TNF -induced insulin resistance in adipocytes as a membrane microdomain disorder: involvement of ganglioside GM3

Abstract

Membrane microdomains (lipid rafts) are now recognized as critical for proper compartmentalization of insulin signaling, but their role in the pathogenesis of insulin resistance has not been investigated. Detergent-resistant membrane microdomains (DRMs), isolated in the low-density fractions, are highly enriched in cholesterol, glycosphingolipids and various signaling molecules. Tumor necrosis factor alpha (TNFalpha) induces insulin resistance in type 2 diabetes, but its mechanism of action is not fully understood. In other studies we have found a selective increase in the acidic glycosphingolipid ganglioside GM3 in 3T3-L1 adipocytes treated with TNFalpha, suggesting a specific function for GM3. In the DRMs from TNFalpha-treated 3T3-L1 adipocytes, GM3 levels were doubled compared with results in normal adipocytes. Additionally, insulin receptor (IR) accumulations in the DRMs were diminished, whereas caveolin and flotillin levels were unchanged. Furthermore, insulin-dependent IR internalization and intracellular movement of the IR substrate 1(IRS-1) were both greatly suppressed in the treated cells, leading to an uncoupling of IR-IRS-1 signaling. GM3 depletion was able to counteract the TNFalpha-induced inhibitions of IR internalization and accumulation into DRMs. Together, these findings provide compelling evidence that in insulin resistance the insulin metabolic signaling defect can be attributed to a loss of IRs in the microdomains due to an accumulation of GM3.

Efficacy of nutritional interventions to lower circulating ceramides in young adults: FRUVEDomic pilot study

“…2002), and excessive ganglioside content can disrupt insulin signaling by displacing the insulin receptor from these microdomains (Kabayama et al. 2004). Modifying dietary energy intake is a likely means to control glycosylated ceramide supply.…”

Diabetes Alters Sphingolipid Metabolism in the Retina

“…In fact, we have recently found that cholesterol depletion, which disrupts lipid microdomains, reduces insulin receptor autophosphorylation by insulin in R28 retinal neurons (T.E.F., M.K., unpublished data). In addition, GM3 within microdomains (18) has been implicated in insulin resistance in response to TNF-␣ (15), and, conversely, mice deficient in GM3 synthase exhibit greater insulin sensitivity (21). Recent reports suggest that glycosphingolipids can also mediate apoptosis and cellular stress.…”

“…Simple glycosphingolipids, such as glucosyl and galactosylceramide (cerebrosides or monohexosylceramides), serve as building blocks for more complex glycosphingolipids, including sulfatides, globosides, and gangliosides. Recent reports (15)(16)(17)(18)(19)(20)(21) suggest that these glycosphingolipids can mediate apoptosis, insulin resistance, and cellular stress. In addition, altered sphingolipid and glycosphingolipid metabolism causes several retinal diseases.…”

Fabrication of GM3‐Enriched Sphingomyelin/Cholesterol Solid‐Supported Lipid Membranes on Au/SiO2 Plasmonic Substrates

“…Among such molecules, the monosialodihexosylganglioside, GM3, whose abundance in lipid rafts has been documented by Simons and Ikonen [4], plays important roles in receptor functions and signal transduction [5], like for instance the suppression of the phosphorylation of the epidermal growth factor receptor [6,7] and insulin receptor [8,9] or the recognition of the influenza virus via its binding to the sialylgalactose structure of GM3 during the adsorption-fusion process [10]. Other experimental findings [11] indicate that the ganglioside GM3 blocks the cells proliferation induced by vascular endothelial growth factor (VEGF) and by the ganglioside GD1a, and it is also able to inhibit the linking between the urokinase plasminogen activator receptor (uPAR) and the integrin a 5 b 1 necessary for the migration of the endothelial cells [12].…”