Reduced Serotonin Reuptake Transporter (SERT) Function Causes Insulin Resistance and Hepatic Steatosis Independent of Food Intake Xiaoning Chen 1 , Kara J. Margolis3, Michael D. Gershon 3 , Gary J. Schwartz2, Ji Y. Sze1* 1 Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, United States of America, 2 Department of Medicine and Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America, 3 Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America Abstract Serotonin reuptake transporter (SERT) is a key regulator of serotonin neurotransmission and a major target of antidepressants. Antidepressants, such as selectively serotonin reuptake inhibitors (SSRIs), that block SERT function are known to affect food intake and body weight. Here, we provide genetic evidence that food intake and metabolism are regulated by separable mechanisms of SERT function. SERT-deficient mice ate less during both normal diet and high fat diet feeding. The reduced food intake was accompanied with markedly elevated plasma leptin levels. Despite reduced food intake, SERT-deficient mice exhibited glucose intolerance and insulin resistance, and progressively developed obesity and hepatic steatosis. Several lines of evidence indicate that the metabolic deficits of SERT-deficient mice are attributable to reduced insulin-sensitivity in peripheral tissues. First, SERT-deficient mice exhibited beta-cell hyperplasia and islet-mass expansion. Second, biochemical analyses revealed constitutively elevated JNK activity and diminished insulin-induced AKT activation in the liver of SERT-deficient mice. SERT-deficient mice exhibited hyper-JNK activity and hyperinsulinemia prior to the development of obesity. Third, enhancing AKT signaling by PTEN deficiency corrected glucose tolerance in SERT- deficient mice. These findings have potential implications for designing selective SERT drugs for weight control and the treatment of metabolic syndromes. Citation: Chen X, Margolis KJ, Gershon MD, Schwartz GJ, Sze JY (2012) Reduced Serotonin Reuptake Transporter (SERT) Function Causes Insulin Resistance and Hepatic Steatosis Independent of Food Intake. PLoS ONE 7(3): e32511. doi:10.1371/journal.pone.0032511 Editor: Giorgio Sesti, Universita Magna-Graecia di Catanzaro, Italy Received September 13, 2011; Accepted January 27, 2012; Published March 8, 2012 Copyright: 2012 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the National Institutes of Health (MH083982)(JS), NIH DK 020541 DK 026687(GJS). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: jiying.sze@einstein.yu.edu Introduction Disturbances in glucose homeostasis among psychiatric popu- lations have been documented extensively [1,2]. The mechanisms for this comorbidity are currently unknown, and are likely to involve diverse genetic, behavioral and environmental factors. Therefore, identifying the regulation of metabolic homeostasis by genes implicated in anxiety-related disorders may reveal insights into the pathophysiology of both mental and metabolic disorders. The serotonin reuptake transporter (SERT) is a major target of antidepressants. Selective serotonin reuptake inhibitors (SSRIs) are believed to exert antidepressant effects by blocking SERT uptaking serotonin (5-HT) from extracellular space, thereby enhancing 5-HT signaling [3]. In this study, we focused on the impact of constitutive SERT deficiency on energy balance and glucose homeostasis in mice. Pharmacological studies have long implicated 5-HT in reducing food intake and body weight [4,5,6]. Subsequent genetic analyses in rodents demonstrated that hypothalamic 5-HT signaling controls food intake. For example, the 5-HT receptor 5HTR2C is highly expressed in the hypothalamus and 5HTR2C knockout mice develop hyperphagia, obesity and insulin resistance [7,8]. In addition, the 5-HT receptor 5-HTR1B modulates the activity of melanocortin neurons to influence food intake [9]. By contrast, the impact of SSRIs on metabolism is less clear. Meta-analyses of clinical trials reported significant weight loss in subjects treated with fluoxetine [10,11]. The effect of SSRIs on weight loss is, however, short term, and individuals regain or increase weight, despite continued SSRIs treatments [12,13]. In some cases, SSRI treatments yielded hyperglycemia and a trend towards diabetes [13,14,15]. Accumulating evidence suggests that the effects of SSRIs on metabolisms are not merely secondary to improvement in affective states, but that 5-HT may act at both the brain and peripheral tissues to influence metabolism [16,17,18,19]. However, the impact of SERT inactivation on glucose homeostasis and insulin signaling has not been systemat- ically analyzed to date. The purpose of this study was to test whether mice lacking SERT gene Slc6a4 function (SERT2/2) exhibit reduced food intake, thereby protecting them against obesity and diabetes. To circumvent potential complications of reproductive hormone cycles in females, we focused on male mice. As expected, we found SERT2/2 mice ate less. However, contrary to our expectations, SERT deficient mice exhibited glucose intolerance and insulin resistance, and progressively developed obesity and liver steatosis. We found that SERT2/2 mice were hyperlepti- nemic, hyperglycemic and hyperinsulinemic prior to exhibiting a measurable increase in body fat content. We identified that C-Jun- PLoS ONE | www.plosone.org 1 March 2012 | Volume 7 | Issue 3 | e32511