Inhibition of Ceramide Production Reverses TNF-Induced Insulin Resistance

doi:10.1006/bbrc.2001.5694

Biochemical and Biophysical Research Communications

Volume 287, Issue 5, 12 October 2001, Pages 1121-1124

https://doi.org/10.1006/bbrc.2001.5694 Get rights and content

Abstract

Ceramide has been implicated as a mediator of insulin resistance induced by tumor necrosis factor-α (TNF) in adipocytes. Adipocytes contain numerous caveolae, sphingolipid and cholesterol-enriched lipid microdomains, that are also enriched in insulin receptor (IR). Since caveolae may be important sites for crosstalk between tyrosine kinase and sphingolipid signaling pathways, we examined the role of increased caveolar pools of ceramide in regulating tyrosine phosphorylation of the IR and its main substrate, insulin receptor substrate-1 (IRS-1). Neither exogenous short-chain ceramide analogs nor pharmacologic increases in endogenous caveolar pools of ceramide inhibited insulin-induced tyrosine phosphorylation of the IR and IRS-1. However, inhibition of TNF-induced caveolar ceramide production reversed the decrease in IR tyrosine phosphorylation in response to TNF. These results suggest that TNF-independent increases in caveolar pools of ceramide are not sufficient to inhibit insulin signaling but that in conjunction with other TNF-dependent signals, caveolar pools of ceramide are a critical component for insulin resistance by TNF.

References (20)

H. Kanety et al.
J. Biol. Chem.
(1995)
P. Peraldi et al.
J. Biol. Chem.
(1996)
H. Kanety et al.
J. Biol. Chem.
(1996)
T. Levade et al.
Biochem. Biophys. Acta
(1999)
A.D. Kohn et al.
J. Biol. Chem.
(1996)
R.T. Dobrowsky et al.
Methods Cell Biol.
(2001)
E.I. de Chaves et al.
J. Biol. Chem.
(1997)
S. Bourteele et al.
J. Biol. Chem.
(1998)
H. Grassme et al.
J. Biol. Chem.
(2001)

There are more references available in the full text version of this article.

