Hyperinsulinemia-induced upregulation of adipocyte TPH2 contributes to peripheral serotonin production, metabolic dysfunction, and obesity
Brian I. Park, … , Michael D. Jensen, Andrew S. Greenberg
Brian I. Park, … , Michael D. Jensen, Andrew S. Greenberg
Published June 2, 2025
Citation Information: J Clin Invest. 2025;135(14):e190765. https://doi.org/10.1172/JCI190765.
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Research Article Endocrinology Metabolism

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

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 brown adipose tissue (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 dramatically elevated in mice with diet-induced obesity (DIO) and ob/ob mice, as well as in obese humans. In mice fed a high-fat diet, adipocyte TPH2 deficiency improved DIO-induced metabolic complications, enhanced BAT thermogenesis, and increased intestinal energy-harvesting efficiency without affecting adiposity. Conversely, TPH2 overexpression in epididymal adipocytes of chow-fed mice raised adipose and plasma 5-HT levels, suppressed BAT thermogenesis, and exacerbated obesity and metabolic dysfunction. We found that obesity-induced hyperinsulinemia upregulated adipocyte TPH2 expression via activation of mechanistic target of rapamycin complex 1 and SREBP1. In humans, TPH2 mRNA levels in subcutaneous adipose tissue, but not those of TPH1, are 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.

Authors

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

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Figure 2

Mice with adipocyte-specific deficiency of TPH2 are not resistant to HFD-induced weight gain but have improved glucose tolerance and insulin sensitivity, and reduced circulating 5-HT levels.

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Mice with adipocyte-specific deficiency of TPH2 are not resistant to HFD...
(A) Overview of generating adipocyte-specific TPH2-deficient mice (B) Representative photograph of HFD-Fl and HFD-KO mice after 12 weeks of HFD feeding. (C–E) Time course of body weight (C), fat (D), and lean mass (E) following HFD feeding (n = 8 for Chow-Fl and Chow-KO; n = 14 for HFD-Fl and HFD-KO). (F–H) Tissue weights of inguinal white adipose tissue (iWAT), eWAT, liver (F), and BAT (G), and representative photographs of collected tissues (H) (n = 8 for Chow-Fl and Chow-KO; n = 13 for HFD-Fl and HFD-KO). (I) Plasma levels of 5-HT from HFD-Fl and HFD-KO mice after 12 weeks of HFD feeding (n = 6 per group). (J) Glucose tolerance test (GTT) and AUC performed after 7 weeks of HFD feeding (n = 7 per group). (K) Insulin tolerance test (ITT) and AUC performed after 9 weeks of HFD feeding (n = 8 per group). (L and M) Fasting blood glucose (n = 13 per group) and plasma insulin levels (n = 7 per group) after 12 weeks of HFD feeding. (N) Relative levels of phosphorylated Akt (Ser473) to total Akt in liver, eWAT, and gastrocnemius muscle of HFD-Fl and HFD-KO mice, 15 minutes after an insulin injection following 8 weeks of HFD feeding (n = 5 per group). Data are presented as mean ± SEM. For statistical analysis, 2-way ANOVA with Dunnett’s test (C–G) or 2-tailed Student’s t test (I–N) was used. *P < 0.05, **P < 0.01, ***P < 0.001.