Long‐term effects of tumor necrosis factor‐α treatment on insulin signaling pathway in HepG2 cells and HepG2 cells overexpressing constitutively active Akt/PKB

Gupta, Dhananjay; Varma, Shailly; Khandelwal, Ramji L.

doi:10.1002/jcb.21080

Cited by 43 publications

(32 citation statements)

References 66 publications

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“…This finding is consistent with a finding of a previous study in HEK293 cells and mouse embryonic fibroblasts (49), where TNF-␣-mediated activation of ERK was partly dependent on GSK3␤ phosphorylation. Conversely, TNF-␣ exposure has also been shown to prevent insulin-stimulated phosphorylation of GSK3␤ in HEPG2 cells (50). Here, we report that IKK␤ silencing prevents the TNF-␣-mediated increase in GSK3␤ phosphorylation; however, the functional consequence requires further investigation.…”

Section: Discussionmentioning

confidence: 65%

siRNA-Mediated Reduction of Inhibitor of Nuclear Factor-κB Kinase Prevents Tumor Necrosis Factor-α–Induced Insulin Resistance in Human Skeletal Muscle

et al. 2008

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OBJECTIVE-Proinflammatory cytokines contribute to systemic low-grade inflammation and insulin resistance. Tumor necrosis factor (TNF)-␣ impedes insulin signaling in insulin target tissues. We determined the role of inhibitor of nuclear factor-B kinase (IKK)␤ in TNF-␣-induced impairments in insulin signaling and glucose metabolism in skeletal muscle.RESEARCH DESIGN AND METHODS-Small interfering RNA (siRNA) was used to silence IKK␤ gene expression in primary human skeletal muscle myotubes from nondiabetic subjects. siRNA gene silencing reduced IKK␤ protein expression 73% (P Ͻ 0.05). Myotubes were incubated in the absence or presence of insulin and/or TNF-␣, and effects of IKK␤ silencing on insulin signaling and glucose metabolism were determined.RESULTS-Insulin increased glucose uptake 1.7-fold (P Ͻ 0.05) and glucose incorporation into glycogen 3.8-fold (P Ͻ 0.05) in myotubes from nondiabetic subjects. TNF-␣ exposure fully impaired insulin-mediated glucose uptake and metabolism. IKK␤ siRNA protected against TNF-␣-induced impairments in glucose metabolism, since insulin-induced increases in glucose uptake (1.5-fold; P Ͻ 0.05) and glycogen synthesis (3.5-fold; P Ͻ 0.05) were restored. Conversely, TNF-␣-induced increases in insulin receptor substrate-1 serine phosphorylation (Ser 312 ), Jun NH 2 -terminal kinase phosphorylation, and extracellular signal-related kinase-1/2 mitogen-activated protein kinase (MAPK) phosphorylation were unaltered by siRNA-mediated IKK␤ reduction. siRNA-mediated IKK␤ reduction prevented TNF-␣-induced insulin resistance on Akt Ser 473 and Thr 308 phosphorylation and phosphorylation of the 160-kDa Akt substrate AS160. IKK␤ silencing had no effect on cell differentiation. Finally, mRNA expression of GLUT1 or GLUT4 and protein expression of MAPK kinase kinase kinase isoform 4 (MAP4K4) was unaltered by IKK␤ siRNA.CONCLUSIONS-IKK␤ silencing prevents TNF-␣-induced impairments in insulin action on Akt phosphorylation and glucose uptake and metabolism in human skeletal muscle.

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Section: Discussionmentioning

confidence: 65%

siRNA-Mediated Reduction of Inhibitor of Nuclear Factor-κB Kinase Prevents Tumor Necrosis Factor-α–Induced Insulin Resistance in Human Skeletal Muscle

et al. 2008

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“…1). Animal models (22,39) and both in vitro (40) and in vivo (41) human studies provided evidence that not fat accumulation itself but fat-derived cytokines play a role in (obesity-related) insulin resistance. The pleiotropic cytokine TNF-a interferes with the hepatic insulin receptor and the intrahepatocellular insulin signalling cascade (22,40), causing both hepatic and systemic insulin resistance (22,40).…”

Section: Inflammationmentioning

confidence: 99%

“…Animal models (22,39) and both in vitro (40) and in vivo (41) human studies provided evidence that not fat accumulation itself but fat-derived cytokines play a role in (obesity-related) insulin resistance. The pleiotropic cytokine TNF-a interferes with the hepatic insulin receptor and the intrahepatocellular insulin signalling cascade (22,40), causing both hepatic and systemic insulin resistance (22,40). Additionally, administration of human recombinant TNF-a in human cancer patients resulted in increased levels of very low-density lipoprotein (VLDL) and TG and decreased levels of high-density lipoprotein (HDL) (41), which are features of diabetic dyslipideamia (42).…”

Section: Inflammationmentioning

confidence: 99%

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Non‐alcoholic fatty liver disease is associated with cardiovascular disease risk markers

Edens¹,

Kuipers

Stolk³

2009

Obesity Reviews

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SummaryRecognition of the link between non‐alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) has boosted research in this area. The main objective of this paper is to review the literature on NAFLD in the context of CVD, focussing on underlying mechanisms and treatment. Besides excessive fatty acid influx, etiologic factors may include components of the metabolic syndrome, cytokines and mitochondrial dysfunction. NAFLD is associated with both hepatic and systemic insulin resistance. In the case of NAFLD, the liver overproduces several atherogenic factors, notably inflammatory cytokines, glucose, lipoproteins and coagulation factors, and factors increasing blood pressure. Intervention studies on diet and laparoscopic surgery revealed improvements of hepatic fat content and CVD risk profile. Pharmacological approaches with potential benefit have been developed as well, but effects are often confounded by weight change. NAFLD is associated with an increased CVD risk profile (and hepatic risk). In order to improve CVD risk profile, prevention and treatment of NAFLD seem advisable. However, well‐designed intervention studies, randomized clinical trials and long‐term follow‐up studies are scarce.

