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 4

Mice lacking adipocyte TPH2 expression exhibit increased BAT thermogenesis and systemic EE while retaining more energy by reducing fecal energy loss.

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Mice lacking adipocyte TPH2 expression exhibit increased BAT thermogenes...
(A) Systemic EE during 72 hours of indirect calorimetry (n = 6 per group). (B) Regression plot of average EE during 72 hours of measurement. ANCOVA was performed using body weight as a covariate (n = 6 per group). (C and D) Diet intake (C) and total distance moved (D) during 72 hours of indirect calorimetry measurement (n = 6 per group). (E and F) Representative thermal images of dorsal interscapular area (E) and dorsal interscapular surface temperature (F) (n = 10 per group). (G) mRNA levels of Tph2 and Tph1 in BAT after 12 weeks of HFD feeding (n = 8 per group). (H) mRNA levels of thermogenic genes and UCP1 protein expression in BAT after 12 weeks of HFD feeding (n = 8 for mRNA and 4 for protein per group). (I) Total gastrointestinal transit time after 8 weeks of HFD feeding (n = 10 per group). (J–L) Daily wet feces weight (J), water content of feces (K), and daily dried fecal weight (L) (n = 8 per group). (M–P) Fecal calorie content per gram measured by bomb calorimetry (M), daily energy loss via feces (N), daily energy intake during the fecal collection period (O), and daily level of energy harvest efficiency (P) (n = 8 per group). Data are presented as mean ± SEM. For statistical analysis, 2-tailed Student’s t test was used. *P < 0.05, **P < 0.01.