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J. Biol. Chem., Vol. 275, Issue 51, 40148-40154, December 22, 2000

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Specific Desensitization of Glycogen Synthase Activation by Insulin in 3T3-L1 Adipocytes
CONNECTION BETWEEN ENZYMATIC ACTIVATION AND SUBCELLULAR LOCALIZATION^*

Timothy C. Jensen^§, Sean M. Crosson^§¶, Pavna M. Kartha^¶, and Matthew J. Brady

From the  Department of Cell Biology, Pfizer Global Research and Development, Ann Arbor, Michigan 48105 and the ^¶ Department of Physiology, the University of Michigan School of Medicine, Ann Arbor, Michigan 48109

A protocol was developed in 3T3-L1 adipocytes that resulted in the specific desensitization of glycogen synthase activation by insulin. Cells were pretreated for 15 min with 100 nM insulin, and then recovered for 1.5 h in the absence of hormone. Subsequent basal and insulin-induced phosphorylation of the insulin receptor, IRS-1, MAPK, Akt kinase, and GSK-3 were similar in control and pretreated cells. Additionally, enhanced glucose transport and incorporation into lipid in response to insulin were unaffected. However, pretreatment reduced insulin-stimulated glycogen synthesis by over 50%, due to a nearly complete inhibition of glycogen synthase activation. Removal of extracellular glucose during the recovery period blocked the increase in glycogen levels, and restored insulin-induced glycogen synthase activation. Furthermore, incubation of pretreated 3T3-L1 adipocytes with glycogenolytic agents reversed the desensitization event. Separation of cellular lysates on sucrose gradients revealed that glycogen synthase was primarily located in the dense pellet fraction, with lesser amounts in the lighter fractions. Insulin induced glycogen synthase translocation from the lighter to the denser glycogen-containing fractions. Interestingly, insulin preferentially activated translocated enzyme while having little effect on the majority of glycogen synthase activity in the pellet fraction. In insulin-pretreated cells, glycogen synthase did not return to the lighter fractions during recovery, and thus did not move in response to the second insulin exposure. These results suggest that, in 3T3-L1 adipocytes, the translocation of glycogen synthase may be an important step in the regulation of glycogen synthesis by insulin. Furthermore, intracellular glycogen levels can regulate glycogen synthase activation, potentially through modulation of enzymatic localization.

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