Reduced serotonin reuptake transporter (SERT) function causes insulin resistance and hepatic steatosis independent of food intake

Xiaoning Chen, Kara J. Margolis, Michael D. Gershon, Gary J. Schwartz, Ji Ying Sze

Research output: Contribution to journalArticle

49 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere32511
JournalPLoS One
Volume7
Issue number3
DOIs
StatePublished - Mar 8 2012

Fingerprint

Serotonin Plasma Membrane Transport Proteins
fatty liver
serotonin
insulin resistance
transporters
Insulin Resistance
food intake
Serotonin
Eating
Insulin
Liver
mice
antidepressants
Nutrition
Antidepressive Agents
Obesity
obesity
Weight control
Glucose Intolerance
Glucose

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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 Ying.

In: PLoS One, Vol. 7, No. 3, e32511, 08.03.2012.

Research output: Contribution to journalArticle

@article{4922166b6a684bbea4b3e818d57ed988,
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.",
author = "Xiaoning Chen and Margolis, {Kara J.} and Gershon, {Michael D.} and Schwartz, {Gary J.} and Sze, {Ji Ying}",
year = "2012",
month = "3",
day = "8",
doi = "10.1371/journal.pone.0032511",
language = "English (US)",
volume = "7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "3",

}

TY - JOUR

T1 - Reduced serotonin reuptake transporter (SERT) function causes insulin resistance and hepatic steatosis independent of food intake

AU - Chen, Xiaoning

AU - Margolis, Kara J.

AU - Gershon, Michael D.

AU - Schwartz, Gary J.

AU - Sze, Ji Ying

PY - 2012/3/8

Y1 - 2012/3/8

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84863262841&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863262841&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0032511

DO - 10.1371/journal.pone.0032511

M3 - Article

C2 - 22412882

AN - SCOPUS:84863262841

VL - 7

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 3

M1 - e32511

ER -