyond Lili Jiang, Dandan Han, Youling Hao, Zhuan Song, Zhiyuan Sun, Zhaolai Dai Critical Reviews in Food Science and Nutrition.2024; 64(21): 7291. CrossRef
Gut microbiota dysbiosis and decreased levels of acetic and propionic acid participate in glucocorticoid-induced glycolipid metabolism disorder Qin Zhang, Gaopeng Guan, Jie Liu, Wenmu Hu, Ping Jin, Yung-Fu Chang mBio.2024;[Epub] CrossRef
Exploring the contribution of mammary-derived serotonin on liver and pancreas metabolism during lactation Sena L. Field, Everardo Anta Galvan, Laura L. Hernandez, Jimena Laporta, Sina Safayi PLOS ONE.2024; 19(6): e0304910. CrossRef
Metabolic profiling of tryptophan pathways: Implications for obesity and metabolic dysfunction‐associated steatotic liver disease Carmen Arto, Elena Cristina Rusu, Helena Clavero‐Mestres, Andrea Barrientos‐Riosalido, Laia Bertran, Razieh Mahmoudian, Carmen Aguilar, David Riesco, Javier Ugarte Chicote, David Parada, Salomé Martínez, Fàtima Sabench, Cristóbal Richart, Teresa Auguet European Journal of Clinical Investigation.2024;[Epub] CrossRef
Peripheral Serotonin Controls Dietary Fat Absorption and Chylomicron Secretion via 5-HT4 Receptor in Males Fitore Raka, Simon Hoffman, Asal Nady, Henry Guan, Rianna Zhang, Huaqing Wang, Waliul I Khan, Khosrow Adeli Endocrinology.2024;[Epub] CrossRef
The 5-HT-related gut-brain axis in obesity Chaoyong Jiang, Qiong Zhan, Chang Zeng Life Sciences.2024; 358: 123171. CrossRef
The Chain-Mediating Effect of Obesity, Depressive Symptoms on the Association between Dietary Quality and Cardiovascular Disease Risk Shuai Zhang, Limei E, Zhonghai Lu, Yingying Yu, Xuebin Yang, Yao Chen, Xiubo Jiang Nutrients.2023; 15(3): 629. CrossRef
Metabolic and Molecular Response to High-Fat Diet Differs between Rats with Constitutionally High and Low Serotonin Tone Petra Baković, Maja Kesić, Darko Kolarić, Jasminka Štefulj, Lipa Čičin-Šain International Journal of Molecular Sciences.2023; 24(3): 2169. CrossRef
Serotonin transporter-deficient mice display enhanced adipose tissue inflammation after chronic high-fat diet feeding Johannes Hoch, Niklas Burkhard, Shanshan Zhang, Marina Rieder, Timoteo Marchini, Vincent Geest, Krystin Krauel, Timm Zahn, Nicolas Schommer, Muataz Ali Hamad, Carolina Bauer, Nadine Gauchel, Daniela Stallmann, Claus Normann, Dennis Wolf, Rüdiger Eberhard Frontiers in Immunology.2023;[Epub] CrossRef
The role of serotonin in prenatal ontogenesis Inna I. Evsyukova Journal of obstetrics and women's diseases.2023; 72(4): 81. CrossRef
Genome-wide survey and functional analysis reveal TCF21 promotes chicken preadipocyte differentiation by directly upregulating HTR2A Xinyang Zhang, Bohan Cheng, Yanyan Ma, Yumeng Liu, Ning Wang, Hui Zhang, Yumao Li, Yuxiang Wang, Peng Luan, Zhiping Cao, Hui Li Biochemical and Biophysical Research Communications.2022; 587: 131. CrossRef
Maternal Metabolic State and Fetal Sex and Genotype Modulate Methylation of the Serotonin Receptor Type 2A Gene (HTR2A) in the Human Placenta Marina Horvatiček, Maja Perić, Ivona Bečeheli, Marija Klasić, Maja Žutić, Maja Kesić, Gernot Desoye, Sandra Nakić Radoš, Marina Ivanišević, Dubravka Hranilovic, Jasminka Štefulj Biomedicines.2022; 10(2): 467. CrossRef
