Serotonin transporter deficiency drives estrogen-dependent obesity and glucose intolerance

• Published in: Scientific reports Vol. 7; no. 1; pp. 1137 - 14
• Main Authors: Zha, Weibin, Ho, Horace T. B., Hu, Tao, Hebert, Mary F., Wang, Joanne
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.04.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/51; 14; 14/63; 17β-Estradiol; 38; 38/77; 64; 64/60; 692/163/2743/393; 692/699/476/1414; Adipose tissue; Animals; Aromatase; Chromium; Estradiol - metabolism; Glucose; Glucose Intolerance - physiopathology; Glucose tolerance; Humanities and Social Sciences; Insulin; Insulin Resistance; Intolerance; Mental depression; Mice; Mice, Knockout; multidisciplinary; Obesity; Obesity - physiopathology; Paroxetine; Pregnancy; Science; Science (multidisciplinary); Serotonin; Serotonin Plasma Membrane Transport Proteins - deficiency; Serotonin transporter
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-01291-5

Depression and use of antidepressant medications are both associated with increased risk of obesity, potentially attributed to a reduced serotonin transporter (SERT) function. However, how SERT deficiency promotes obesity is unknown. Here, we demonstrated that SERT −/− mice display abnormal fat accumulation in both white and brown adipose tissues, glucose intolerance and insulin resistance while exhibiting suppressed aromatase (Cyp19a1) expression and reduced circulating 17β-estradiol levels. 17β-estradiol replacement in SERT −/− mice reversed the obesity and glucose intolerance, supporting a role for estrogen in SERT deficiency-associated obesity and glucose intolerance. Treatment of wild type mice with paroxetine, a chemical inhibitor of SERT, also resulted in Cyp19a1 suppression, decreased circulating 17β-estradiol levels, abnormal fat accumulation, and glucose intolerance. Such effects were not observed in paroxetine-treated SERT −/− mice. Conversely, pregnant SERT −/− mice displayed normalized estrogen levels, markedly reduced fat accumulation, and improved glucose tolerance, which can be eliminated by an antagonist of estrogen receptor α (ERα). Together, these findings support that estrogen suppression is involved in SERT deficiency-induced obesity and glucose intolerance, and suggest approaches to restore 17β-estradiol levels as a novel treatment option for SERT deficiency associated obesity and metabolic abnormalities.