Interferon γ attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway

Fiona C. McGillicuddy, Elise H. Chiquoine, Christine C. Hinkle, Roy J. Kim, Rachana Shah, Helen M. Roche, Emer M. Smyth, Muredach P. Reilly

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

Recent reports demonstrate T-cell infiltration of adipose tissue in early obesity. We hypothesized that interferon (IFN) γ, a major T-cell inflammatory cytokine, would attenuate human adipocyte functions and sought to establish signaling mechanisms. Differentiated human adipocytes were treated with IFNγ ± pharmacological inhibitors prior to insulin stimulation. [3H]Glucose uptake and AKT phosphorylation were assessed as markers of insulin sensitivity. IFNγ induced sustained loss of insulin-stimulated glucose uptake in human adipocytes, coincident with reduced Akt phosphorylation and down-regulation of the insulin receptor, insulin receptor substrate-1, and GLUT4. Loss of adipocyte triglyceride storage was observed with IFNγ co-incident with reduced expression of peroxisome proliferator-activated receptor γ, adiponectin, perilipin, fatty acid synthase, and lipoprotein lipase. Treatment with IFNγ also blocked differentiation of pre-adipocytes to the mature phenotype. IFNγ-induced robust STAT1 phosphorylation and SOCS1 mRNA expression, with modest, transient STAT3 phosphorylation and SOCS3 induction. Preincubation with a non-selective JAK inhibitor restored glucose uptake and Akt phosphorylation while completely reversing IFNγ suppression of adipogenic mRNAs and adipocyte differentiation. Specific inhibition of JAK2 or JAK3 failed to block IFNγ effects suggesting a predominant role for JAK1-STAT1. We demonstrate that IFNγ attenuates insulin sensitivity and suppresses differentiation in human adipocytes, an effect most likely mediated via sustained JAK-STAT1 pathway activation.

Original languageEnglish (US)
Pages (from-to)31936-31944
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number46
DOIs
StatePublished - 2009

Fingerprint

Adipocytes
Interferons
Chemical activation
Insulin
Phosphorylation
Lipids
T-cells
Glucose
Insulin Resistance
T-Lymphocytes
Insulin Receptor Substrate Proteins
Fatty Acid Synthases
Messenger RNA
Peroxisome Proliferator-Activated Receptors
Lipoprotein Lipase
Adiponectin
Insulin Receptor
Lipase
Infiltration
Adipose Tissue

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

McGillicuddy, F. C., Chiquoine, E. H., Hinkle, C. C., Kim, R. J., Shah, R., Roche, H. M., ... Reilly, M. P. (2009). Interferon γ attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway. Journal of Biological Chemistry, 284(46), 31936-31944. https://doi.org/10.1074/jbc.M109.061655

Interferon γ attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway. / McGillicuddy, Fiona C.; Chiquoine, Elise H.; Hinkle, Christine C.; Kim, Roy J.; Shah, Rachana; Roche, Helen M.; Smyth, Emer M.; Reilly, Muredach P.

In: Journal of Biological Chemistry, Vol. 284, No. 46, 2009, p. 31936-31944.

Research output: Contribution to journalArticle

McGillicuddy, FC, Chiquoine, EH, Hinkle, CC, Kim, RJ, Shah, R, Roche, HM, Smyth, EM & Reilly, MP 2009, 'Interferon γ attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway', Journal of Biological Chemistry, vol. 284, no. 46, pp. 31936-31944. https://doi.org/10.1074/jbc.M109.061655
McGillicuddy, Fiona C. ; Chiquoine, Elise H. ; Hinkle, Christine C. ; Kim, Roy J. ; Shah, Rachana ; Roche, Helen M. ; Smyth, Emer M. ; Reilly, Muredach P. / Interferon γ attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 46. pp. 31936-31944.
@article{96bccf3baada49aa892f9900ad1d87d4,
title = "Interferon γ attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway",
abstract = "Recent reports demonstrate T-cell infiltration of adipose tissue in early obesity. We hypothesized that interferon (IFN) γ, a major T-cell inflammatory cytokine, would attenuate human adipocyte functions and sought to establish signaling mechanisms. Differentiated human adipocytes were treated with IFNγ ± pharmacological inhibitors prior to insulin stimulation. [3H]Glucose uptake and AKT phosphorylation were assessed as markers of insulin sensitivity. IFNγ induced sustained loss of insulin-stimulated glucose uptake in human adipocytes, coincident with reduced Akt phosphorylation and down-regulation of the insulin receptor, insulin receptor substrate-1, and GLUT4. Loss of adipocyte triglyceride storage was observed with IFNγ co-incident with reduced expression of peroxisome proliferator-activated receptor γ, adiponectin, perilipin, fatty acid synthase, and lipoprotein lipase. Treatment with IFNγ also blocked differentiation of pre-adipocytes to the mature phenotype. IFNγ-induced robust STAT1 phosphorylation and SOCS1 mRNA expression, with modest, transient STAT3 phosphorylation and SOCS3 induction. Preincubation with a non-selective JAK inhibitor restored glucose uptake and Akt phosphorylation while completely reversing IFNγ suppression of adipogenic mRNAs and adipocyte differentiation. Specific inhibition of JAK2 or JAK3 failed to block IFNγ effects suggesting a predominant role for JAK1-STAT1. We demonstrate that IFNγ attenuates insulin sensitivity and suppresses differentiation in human adipocytes, an effect most likely mediated via sustained JAK-STAT1 pathway activation.",
author = "McGillicuddy, {Fiona C.} and Chiquoine, {Elise H.} and Hinkle, {Christine C.} and Kim, {Roy J.} and Rachana Shah and Roche, {Helen M.} and Smyth, {Emer M.} and Reilly, {Muredach P.}",
year = "2009",
doi = "10.1074/jbc.M109.061655",
language = "English (US)",
volume = "284",
pages = "31936--31944",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "46",

}

TY - JOUR

T1 - Interferon γ attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway

AU - McGillicuddy, Fiona C.

AU - Chiquoine, Elise H.

AU - Hinkle, Christine C.

AU - Kim, Roy J.

AU - Shah, Rachana

AU - Roche, Helen M.

AU - Smyth, Emer M.

AU - Reilly, Muredach P.

PY - 2009

Y1 - 2009

N2 - Recent reports demonstrate T-cell infiltration of adipose tissue in early obesity. We hypothesized that interferon (IFN) γ, a major T-cell inflammatory cytokine, would attenuate human adipocyte functions and sought to establish signaling mechanisms. Differentiated human adipocytes were treated with IFNγ ± pharmacological inhibitors prior to insulin stimulation. [3H]Glucose uptake and AKT phosphorylation were assessed as markers of insulin sensitivity. IFNγ induced sustained loss of insulin-stimulated glucose uptake in human adipocytes, coincident with reduced Akt phosphorylation and down-regulation of the insulin receptor, insulin receptor substrate-1, and GLUT4. Loss of adipocyte triglyceride storage was observed with IFNγ co-incident with reduced expression of peroxisome proliferator-activated receptor γ, adiponectin, perilipin, fatty acid synthase, and lipoprotein lipase. Treatment with IFNγ also blocked differentiation of pre-adipocytes to the mature phenotype. IFNγ-induced robust STAT1 phosphorylation and SOCS1 mRNA expression, with modest, transient STAT3 phosphorylation and SOCS3 induction. Preincubation with a non-selective JAK inhibitor restored glucose uptake and Akt phosphorylation while completely reversing IFNγ suppression of adipogenic mRNAs and adipocyte differentiation. Specific inhibition of JAK2 or JAK3 failed to block IFNγ effects suggesting a predominant role for JAK1-STAT1. We demonstrate that IFNγ attenuates insulin sensitivity and suppresses differentiation in human adipocytes, an effect most likely mediated via sustained JAK-STAT1 pathway activation.

AB - Recent reports demonstrate T-cell infiltration of adipose tissue in early obesity. We hypothesized that interferon (IFN) γ, a major T-cell inflammatory cytokine, would attenuate human adipocyte functions and sought to establish signaling mechanisms. Differentiated human adipocytes were treated with IFNγ ± pharmacological inhibitors prior to insulin stimulation. [3H]Glucose uptake and AKT phosphorylation were assessed as markers of insulin sensitivity. IFNγ induced sustained loss of insulin-stimulated glucose uptake in human adipocytes, coincident with reduced Akt phosphorylation and down-regulation of the insulin receptor, insulin receptor substrate-1, and GLUT4. Loss of adipocyte triglyceride storage was observed with IFNγ co-incident with reduced expression of peroxisome proliferator-activated receptor γ, adiponectin, perilipin, fatty acid synthase, and lipoprotein lipase. Treatment with IFNγ also blocked differentiation of pre-adipocytes to the mature phenotype. IFNγ-induced robust STAT1 phosphorylation and SOCS1 mRNA expression, with modest, transient STAT3 phosphorylation and SOCS3 induction. Preincubation with a non-selective JAK inhibitor restored glucose uptake and Akt phosphorylation while completely reversing IFNγ suppression of adipogenic mRNAs and adipocyte differentiation. Specific inhibition of JAK2 or JAK3 failed to block IFNγ effects suggesting a predominant role for JAK1-STAT1. We demonstrate that IFNγ attenuates insulin sensitivity and suppresses differentiation in human adipocytes, an effect most likely mediated via sustained JAK-STAT1 pathway activation.

UR - http://www.scopus.com/inward/record.url?scp=70450277113&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70450277113&partnerID=8YFLogxK

U2 - 10.1074/jbc.M109.061655

DO - 10.1074/jbc.M109.061655

M3 - Article

C2 - 19776010

AN - SCOPUS:70450277113

VL - 284

SP - 31936

EP - 31944

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 46

ER -