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“…Here, we demonstrated that diabetic animals show a higher level of oxidative stress and inflammation when compared with nondiabetic animals and, most notably, insulin and TDZD-8 partially affect oxidative stress and cause a substantial decrease of the inflammatory response. TNF-␣ has been identified as one of the pivotal proinflammatory cytokines that exacerbate I/R injury (33), and recently, the attenuation of insulin signaling cascade evoked by TNF-␣ has been suggested to involve Ser9 phosphorylation of GSK-3␤ (34). In our experimental model, the ability of both insulin and TDZD-8 to abolish the increase in serum levels of TNF-␣ and, at the same time, to reduce the expression of iNOS and COX-2 confirms the role of GSK-3␤ in contributing to protection against I/R injury.…”

Section: -24 Hmentioning

confidence: 99%

Insulin Reduces Cerebral Ischemia/Reperfusion Injury in the Hippocampus of Diabetic Rats

et al. 2009

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OBJECTIVE-There is evidence that insulin reduces brain injury evoked by ischemia/reperfusion (I/R). However, the molecular mechanisms underlying the protective effects of insulin remain unknown. Insulin is a well-known inhibitor of glycogen synthase kinase-3␤ (GSK-3␤). Here, we investigate the role of GSK-3␤ inhibition on I/R-induced cerebral injury in a rat model of insulinopenic diabetes. RESEARCH DESIGN AND METHODS-Ratswith streptozotocin-induced diabetes were subjected to 30-min occlusion of common carotid arteries followed by 1 or 24 h of reperfusion. Insulin (2-12 IU/kg i.v.) or the selective GSK-3␤ inhibitor TDZD-8 (0.2-3 mg/kg i.v.) was administered during reperfusion.RESULTS-Insulin or TDZD-8 dramatically reduced infarct volume and levels of S100B protein, a marker of cerebral injury. Both drugs induced phosphorylation of the Ser9 residue, thereby inactivating GSK-3␤ in the rat hippocampus. Insulin, but not TDZD-8, lowered blood glucose. The hippocampi of the drugtreated animals displayed reduced oxidative stress at 1 h of reperfusion as shown by the decreased generation of reactive oxygen species and lipid peroxidation. I/R-induced activation of nuclear factor-B was attenuated by both drug treatments. At 24 h of reperfusion, TDZD-8 and insulin significantly reduced plasma levels of tumor necrosis factor-␣; neutrophil infiltration, measured as myeloperoxidase activity and intercellular-adhesion-molecule-1 expression; and cyclooxygenase-2 and inducible-NO-synthase expression.CONCLUSIONS-Acute administration of insulin or TDZD-8 reduced cerebral I/R injury in diabetic rats. We propose that the inhibitory effect on the activity of GSK-3␤ contributes to the protective effect of insulin independently of any effects on blood glucose. Diabetes 58:235-242, 2009 E pidemiological studies have shown that diabetes is a leading risk factor for ischemic cerebrovascular diseases (1). Animal and human studies demonstrate that insulin reduces brain damage evoked by ischemia/reperfusion (I/R) injury (2,3). Glycemic control by insulin may be involved in this protective effect, but the molecular mechanisms underlying the protective effects of insulin are debated and still poorly understood (4). One important pharmacological effect of insulin is its ability to inhibit the activity of the glycogen synthase kinase (GSK)-3, a serine/threonine kinase that was originally identified for its key role in glucose metabolism (5). More recently, GSK-3 has emerged as a key regulatory switch in the modulation of neurodegeneration and inflammation (6,7). There are two mammalian isoforms of GSK-3: GSK-3␣ and GSK-3␤. GSK-3␤ is highly expressed in the central nervous system (8). Unlike most kinases, GSK-3␤ is constitutively active in cells and can be inactivated by phosphorylation at Ser9 (9). Binding of insulin to its receptor activates phosphatidylinositol 3-kinase, leading to the subsequent activation of protein kinase B/Akt, and the inactivation of GSK-3␤ by phosphorylation on the regulatory Ser-9. This contributes to the insulin-induce...

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Long‐term effects of tumor necrosis factor‐α treatment on insulin signaling pathway in HepG2 cells and HepG2 cells overexpressing constitutively active Akt/PKB

Cited by 43 publications

References 66 publications

siRNA-Mediated Reduction of Inhibitor of Nuclear Factor-κB Kinase Prevents Tumor Necrosis Factor-α–Induced Insulin Resistance in Human Skeletal Muscle

siRNA-Mediated Reduction of Inhibitor of Nuclear Factor-κB Kinase Prevents Tumor Necrosis Factor-α–Induced Insulin Resistance in Human Skeletal Muscle

Non‐alcoholic fatty liver disease is associated with cardiovascular disease risk markers

Insulin Reduces Cerebral Ischemia/Reperfusion Injury in the Hippocampus of Diabetic Rats

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