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J. Biol. Chem., Vol. 283, Issue 41, 27565-27574, October 10, 2008

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Glyceroneogenesis Is the Dominant Pathway for Triglyceride Glycerol Synthesis in Vivo in the Rat^*

Colleen K. Nye¹, Richard W. Hanson, and Satish C. Kalhan^¶2

From the Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, ^¶Department of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and Departments of Gastroenterology and Pathobiology, Cleveland Clinic, Cleveland, Ohio 44195

Triglyceride synthesis in mammalian tissues requires glycerol 3-phosphate as the source of triglyceride glycerol. In this study the relative contribution of glyceroneogenesis and glycolysis to triglyceride glycerol synthesis was quantified in vivo in adipose tissue, skeletal muscle, and liver of the rat in response to a chow diet (controls), 48-h fast, and lipogenic (high sucrose) diet. The rate of glyceroneogenesis was quantified using the tritium ([³H₂]O) labeling of body water, and the contribution of glucose, via glycolysis, was determined using a [U-¹⁴C]glucose tracer. In epididymal and mesenteric adipose tissue of control rats, glyceroneogenesis accounted for 90% of triglyceride glycerol synthesis. Fasting for 48 h did not alter glyceroneogenesis in adipose tissue, whereas the contribution of glucose was negligible. In response to sucrose feeding, the synthesis of triglyceride glycerol via both glyceroneogenesis and glycolysis nearly doubled (versus controls); however, glyceroneogenesis remained quantitatively higher as compared with the contribution of glucose. Enhancement of triglyceride-fatty acid cycling by epinephrine infusion resulted in a higher rate of glyceroneogenesis in adipose tissue, as compared with controls, whereas the contribution of glucose via glycolysis was not measurable. Glyceroneogenesis provided the majority of triglyceride glycerol in the gastrocnemius and soleus. In the liver the fractional contribution of glyceroneogenesis remained constant (60%) under all conditions and was higher than that of glucose. Thus, glyceroneogenesis, in contrast to glucose, via glycolysis, is quantitatively the predominant source of triglyceride glycerol in adipose tissue, skeletal muscle, and liver of the rat during fasting and high sucrose feeding.

Received for publication, June 6, 2008 , and in revised form, July 22, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants DK-58620 and DK-25541 (to R. W. H.) and HD-11089 and HD-042154 (to S. C. K.). 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.

¹ A Trainee on the National Institutes of Health Metabolism Training Grant DK-21859 at Case Western Reserve University School of Medicine.

² To whom correspondence should be addressed: Dept. of Pathobiology, Lerner Research Institute, 9500 Euclid Ave., NE40; Cleveland, OH 44195. Tel.: 216-444-3445; E-mail: satish.kalhan{at}case.edu.

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