Serotonin transporter deficiency drives estrogen-dependent obesity and glucose intolerance

Abstract

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.

Constitutionally High Serotonin Tone Favors Obesity: Study on Rat Sublines With Altered Serotonin Homeostasis

“…Understanding how endogenous brain 5HTT activity contributes to the body weight regulation is not clear. Similarly to obese high-5HT rats, rodents with genetic deletion of 5HTT have elevated extracellular 5HT levels and tissue 5HIAA/5HT ratios, but findings regarding their obese phenotype are inconsistent (Kim et al, 2005;Homberg et al, 2007;Murphy and Lesch, 2008;Homberg et al, 2010;Zha et al, 2017). Further, human neuroimaging studies support both increase and decrease, as well as no change in intrasynaptic 5HT level in obesity (Koskela et al, 2008;Erritzoe et al, 2010;Hesse et al, 2016;Wu et al, 2017;van Galen et al, 2018).…”

Estrogen deprivation aggravates cardiac hypertrophy in nonobese Type 2 diabetic Goto–Kakizaki (GK) rats

“…In WTO rats, estrogen deprivation augmented lipogenesis, adipocyte hypertrophy, reduced fatty acid oxidation, and increased lipid accumulation in adipose tissue, all of which caused an increased body weight [ 25 ]. Moreover, adipocyte hypertrophy and lipid accumulation could increase oxidative stress and inflammation, and NF-κB activation.…”

Metabolic, Molecular, and Behavioral Effects of Western Diet in Serotonin Transporter-Deficient Mice: Rescue by Heterozygosity?

“…Animal studies support the observations made in humans concerning the relationship between SERT deficiency and diabetes-like metabolic changes. Sert-deficient mice (Sert −/− : KO) were reported to display decreased glucose tolerance, increased deposition of white adipose tissue that increases with aging, and late-onset obesity; these changes were particularly marked in females (Murphy and Lesch, 2008;Üçeyler et al, 2010;Chen et al, 2012;Zha et al, 2017).…”