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ResearchIn-Press PreviewEndocrinologyMetabolism
Open Access | 10.1172/JCI190765
1Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, United States of America
2Department of Nutrition Science, Purdue University, West Lafayette, United States of America
3Endocrine Research Unit, Mayo Clinic, Rochester, United States of America
Find articles by Park, B. in: PubMed | Google Scholar
1Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, United States of America
2Department of Nutrition Science, Purdue University, West Lafayette, United States of America
3Endocrine Research Unit, Mayo Clinic, Rochester, United States of America
Find articles by Reeves, A. in: PubMed | Google Scholar
1Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, United States of America
2Department of Nutrition Science, Purdue University, West Lafayette, United States of America
3Endocrine Research Unit, Mayo Clinic, Rochester, United States of America
Find articles by Zhu, Y. in: PubMed | Google Scholar
1Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, United States of America
2Department of Nutrition Science, Purdue University, West Lafayette, United States of America
3Endocrine Research Unit, Mayo Clinic, Rochester, United States of America
Find articles by Wilson, R. in: PubMed | Google Scholar
1Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, United States of America
2Department of Nutrition Science, Purdue University, West Lafayette, United States of America
3Endocrine Research Unit, Mayo Clinic, Rochester, United States of America
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1Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, United States of America
2Department of Nutrition Science, Purdue University, West Lafayette, United States of America
3Endocrine Research Unit, Mayo Clinic, Rochester, United States of America
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1Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, United States of America
2Department of Nutrition Science, Purdue University, West Lafayette, United States of America
3Endocrine Research Unit, Mayo Clinic, Rochester, United States of America
Find articles by Lytle, K. in: PubMed | Google Scholar
1Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, United States of America
2Department of Nutrition Science, Purdue University, West Lafayette, United States of America
3Endocrine Research Unit, Mayo Clinic, Rochester, United States of America
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1Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, United States of America
2Department of Nutrition Science, Purdue University, West Lafayette, United States of America
3Endocrine Research Unit, Mayo Clinic, Rochester, United States of America
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Published June 2, 2025 - More info
Tryptophan hydroxylase (TPH) is a rate-limiting enzyme for serotonin or 5-hydroxytryptamine (5-HT) synthesis. Previously, adipocyte TPH1 has been linked to increased adipose 5-HT, reduced BAT thermogenesis, and obesity. However, the role of TPH2, a neural isoform highly expressed in obese adipose tissue, is unknown. Here, we report that adipose tissue expression of TPH2 is significantly elevated in both diet-induced obese (DIO) and ob/ob mice, as well as in obese humans. In high-fat diet (HFD)-fed mice, adipocyte TPH2 deficiency improves DIO-induced metabolic complications, enhances BAT thermogenesis, and increases intestinal energy harvesting efficiency without affecting adiposity. Conversely, TPH2 overexpression in epididymal adipocytes of chow-fed mice raises adipose and plasma 5-HT levels, suppresses BAT thermogenesis, and exacerbates obesity and metabolic dysfunction. We found that obesity-induced hyperinsulinemia upregulates adipocyte TPH2 expression via activation of mechanistic target of rapamycin complex 1 (mTORC1) and sterol regulatory element binding protein 1 (SREBP1). In humans, TPH2 mRNA levels in subcutaneous adipose tissue, but not TPH1, is positively correlated with fasting plasma insulin concentrations. In summary, our study demonstrates that obesity-associated increases in adipocyte TPH2 can regulate distal tissue physiology and energy metabolism, suggesting that TPH2 could be a potential therapeutic target for obesity and its associated complications.