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J. Biol. Chem., Vol. 280, Issue 27, 25396-25402, July 8, 2005

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Physiologic and Pharmacologic Factors Influencing Glyceroneogenic Contribution to Triacylglyceride Glycerol Measured by Mass Isotopomer Distribution Analysis^*

Jerry L. Chen, Erin Peacock, Waheeda Samady, Scott M. Turner, Richard A. Neese, Marc K. Hellerstein, and Elizabeth J. Murphy¶

From the Department of Nutritional Sciences & Toxicology, University of California-Berkeley, Berkeley, California 94720 and the Department of Medicine, San Francisco General Hospital, University of California-San Francisco, San Francisco, California 94110

An imbalance between triacylglycerol synthesis and breakdown is necessary for the development of obesity. The direct precursor for triacylglycerol biosynthesis is -glycerol phosphate, which can have glycolytic and glyceroneogenic origins. We present a technique for determining the relative glyceroneogenic contribution to triacylglyceride glycerol by labeling the glycerol moiety with ²H₂O. The number of hydrogen atoms (n) incorporated from H₂O into C–H bonds reflects the metabolic source of -glycerol phosphate and can be calculated by combinatorial analysis of the distribution of mass isotopomers in triacylglyceride glycerol. Three physiological settings with potential effects on glyceroneogenesis and glycolysis were studied in rodents. Adipose tissue acylglyceride glycerol in mice fed a low carbohydrate diet had significantly higher values of n than in mice fed a high carbohydrate diet, suggesting an increased contribution from glyceroneogenesis of from 17 to 50% on the low carbohydrate diet. Similarly, mice administered rosiglitazone had a significant relative increase in glyceroneogenesis (from 17 to 53%), indicated by an increase in adipose acylglyceride glycerol n. Fructose infusion in overnight fasted rats rapidly lowered plasma triacylglyceride glycerol n, reflecting a decreased contribution from glyceroneogenesis (from 66 to 34%) presumably because of increased glycolytic input. In conclusion, we demonstrate that the number of C–H atoms derived from cellular H₂O in triacylglyceride glycerol is an informative indicator of -glycerol phosphate origin and, ultimately, triacylglycerol metabolism. Under certain physiological conditions, glyceroneogenesis can be up-regulated in adipose (e.g. low carbohydrate diet) or down-regulated in liver (e.g. fructose infusion). Additionally, stimulation of glyceroneogenesis by rosiglitazone in adipose tissue may be an important factor in the antilipolytic actions of thiazolidinediones.

Received for publication, December 13, 2004 , and in revised form, May 11, 2005.

^* These studies were supported in part by National Institutes of Health Grant NHLBI HL65919 (to M. H. K.), College of Natural Resources at UC Berkeley Hatch award (to M. K. H.), and a Pfizer post-doctoral fellowship (to E. J. M.). 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.

^¶ To whom correspondence should be addressed: San Francisco General Hospital, 1001 Potrero Ave., Bldg. 30, Rm. 3501-K, San Francisco, CA 94110. E-mail: smurph{at}itsa.ucsf.edu.

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