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

doi:10.1172/JCI190765

Hyperinsulinemia-induced upregulation of adipocyte TPH2 contributes to peripheral serotonin production, metabolic dysfunction, and obesity

Brian I. Park,¹ Andrew R. Reeves,¹ Ying Zhu,¹ Robin A. Wilson,¹ Sophia C. Fernandes,¹ Kimberly K. Buhman,² Kelli A. Lytle,³ Michael D. Jensen,³ and Andrew S. Greenberg¹

Published June 2, 2025 - More info

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Abstract

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.

Hyperinsulinemia-induced upregulation of adipocyte TPH2 contributes to peripheral serotonin production, metabolic dysfunction, and obesity

Brian I. Park,¹ Andrew R. Reeves,¹ Ying Zhu,¹ Robin A. Wilson,¹ Sophia C. Fernandes,¹ Kimberly K. Buhman,² Kelli A. Lytle,³ Michael D. Jensen,³ and Andrew S. Greenberg¹

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Hyperinsulinemia-induced upregulation of adipocyte TPH2 contributes to peripheral serotonin production, metabolic dysfunction, and obesity

Brian I. Park,1 Andrew R. Reeves,1 Ying Zhu,1 Robin A. Wilson,1 Sophia C. Fernandes,1 Kimberly K. Buhman,2 Kelli A. Lytle,3 Michael D. Jensen,3 and Andrew S. Greenberg1

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Brian I. Park,¹ Andrew R. Reeves,¹ Ying Zhu,¹ Robin A. Wilson,¹ Sophia C. Fernandes,¹ Kimberly K. Buhman,² Kelli A. Lytle,³ Michael D. Jensen,³ and Andrew S. Greenberg¹