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J. Biol. Chem., Vol. 279, Issue 6, 4051-4057, February 6, 2004

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Acylation-stimulating Protein (ASP)/Complement C3adesArg Deficiency Results in Increased Energy Expenditure in Mice^*

Zhunan Xia, Kimber L. Stanhope, Erin Digitale, Oana-Maria Simion, Lanying Chen¶||, Peter Havel, and Katherine Cianflone**

From the Mike Rosenbloom Laboratory for Cardiovascular Research, McGill University Health Centre, Montreal H3A 1A1, Canada, the Department of Nutrition, University of California, Davis, California 95616, and the ^¶Biochemistry Department, Cardiovascular Institute and FuWai Hospital, Beijing, Peoples Republic of China

Acylation-stimulating protein (ASP) acts as a paracrine signal to increase triglyceride synthesis in adipocytes. In mice, C3 (the precursor to ASP) knock-out (KO) results in ASP deficiency and leads to reduced body fat and leptin levels yet they are hyperphagic. In the present study, we investigated the mechanism for this energy repartitioning. Compared with wild-type (WT) mice, male and female C3(–/–) ASP-deficient mice had elevated oxygen consumption (VO₂) in both the active (dark) and resting (light) phases of the diurnal cycle: +8.9% males (p < 0.05) +9.4% females (p < 0.05). Increased physical activity (movement) was observed during the dark phase in female but not in male KO animals. Female WT mice moved 16.9 ± 2.4 m whereas KO mice moved 30.1 ± 5.4 m, over 12 h, +78.4%, p < 0.05). In contrast, there was no difference in physical activity in male mice, but a repartitioning of dietary fat following intragastric fat administration was noted. This was reflected by increased fatty acid oxidation in liver and muscle in KO mice, with increased UCP2 (inguinal fat) and UCP3 (muscle) mRNA expression (p = 0.005 and 0.036, respectively). Fatty acid uptake into brown adipose tissue (BAT) and white adipose tissue (WAT) was reduced as reflected by a decrease in the fatty acid incorporation into lipids (BAT –68%, WAT –29%. The decrease of FA incorporation was normalized by intraperitoneal administration of ASP at the time of oral fat administration. These results suggest that ASP deficiency results in energy repartitioning through different mechanisms in male and female mice.

Received for publication, October 15, 2003

^* This study was supported by grants from the National Science and Engineering Council of Canada (NSERC, to K. C.), University of California, Davis, Clinical Nutrition Research Unit, National Institutes of Health Grants DK-50129, DK-35747, and the American Diabetes Association (to P. H.). 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.

^|| Supported by a visiting scholarship from FRSQ/National Science Foundation of China.

^** Research scholar of Les Fonds de Recherche en Sante du Quebec (FRSQ). To whom correspondence should be addressed: Cardiology, H7.30, Royal Victoria Hospital, 687 Pine Ave West, Montreal, Quebec H3A 1A1, Canada. Tel.: 514-842-1231 (ext 35426); Fax: 514-843-2843; E-mail: katherine.cianflone{at}mcgill.ca.

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