Cargando…

Reduced Serotonin Reuptake Transporter (SERT) Function Causes Insulin Resistance and Hepatic Steatosis Independent of Food Intake

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 geneti...

Descripción completa

Detalles Bibliográficos
Autores principales: Chen, Xiaoning, Margolis, Kara J., Gershon, Michael D., Schwartz, Gary J., Sze, Ji Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297606/
https://www.ncbi.nlm.nih.gov/pubmed/22412882
http://dx.doi.org/10.1371/journal.pone.0032511
_version_ 1782225898820337664
author Chen, Xiaoning
Margolis, Kara J.
Gershon, Michael D.
Schwartz, Gary J.
Sze, Ji Y.
author_facet Chen, Xiaoning
Margolis, Kara J.
Gershon, Michael D.
Schwartz, Gary J.
Sze, Ji Y.
author_sort Chen, Xiaoning
collection PubMed
description 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.
format Online
Article
Text
id pubmed-3297606
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-32976062012-03-12 Reduced Serotonin Reuptake Transporter (SERT) Function Causes Insulin Resistance and Hepatic Steatosis Independent of Food Intake Chen, Xiaoning Margolis, Kara J. Gershon, Michael D. Schwartz, Gary J. Sze, Ji Y. PLoS One Research Article 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. Public Library of Science 2012-03-08 /pmc/articles/PMC3297606/ /pubmed/22412882 http://dx.doi.org/10.1371/journal.pone.0032511 Text en Chen et al. http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
Chen, Xiaoning
Margolis, Kara J.
Gershon, Michael D.
Schwartz, Gary J.
Sze, Ji Y.
Reduced Serotonin Reuptake Transporter (SERT) Function Causes Insulin Resistance and Hepatic Steatosis Independent of Food Intake
title Reduced Serotonin Reuptake Transporter (SERT) Function Causes Insulin Resistance and Hepatic Steatosis Independent of Food Intake
title_full Reduced Serotonin Reuptake Transporter (SERT) Function Causes Insulin Resistance and Hepatic Steatosis Independent of Food Intake
title_fullStr Reduced Serotonin Reuptake Transporter (SERT) Function Causes Insulin Resistance and Hepatic Steatosis Independent of Food Intake
title_full_unstemmed Reduced Serotonin Reuptake Transporter (SERT) Function Causes Insulin Resistance and Hepatic Steatosis Independent of Food Intake
title_short Reduced Serotonin Reuptake Transporter (SERT) Function Causes Insulin Resistance and Hepatic Steatosis Independent of Food Intake
title_sort reduced serotonin reuptake transporter (sert) function causes insulin resistance and hepatic steatosis independent of food intake
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297606/
https://www.ncbi.nlm.nih.gov/pubmed/22412882
http://dx.doi.org/10.1371/journal.pone.0032511
work_keys_str_mv AT chenxiaoning reducedserotoninreuptaketransportersertfunctioncausesinsulinresistanceandhepaticsteatosisindependentoffoodintake
AT margoliskaraj reducedserotoninreuptaketransportersertfunctioncausesinsulinresistanceandhepaticsteatosisindependentoffoodintake
AT gershonmichaeld reducedserotoninreuptaketransportersertfunctioncausesinsulinresistanceandhepaticsteatosisindependentoffoodintake
AT schwartzgaryj reducedserotoninreuptaketransportersertfunctioncausesinsulinresistanceandhepaticsteatosisindependentoffoodintake
AT szejiy reducedserotoninreuptaketransportersertfunctioncausesinsulinresistanceandhepaticsteatosisindependentoffoodintake