Cell Biology
Selective Insulin Resistance in Adipocytes*

https://doi.org/10.1074/jbc.M114.623686Get rights and content
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Aside from glucose metabolism, insulin regulates a variety of pathways in peripheral tissues. Under insulin-resistant conditions, it is well known that insulin-stimulated glucose uptake is impaired, and many studies attribute this to a defect in Akt signaling. Here we make use of several insulin resistance models, including insulin-resistant 3T3-L1 adipocytes and fat explants prepared from high fat-fed C57BL/6J and ob/ob mice, to comprehensively distinguish defective from unaffected aspects of insulin signaling and its downstream consequences in adipocytes. Defective regulation of glucose uptake was observed in all models of insulin resistance, whereas other major actions of insulin such as protein synthesis and anti-lipolysis were normal. This defect corresponded to a reduction in the maximum response to insulin. The pattern of change observed for phosphorylation in the Akt pathway was inconsistent with a simple defect at the level of Akt. The only Akt substrate that showed consistently reduced phosphorylation was the RabGAP AS160 that regulates GLUT4 translocation. We conclude that insulin resistance in adipose tissue is highly selective for glucose metabolism and likely involves a defect in one of the components regulating GLUT4 translocation to the cell surface in response to insulin.

Background: Insulin resistance is an early risk factor for metabolic disease.

Results: Using various insulin resistance models, insulin regulation of glucose metabolism was universally blunted, whereas other actions (protein synthesis and anti-lipolysis) were unimpaired.

Conclusion: Insulin resistance is selective for glucose metabolism in adipocytes.

Significance: Chronic hyperactivation of unaffected insulin action pathways in the context of the metabolic syndrome likely contributes to disease progression.

Adipocyte
Glucose Metabolism
Insulin
Insulin Resistance
Lipolysis
Insulin Action
Selective Insulin Resistance
White Adipose

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*

This work was supported by National Health and Medical Research Council Project Grants GNT1061122 and GNT1047067.

1

These authors contributed equally to this work.

2

Present address: Institute of Molecular and Cell Biology, Singapore.

3

Present address: Dept. of Physiology, Fourth Military Medical University, Xi'an, Shaanxi Province, China.