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
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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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 5

ob/ob mice have elevated TPH2 expression in adipocytes, and mice overexpressing eWAT TPH2 develop metabolic dysfunction and have higher levels of circulating 5-HT level in the absence of HFD feeding.

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ob/ob mice have elevated TPH2 expression in adipocytes, and mice overex...
(A) Body weights of mice after 6 weeks of either chow or HFD feeding (n = 7 for chow, 10 for HFD, and 4 for ob/ob). (B) mRNA levels of Tph1 and Tph2 of isolated epididymal white adipocytes in chow- or HFD-fed C57BL6J mice and chow-fed ob/ob mice for 6 weeks (n = 4 for chow, 8 for HFD, and 4 for ob/ob). (C) mRNA levels of Tph1 and Tph2 of isolated brown adipocytes in chow- or HFD-fed C57BL6J mice and chow-fed ob/ob mice for 6 weeks (n = 4 for chow, 8 for HFD, and 4 for ob/ob). (D) Plasma 5-HT levels in ob/ob and HFD- and chow-fed mice for 6 weeks (n = 6 for chow and HFD; n = 4 for ob/ob). (E) Overview of generating AAV-induced adipocyte-specific TPH2-OE mice. (F) Representative photograph of control and TPH2-OE, taken 20 weeks after AAV-TPH2 injection. (G–I) Time course of body weight (H), fat (I), and lean mass (J) 20 weeks after AAV-TPH2 injection (n = 9 per group). (J–L) Tissue weights (J and K) and representative photographs of collected tissues (L) (n = 9 per group). (M) Circulating levels of 5-HT from control and TPH2-OE mice, measured 20 weeks after AAV-TPH2 injection (n = 6 per group). (N) GTT and its AUC, performed 7 weeks after AAV-TPH2 injection (n = 7 per group). (O) ITT and its AUC, performed 9 weeks after AAV-TPH2 injection (n = 8 per group). (P and Q) Fasting blood glucose (n = 9 per group) and plasma insulin levels (n = 6 per group), measured 20 weeks after AAV-TPH2 injection. (R) Relative levels of phospho-Akt (Ser473) to total Akt in liver, eWAT, and gastrocnemius muscle of control and TPH2-OE mice, 8 weeks after AAV-TPH2 injection with insulin stimulation (15 minutes, n = 5 per group). Data are presented as mean ± SEM. For statistical analysis, 1-way ANOVA with Tukey’s multiple-comparison test (A–D), 2-way ANOVA with Dunnett’s test (G–I), or 2-tailed Student’s t test (J, K, and M–R) was used. *P < 0.05, **P < 0.01, ***P < 0.001.