title: Reduced serotonin reuptake transporter (SERT) function causes insulin resistance and hepatic steatosis independent of food intake.
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.
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Chen
authors.forename: Kara J
authors.initials: KJ
authors.lastname: Margolis
authors.forename: Michael D
authors.initials: MD
authors.lastname: Gershon
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Schwartz
authors.forename: Ji Y
authors.initials: JY
authors.lastname: Sze
mesh_terms: D000818:Animals; D001835:Body Weight; D004435:Eating / Q000235:genetics / Q000523:psychology*; D004789:Enzyme Activation / Q000235:genetics; D005234:Fatty Liver / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D006984:Hypertrophy; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics; D007515:Islets of Langerhans / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009132:Muscles / Q000378:metabolism; D009154:Mutation; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; D020738:Leptin; D050486:Serotonin Plasma Membrane Transport Proteins; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase