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c-Jun N-terminal kinase 1/2 activation by tumor necrosis factor-alpha induces insulin resistance in human visceral but not subcutaneous adipocytes: reversal by liver X receptor agonists.
J Clin Endocrinol Metab. 2009 Sep; 94(9):3583-93.JC

Abstract

AIMS

Obesity is associated with a chronic systemic low-grade inflammatory state. Markers of inflammation such as TNF-alpha are linked with increased risk for insulin resistance and type 2 diabetes. The objective of the present study was to dissect the molecular mechanisms that may regulate TNF-alpha-induced insulin resistance in human adipose tissue.

METHODS

We analyzed the impact of TNF-alpha on glucose uptake and insulin action in human visceral and sc adipocytes. The contribution of different intracellular signaling pathways on metabolic effects of TNF-alpha and the reversal of some of these effects with nuclear receptor agonists were also studied.

RESULTS

TNF-alpha per se increased glucose transporter-4 translocation to the plasma membrane and glucose uptake by activating the AMP-activated protein kinase/AS160 pathway in both visceral and sc adipocytes. Nevertheless, this cytokine induced an insulin-resistant state in visceral adipocytes by impairing insulin-stimulated glucose uptake and insulin signaling at the insulin receptor substrate (IRS)-1/AKT level. Activation of c-Jun N-terminal kinase (JNK) 1/2 seems to be involved in TNF-alpha-induced insulin resistance, causing phosphorylation of IRS1 at the Ser312 residue. Accordingly, silencing JNK1/2 with either small interfering RNA or chemical inhibitors impaired serine phosphorylation of IRS1, restored downstream insulin signaling, and normalized insulin-induced glucose uptake in the presence of TNF-alpha. Furthermore, TNF-alpha increased the secretion of other proinflammatory cytokines such as IL-6. Pharmacological treatment of adipocytes with liver X receptor agonists reestablished insulin sensitivity by impairing TNF-alpha induction of JNK1/2, phosphorylation of IRS1 (Ser312), and stabilizing IL-6 secretion.

CONCLUSIONS

TNF-alpha induces insulin resistance on glucose uptake in human visceral but not sc adipocytes, suggesting depot-specific effects of TNF-alpha on glucose uptake. Activation of JNK1/2 appears to be involved in serine phosphorylation of IRS1 and subsequently insulin resistance on glucose uptake, a state that can be reversed by liver X receptor agonists.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University, 28040, Madrid, Spain. soferve@farm.ucm.esNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19567513

Citation

Fernández-Veledo, Sonia, et al. "C-Jun N-terminal Kinase 1/2 Activation By Tumor Necrosis Factor-alpha Induces Insulin Resistance in Human Visceral but Not Subcutaneous Adipocytes: Reversal By Liver X Receptor Agonists." The Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 9, 2009, pp. 3583-93.
Fernández-Veledo S, Vila-Bedmar R, Nieto-Vazquez I, et al. C-Jun N-terminal kinase 1/2 activation by tumor necrosis factor-alpha induces insulin resistance in human visceral but not subcutaneous adipocytes: reversal by liver X receptor agonists. J Clin Endocrinol Metab. 2009;94(9):3583-93.
Fernández-Veledo, S., Vila-Bedmar, R., Nieto-Vazquez, I., & Lorenzo, M. (2009). C-Jun N-terminal kinase 1/2 activation by tumor necrosis factor-alpha induces insulin resistance in human visceral but not subcutaneous adipocytes: reversal by liver X receptor agonists. The Journal of Clinical Endocrinology and Metabolism, 94(9), 3583-93. https://doi.org/10.1210/jc.2009-0558
Fernández-Veledo S, et al. C-Jun N-terminal Kinase 1/2 Activation By Tumor Necrosis Factor-alpha Induces Insulin Resistance in Human Visceral but Not Subcutaneous Adipocytes: Reversal By Liver X Receptor Agonists. J Clin Endocrinol Metab. 2009;94(9):3583-93. PubMed PMID: 19567513.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - c-Jun N-terminal kinase 1/2 activation by tumor necrosis factor-alpha induces insulin resistance in human visceral but not subcutaneous adipocytes: reversal by liver X receptor agonists. AU - Fernández-Veledo,Sonia, AU - Vila-Bedmar,Rocio, AU - Nieto-Vazquez,Iria, AU - Lorenzo,Margarita, Y1 - 2009/06/30/ PY - 2009/7/2/entrez PY - 2009/7/2/pubmed PY - 2009/9/24/medline SP - 3583 EP - 93 JF - The Journal of clinical endocrinology and metabolism JO - J. Clin. Endocrinol. Metab. VL - 94 IS - 9 N2 - AIMS: Obesity is associated with a chronic systemic low-grade inflammatory state. Markers of inflammation such as TNF-alpha are linked with increased risk for insulin resistance and type 2 diabetes. The objective of the present study was to dissect the molecular mechanisms that may regulate TNF-alpha-induced insulin resistance in human adipose tissue. METHODS: We analyzed the impact of TNF-alpha on glucose uptake and insulin action in human visceral and sc adipocytes. The contribution of different intracellular signaling pathways on metabolic effects of TNF-alpha and the reversal of some of these effects with nuclear receptor agonists were also studied. RESULTS: TNF-alpha per se increased glucose transporter-4 translocation to the plasma membrane and glucose uptake by activating the AMP-activated protein kinase/AS160 pathway in both visceral and sc adipocytes. Nevertheless, this cytokine induced an insulin-resistant state in visceral adipocytes by impairing insulin-stimulated glucose uptake and insulin signaling at the insulin receptor substrate (IRS)-1/AKT level. Activation of c-Jun N-terminal kinase (JNK) 1/2 seems to be involved in TNF-alpha-induced insulin resistance, causing phosphorylation of IRS1 at the Ser312 residue. Accordingly, silencing JNK1/2 with either small interfering RNA or chemical inhibitors impaired serine phosphorylation of IRS1, restored downstream insulin signaling, and normalized insulin-induced glucose uptake in the presence of TNF-alpha. Furthermore, TNF-alpha increased the secretion of other proinflammatory cytokines such as IL-6. Pharmacological treatment of adipocytes with liver X receptor agonists reestablished insulin sensitivity by impairing TNF-alpha induction of JNK1/2, phosphorylation of IRS1 (Ser312), and stabilizing IL-6 secretion. CONCLUSIONS: TNF-alpha induces insulin resistance on glucose uptake in human visceral but not sc adipocytes, suggesting depot-specific effects of TNF-alpha on glucose uptake. Activation of JNK1/2 appears to be involved in serine phosphorylation of IRS1 and subsequently insulin resistance on glucose uptake, a state that can be reversed by liver X receptor agonists. SN - 1945-7197 UR - https://www.unboundmedicine.com/medline/citation/19567513/c_Jun_N_terminal_kinase_1/2_activation_by_tumor_necrosis_factor_alpha_induces_insulin_resistance_in_human_visceral_but_not_subcutaneous_adipocytes:_reversal_by_liver_X_receptor_agonists_ L2 - https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2009-0558 DB - PRIME DP - Unbound Medicine ER -