Synthesis and biological evaluation of tyrosine derivatives as peripheral 5HT2A receptor antagonists for nonalcoholic fatty liver disease Minhee Kim, Wonil Choi, Jihyeon Yoon, Byung-kwan Jeong, Suvarna H. Pagire, Haushabhau S. Pagire, Jungsun Park, Jung Eun Nam, Chang Joo Oh, Jae-Han Jeon, Seong Soon Kim, Byung Hoi Lee, Jin Sook Song, Myung Ae Bae, In-Kyu Lee, Hail Kim, Jin Hee Ahn European Journal of Medicinal Chemistry.2022; 239: 114517. CrossRef
Serotonin in the regulation of systemic energy metabolism Joon Ho Moon, Chang‐Myung Oh, Hail Kim Journal of Diabetes Investigation.2022; 13(10): 1639. CrossRef
Traumatic brain injury alters the gut-derived serotonergic system and associated peripheral organs Natosha M. Mercado, Guanglin Zhang, Zhe Ying, Fernando Gómez-Pinilla Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.2022; 1868(11): 166491. CrossRef
Modulation of adipose tissue metabolism by microbial-derived metabolites Wenyun Liu, Ge Yang, Pinyi Liu, Xin Jiang, Ying Xin Frontiers in Microbiology.2022;[Epub] CrossRef
Pancreatic Sirtuin 3 Deficiency Promotes Hepatic Steatosis by Enhancing 5-Hydroxytryptamine Synthesis in Mice With Diet-Induced Obesity Xing Ming, Arthur C.K. Chung, Dandan Mao, Huanyi Cao, Baoqi Fan, Willy K.K. Wong, Chin Chung Ho, Heung Man Lee, Kristina Schoonjans, Johan Auwerx, Guy A. Rutter, Juliana C.N. Chan, Xiao Yu Tian, Alice P.S. Kong Diabetes.2021; 70(1): 119. CrossRef
Peripheral Selective Oxadiazolylphenyl Alanine Derivatives as Tryptophan Hydroxylase 1 Inhibitors for Obesity and Fatty Liver Disease Eun Jung Bae, Won Gun Choi, Haushabhau S. Pagire, Suvarna H. Pagire, Saravanan Parameswaran, Jun-Ho Choi, Jihyeon Yoon, Won-il Choi, Ji Hun Lee, Jin Sook Song, Myung Ae Bae, Mijin Kim, Jae-Han Jeon, In-Kyu Lee, Hail Kim, Jin Hee Ahn Journal of Medicinal Chemistry.2021; 64(2): 1037. CrossRef
A Systems Biology Approach to Investigating the Interaction between Serotonin Synthesis by Tryptophan Hydroxylase and the Metabolic Homeostasis Suhyeon Park, Yumin Kim, Jibeom Lee, Jeong Yun Lee, Hail Kim, Sunjae Lee, Chang-Myung Oh International Journal of Molecular Sciences.2021; 22(5): 2452. CrossRef
Metabolic Disturbances in Rat Sublines with Constitutionally Altered Serotonin Homeostasis Maja Kesić, Petra Baković, Ranko Stojković, Jasminka Štefulj, Lipa Čičin-Šain International Journal of Molecular Sciences.2021; 22(10): 5400. CrossRef
The Mechanism of Secretion and Metabolism of Gut-Derived 5-Hydroxytryptamine Ning Liu, Shiqiang Sun, Pengjie Wang, Yanan Sun, Qingjuan Hu, Xiaoyu Wang International Journal of Molecular Sciences.2021; 22(15): 7931. CrossRef
Inhibiting serotonin signaling through HTR2B in visceral adipose tissue improves obesity-related insulin resistance Won Gun Choi, Wonsuk Choi, Tae Jung Oh, Hye-Na Cha, Inseon Hwang, Yun Kyung Lee, Seung Yeon Lee, Hyemi Shin, Ajin Lim, Dongryeol Ryu, Jae Myoung Suh, So-Young Park, Sung Hee Choi, Hail Kim Journal of Clinical Investigation.2021;[Epub] CrossRef
Serotonergic Regulation of Hepatic Energy Metabolism Jiwon Park, Wooju Jeong, Chahyeon Yun, Hail Kim, Chang-Myung Oh Endocrinology and Metabolism.2021; 36(6): 1151. CrossRef