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
View: Text | PDF
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

×

Figure 8

Insulin signaling promotes adipocyte TPH2 expression via the Akt/mTORC1/SREBP1 pathway.

Options: View larger image (or click on image) Download as PowerPoint
Insulin signaling promotes adipocyte TPH2 expression via the Akt/mTORC1/...
(A) mRNA levels of Tph1, Tph2, and TPH2 protein expression in explants from eWAT after 6 hours of insulin (100 nM) stimulation (n = 4 for mRNA and 3 for protein per group). (B) mRNA levels of Tph2 in differentiated adipocytes from iWAT preadipocytes after 8 hours of different concentrations of insulin treatment (n = 5 per group). (C) mRNA levels of Tph2 in differentiated adipocytes from iWAT preadipocytes after 0, 3, and 6 hours of insulin (100 nM) treatment (n = 5 per group). (D) Correlation between TPH2 expression in human subcutaneous fat and fasting insulin levels of lean and obese individuals (n = 6 per group), Pearson’s r correlation coefficient with corresponding P values. (E) mRNA levels of Tph2 and Tph1 in differentiated adipocytes from iWAT preadipocytes after 6 hours of insulin or AS1842586 (10 μM) treatment (n = 4 per group). (F) mRNA levels of Tph2 in differentiated adipocytes from iWAT preadipocytes after 6 hours of insulin, rapamycin (25 μM), and/or fatostatin (20 μM) treatment (n = 3~4 per group). (G) TPH2 protein expression in differentiated adipocytes from iWAT after 6 hours of insulin, rapamycin (25 μM), and/or fatostatin (20 μM) treatment (n = 4 per group). (H) Graphical summary of how obesity promotes TPH2 expression and the role of TPH2 in developing obesity-induced metabolic dysfunction. Data are presented as mean ± SEM. For statistical analysis, 2-tailed Student’s t test (A), 1-way ANOVA with Tukey’s multiple-comparison test (B–D), or Welch and Brown-Forsythe ANOVA (E) was used. *P < 0.05, **P < 0.01; lowercase letters indicate statistical difference between treatments, P < 0.05.