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J. Biol. Chem., Vol. 282, Issue 48, 35069-35077, November 30, 2007

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Low Utilization of Circulating Glucose after Food Withdrawal in Snell Dwarf Mice^*

Natasha L. Brooks¹, Chad M. Trent¹, Carl F. Raetzsch, Kevin Flurkey, Gunnar Boysen^¶, Michael T. Perfetti, Yo-Chan Jeong^¶, Simon Klebanov^||, Kajal B. Patel, Valerie R. Khodush, Lawrence L. Kupper^**, David Carling, James A. Swenberg^¶, David E. Harrison, and Terry P. Combs²

From the Departments of Nutrition, ^¶Environmental Sciences and Engineering, and ^**Biostatistics, University of North Carolina, Chapel Hill, North Carolina 27599, the Jackson Laboratory, Bar Harbor, Maine 04609, ^||Columbia University College of Physicians & Surgeons, New York, New York 10025, and the Medical Research Council Clinical Sciences Centre, Imperial College of London, London W12 0NN, United Kingdom

Glucose metabolism is altered in long-lived people and mice. Although it is clear that there is an association between altered glucose metabolism and longevity, it is not known whether this link is causal or not. Our current hypothesis is that decreased fasting glucose utilization may increase longevity by reducing oxygen radical production, a potential cause of aging. We observed that whole body fasting glucose utilization was lower in the Snell dwarf, a long-lived mutant mouse. Whole body fasting glucose utilization may be reduced by a decrease in the production of circulating glucose. Our isotope labeling analysis indicated both gluconeogenesis and glycogenolysis were suppressed in Snell dwarfs. Elevated circulating adiponectin may contribute to the reduction of glucose production in Snell dwarfs. Adiponectin lowered the appearance of glucose in the media over hepatoma cells by suppressing gluconeogenesis and glycogenolysis. The suppression of glucose production by adiponectin in vitro depended on AMP-activated protein kinase, a cell mediator of fatty acid oxidation. Elevated fatty acid oxidation was indicated in Snell dwarfs by increased utilization of circulating oleic acid, reduced intracellular triglyceride content, and increased phosphorylation of acetyl-CoA carboxylase. Finally, protein carbonyl content, a marker of oxygen radical damage, was decreased in Snell dwarfs. The correlation between high glucose utilization and elevated oxygen radical production was also observed in vitro by altering the concentrations of glucose and fatty acids in the media or pharmacologic inhibition of glucose and fatty acid oxidation with 4-hydroxycyanocinnamic acid and etomoxir, respectively.

Received for publication, January 17, 2007 , and in revised form, September 4, 2007.

^* This work was supported by NIDDK, National Institutes of Health (NIH) Grants DK075573 and DK056350, NIA, NIH Grants AG025007 and AG18003, and NIEHS, NIH Grant ES10126. 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Nutrition, School of Medicine, School of Public Health, University of North Carolina, Chapel Hill, NC 27599-7461. Tel.: 919-966-7235; Fax: 919-966-7216; E-mail: terrycombs{at}unc.edu.

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