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Results showed that these anti-diabetic effects may be mediated by alleviating pancreatic inflammation and oxidative stress, preserving and repairing damaged islet cells, and reducing islet dysfunction. Previous studies have demonstrated that inflammatory factor-mediated inflammation plays a critical role in diabetes development [14-16]. TNF-α is mainly secreted by macrophages and adipocytes in adipose tissues, sustaining mildly elevated levels under pathological conditions [14].
The aim of the present study was to investigate the hypoglycemic effects of silkworm extract (SE) on experimental type 2 diabetes mellitus (T2DM) rats.
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Tumor Necrosis Factor (TNF)-α-induced repression of GKAP42 protein levels through cGMP-dependent kinase (CGK)-Iα causes insulin resistance in 3T3-L1 adipocytes
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TNF-α is shown to activate various kinases, including Jun kinases, mitogen-activated protein kinases, and protein kinase Cs, to phosphorylate IRS-1, resulting in repression of its tyrosine phosphorylation in response to insulin and insulin bioactivities (25, 50, 51). TNF-α also increases lipids, such as diacylglycerols, ceramides, and ganglioside GM3, resulting in inhibition of insulin-dependent IR activation and its proximal signaling (52–55). In addition, knockdown of cGK-Iα could only restore GKAP42 protein level and not IRS-1 protein level, indicating that a degradation system other than cGK-Iα was induced by TNF-α treatment.
Insulin receptor substrates (IRSs) have been shown to be major mediators of insulin signaling. Recently, we found that IRSs form high-molecular weight complexes, and here, we identify by yeast two-hybrid screening a novel IRS-1-associated protein: a 42-kDa cGMP-dependent protein kinase-anchoring protein (GKAP42). GKAP42 knockdown in 3T3-L1 adipocytes suppressed insulin-dependent IRS-1 tyrosine phosphorylation and downstream signaling, resulting in suppression of GLUT4 translocation to plasma membrane induced by insulin. In addition, GLUT4 translocation was also suppressed in cells overexpressing GKAP42-N (the IRS-1 binding region of GKAP42), which competed with GKAP42 for IRS-1, indicating that GKAP42 binding to IRS-1 is required for insulin-induced GLUT4 translocation. Long term treatment of 3T3-L1 adipocytes with TNF-α, which induced insulin resistance, significantly decreased the GKAP42 protein level. We then investigated the roles of cGMP-dependent kinase (cGK)-Iα, which bound to GKAP42, in these changes. cGK-Iα knockdown partially rescued TNF-α-induced decrease in GKAP42 and impairment of insulin signals. These data indicated that TNF-α-induced repression of GKAP42 via cGK-Iα caused reduction of insulin-induced IRS-1 tyrosine phosphorylation at least in part. The present study describes analysis of the novel TNF-α-induced pathway, cGK-Iα-GKAP42, which regulates insulin-dependent signals and GLUT4 translocation.
IRS-1-associated proteins play roles in modulation of insulin-induced IRS-1 tyrosine phosphorylation.
A novel IRS-1-associated protein, GKAP42, is required to maintain availability of IRS-1 to the insulin receptor. TNF-α treatment suppressed the GKAP42 protein level.
TNF-α-induced insulin resistance is at least partially caused by GKAP42 protein level suppression.
We identified a novel TNF-α-induced pathway involved in insulin resistance.
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2009, Progress in Lipid Research
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A report by Grigsby and Dobrowsky suggests that exposing 3T3-adipocytes to TNFα increases caveolar ceramide concentration and impairs IR function. Prevention of ceramide accumulation using Z-VAD-FMK, a caspase inhibitor, restored IR and IRS-1 phosphorylation [78]. Kabayama et al. reported the effect of prolonged TNFα exposure on IR localization in 3T3-adipocytes [79].
Obesity is associated with an increased risk for insulin resistance, a state characterized by impaired responsiveness of liver, muscle and adipose tissue to insulin. One class of lipids involved in the development of insulin resistance are the (glyco)sphingolipids. Ceramide, the most simple sphingolipid, directly inhibits phosphorylation of the insulin signaling mediator Akt/Protein Kinase B. More complex glycosphingolipids, so-called gangliosides, block phosphorylation of the insulin receptor and down-stream signaling, possibly by exclusion of the insulin receptor from specific membrane domains. Pharmacological inhibition of glycosphingolipid synthesis is found to markedly improve insulin sensitivity in rodent models of insulin resistance. Partial glycosphingolipid reduction is well tolerated and may thus offer an attractive new treatment modality for obesity-induced insulin resistance and type II diabetes.
TNF-α and adipocyte biology
2008, FEBS Letters
Dyslipidemia and insulin resistance are commonly associated with catabolic or lipodystrophic conditions (such as cancer and sepsis) and with pathological states of nutritional overload (such as obesity-related type 2 diabetes). Two common features of these metabolic disorders are adipose tissue dysfunction and elevated levels of tumour necrosis factor-alpha (TNF-α). Herein, we review the multiple actions of this pro-inflammatory adipokine on adipose tissue biology. These include inhibition of carbohydrate metabolism, lipogenesis, adipogenesis and thermogenesis and stimulation of lipolysis. TNF-α can also impact the endocrine functions of adipose tissue. Taken together, TNF-α contributes to metabolic dysregulation by impairing both adipose tissue function and its ability to store excess fuel. The molecular mechanisms that underlie these actions are discussed.
Tumor necrosis factor (TNF) interferes with insulin signaling through the p55 TNF receptor death domain
2005, Biochemical and Biophysical Research Communications
Tumor necrosis factor (TNF) contributes to insulin resistance by binding to the 55 kDa TNF receptor (TNF-R55), resulting in serine phosphorylation of proteins such as insulin receptor (IR) substrate (IRS)-1, followed by reduced tyrosine phosphorylation of IRS-1 through the IR and, thereby, diminished IR signal transduction. Through independent receptor domains, TNF-R55 activates a neutral (N-SMase) and an acid sphingomyelinase (A-SMase), that both generate the sphingolipid ceramide. Multiple candidate kinases have been identified that serine-phosphorylate IRS-1 in response to TNF or ceramide. However, due to the fact that the receptor domain of TNF-R55 mediating inhibition of the IR has not been mapped, it is currently unknown whether TNF exerts these effects with participation of N-SMase or A-SMase. Here, we identify the death domain of TNF-R55 as responsible for the inhibitory effects of TNF on tyrosine phosphorylation of IRS-1, implicating ceramide generated by A-SMase as a downstream mediator of inhibition of IR signaling.
syn-selective additions to Garner aldehyde: Synthesis of a potent glucosylceramide synthase inhibitor
2002, Tetrahedron Letters

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¹: To whom correspondence and reprint requests should be addressed at Department of Pharmacology and Toxicology, University of Kansas, 5064 Malott Hall, Lawrence, KS 66045. Fax: (785) 864-5219. E-mail: [email protected].

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Regular ArticleInhibition of Ceramide Production Reverses TNF-Induced Insulin Resistance

Abstract

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Acta

J. Biol. Chem.

Methods Cell Biol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Regular Article
Inhibition of Ceramide Production Reverses TNF-Induced Insulin Resistance