Summary
Membrane microdomains (lipid rafts), which are critical for proper compartmentalization of insulin signaling, also play a role in the pathogenesis of insulin resistance, and yet this role has not been investigated. Detergent-resistant membrane microdomains (DRMs), isolated in low density fractions, are rich in cholesterol, glycosphingolipids and various signaling molecules. TNFφ induces insulin resistance in type 2 diabetes, but its action mechanism is not fully understood. We found a selective increase in the acidic glycosphingolipid ganglioside GM3 in 3T3-L1 adipocytes treated with TNFφ, suggesting a specific function for GM3. We extended these in vitro observations to living animals using obese Zucker fa/fa rats and ob/ob mice, in which the GM3 synthase mRNA levels in the white adipose tissues are significantly higher than in their lean controls. In DRMs from TNFφ-treated 3T3-L1 adipocytes, GM3 levels were doubled those of normal adipocytes. Additionally, insulin receptor (IR) accumulations in DRMs were diminished, while caveolin and flotillin levels were unchanged. GM3 depletion counteracted the TNFφ-induced inhibition of IR accumulation into DRMs. Together, these findings provide compelling evidence an insulin metabolic signaling defect can be attributed to a loss of IRs in the microdomains due to an accumulation of GM3. Therefore, it is likely that life-style related diseases, such as type 2 diabetes, are membrane microdomain disorders caused by aberrant expression of glycosphingolipids.
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Inokuchi, Ji., Kabayama, K., Sato, T., Igarashi, Y. (2006). A New Pathological Feature of Insulin Resistance and Type 2 Diabetes: Involvement of Ganglioside GM3 and Membrane Microdomains. In: Hirabayashi, Y., Igarashi, Y., Merrill, A.H. (eds) Sphingolipid Biology. Springer, Tokyo. https://doi.org/10.1007/4-431-34200-1_21
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DOI: https://doi.org/10.1007/4-431-34200-1_21
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