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.
OBJECTIVE
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.
Fernández-Veledo
Sonia
S
Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University, 28040, Madrid, Spain. soferve@farm.ucm.es
Vila-Bedmar
Rocio
R
Nieto-Vazquez
Iria
I
Lorenzo
Margarita
M
D055372:AMP-Activated Protein Kinases / Q000502:physiology; D017667:Adipocytes / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000819:agonists*; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000032:analysis; D051275:Glucose Transporter Type 4 / Q000032:analysis; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000502:physiology; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000378:metabolism*; D000071518:Liver X Receptors; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism*; D057093:Orphan Nuclear Receptors; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D015398:Signal Transduction; D050151:Subcutaneous Fat / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C495677:SLC2A1 protein, human; C495692:SLC2A4 protein, human; D014409:Tumor Necrosis Factor-alpha; D048056:Mitogen-Activated Protein Kinase 9; D051057:Proto-Oncogene Proteins c-akt; D048055:Mitogen-Activated Protein Kinase 8; D055372:AMP-Activated Protein Kinases; D005947:Glucose