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 3

Genetic ablation of adipocyte TPH2 expression protects mice from HFD-induced hepatic steatosis and adipocyte dysfunction.

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Genetic ablation of adipocyte TPH2 expression protects mice from HFD-ind...
(A) Representative images of H&E-stained liver after 12 weeks of HFD feeding (n = 5 per group). Scale bars: 200 μm. (B) TG levels in liver of mice after 12 weeks of HFD feeding (n = 5 per group). (C and D) Serum levels of ALT (C) and AST (D) (n = 5 per group). (E and F) mRNA levels of lipid metabolism–related genes (E) and proinflammatory genes (F) of liver after 12 weeks of HFD feeding (n = 6 per group). (G) Representative images of H&E staining and Galectin-3 (GAL-3 or MAC-2) immunohistochemical staining of eWAT showing CLS formation (indicated by red arrows) after 12 weeks of HFD feeding (n = 5 per group). Scale bars: 1,000 μm (top), 2 mm (bottom). (H) Average adipocyte size of mice after 12 weeks of HFD feeding (n = 5). (I) mRNA levels of Tph2 and Tph1 and TPH2 protein expression in eWAT after 12 weeks of HFD feeding (n = 8 for mRNA and 3 for protein per group). (J) eWAT 5-HT levels in chow- or HFD-fed mice for 12 weeks (n = 12 per group). (K) mRNA levels of lipid metabolism–related genes in eWAT after 12 weeks of HFD feeding (n = 8 per group). (L) Quantification of GAL-3–positive area in eWAT section from HFD-fed mice for 12 weeks (n = 5 per group). (M) mRNA levels of proinflammatory genes in eWAT after 12 weeks of HFD feeding (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, ***P < 0.001.