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

Authors: PARK, BRIAN - Tufts University; REEVES, ANDREW - Tufts University; ZHU, YING - Tufts University; WILSON, ROBIN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; FERNANDES, SOPHIA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; BUHMAN, KIMBERLY - Purdue University; LYTLE, KELLI - Mayo Clinic; JENSEN, MICHAEL - Mayo Clinic; GREENBERG, ANDREW - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Journal of Clinical Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/15/2025
Publication Date: 6/2/2025
Citation: Park, B., Reeves, A., Zhu, Y., Wilson, R., Fernandes, S., Buhman, K., Lytle, K., Jensen, M., Greenberg, A. 2025. Hyperinsulinemia-induced upregulation of adipocyte TPH2 contributes to peripheral serotonin production, metabolic dysfunction, and obesity. Journal of Clinical Investigation. https://doi.org/10.1172/JCI190765.
DOI: https://doi.org/10.1172/JCI190765

Interpretive Summary: We demonstrate that in fat cells of mice and humans, there is increased expression of the protein, tryptophan hydroxylase 2. We find that tryptophan hydroxylase 2 generated serotonin, acts locally on fat cells and circulates in the blood to block the ability of insulin to drive glucose into cells (increasing circulating levels of glucose). Also, serotonin reduces the metabolic rate of the body to promote obesity. This enzyme, tryptophan hydroxylase 2, could be a potential target to reduce age-related obesity and its associated complications.

Technical 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 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 significantly elevated in both diet-induced obese (DIO) and ob/ob mice, as well as in obese humans. In high-fat diet (HFD)-fed mice, adipocyte TPH2 deficiency improves DIO-induced metabolic complications, enhances BAT thermogenesis, and increases intestinal energy harvesting efficiency without affecting adiposity. Conversely, TPH2 overexpression in epididymal adipocytes of chow-fed mice raises adipose and plasma 5-HT levels, suppresses BAT thermogenesis, and exacerbates obesity and metabolic dysfunction. We found that obesity-induced hyperinsulinemia upregulates adipocyte TPH2 expression via activation of mechanistic target of rapamycin complex 1 (mTORC1) and sterol regulatory element binding protein 1 (SREBP1). In humans, TPH2 mRNA levels in subcutaneous adipose tissue, but not TPH1, is 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.