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J. Biol. Chem., Vol. 280, Issue 12, 11018-11024, March 25, 2005

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Glucosamine-induced Activation of Glycogen Biosynthesis in Isolated Adipocytes

EVIDENCE FOR A RAPID ALLOSTERIC CONTROL MECHANISM WITHIN THE HEXOSAMINE BIOSYNTHESIS PATHWAY^*

Stephen Marshall, Owen Nadeau, and Kazumitsu Yamasaki¶

From the Hexos, Incorporated, Woodinville, Washington 98072

Enhanced flux through the hexosamine biosynthesis pathway (HBP) induces insulin resistance and facilitates lipid storage through the up-regulation of enzyme mRNA levels. Both actions occur over several hours and require gene expression. We now identify a regulatory arm of the HBP that involves rapid allosteric activation of glycogen synthase (GS) and stimulation of glycogen biosynthesis (GBS). When insulin-pretreated adipocytes were exposed to 2 mM GlcN, incorporation of [¹⁴C]glucose into glycogen doubled by 10 min (t of <5 min), whereas UDP-glucose levels were concomitantly decreased during this time (t of 1.4 min; >90% depletion). Stimulation of GBS and depletion of UDP-glucose both correlated with an early and rapid rise in the levels of glucosamine-6-phosphate (GlcN-6-P), a known activator of GS. The lowering of GlcN-6-P levels by removing extracellular GlcN (>80% reduction by 45 min) was accompanied by the restoration of UDP-glucose levels. Prolonged GlcN treatment (20 min to 2 h) inhibited GBS, which corresponded to a massive intracellular accumulation of GlcN-6-P (t of 32 min; >1,400 nmol/g). From these data, we conclude the following. 1) GlcN treatment elevated intracellular GlcN-6-P levels within minutes, resulting in allosteric activation of GS, stimulation of GBS, and a reduction in steady-state levels of UDP-glucose due to increased precursor utilization. 2) Prolonged treatment with high concentrations of GlcN caused massive accumulation of GlcN-6-P that adversely affected cellular metabolism and reduced GBS. 3) The biphasic actions of GlcN on GBS may explain many of the discrepant reports on the role of the HBP in glycogen metabolism.

Received for publication, December 1, 2004 , and in revised form, December 29, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Dept. of Biochemistry and Molecular Biology, Kansas University Medical Center, 3901 Rainbow Blvd., Kansas City, KS 64110.

^¶ Present address: School of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305, Japan.

To whom correspondence should be addressed: Hexos, Inc., 18304 N. E. 153rd St., Woodinville, WA 98072. Tel.: 425-844-2527; E-mail: Hexos{at}comcast.net.

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