Details

Autor(en) / Beteiligte

• Fernández-Veledo, Sonia
• Vila-Bedmar, Rocio
• Nieto-Vazquez, Iria
• Lorenzo, Margarita

Titel

c-Jun N-Terminal Kinase 1/2 Activation by Tumor Necrosis Factor-α Induces Insulin Resistance In Human Visceral But Not Subcutaneous Adipocytes: Reversal by Liver X Receptor Agonists

Ist Teil von

• The journal of clinical endocrinology and metabolism, 2009-09, Vol.94 (9), p.3583-3593

Ort / Verlag

Bethesda, MD: Endocrine Society

Erscheinungsjahr

2009

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• Aims: Obesity is associated with a chronic systemic low-grade inflammatory state. Markers of inflammation such as TNF-α 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-α-induced insulin resistance in human adipose tissue. Methods: We analyzed the impact of TNF-α on glucose uptake and insulin action in human visceral and sc adipocytes. The contribution of different intracellular signaling pathways on metabolic effects of TNF-α and the reversal of some of these effects with nuclear receptor agonists were also studied. Results: TNF-α 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-α-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-α. Furthermore, TNF-α 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-α induction of JNK1/2, phosphorylation of IRS1 (Ser312), and stabilizing IL-6 secretion. Conclusions: TNF-α induces insulin resistance on glucose uptake in human visceral but not sc adipocytes, suggesting depot-specific effects of TNF-α 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. TNF-α activates JNK1/2 and induces insulin resistance on glucose uptake in human visceral, but not in subcutaneous, adipocytes, suggesting depot-specific effects of TNF-α.