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Diabetes 54:664-671, 2005
© 2005 by the American Diabetes Association, Inc.

Apolipoprotein C3 Deficiency Results in Diet-Induced Obesity and Aggravated Insulin Resistance in Mice

Ilse Duivenvoorden1,2, Bas Teusink1, Patrick C. Rensen1,2, Johannes A. Romijn3, Louis M. Havekes1,2,4, and Peter J. Voshol1,3

1 TNO Prevention and Health, Gaubius Laboratory, Leiden, the Netherlands
2 Department of General Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
3 Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands
4 Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands

Our aim was to study whether the absence of apolipoprotein (apo) C3, a strong inhibitor of lipoprotein lipase (LPL), accelerates the development of obesity and consequently insulin resistance. Apoc3–/– mice and wild-type littermates were fed a high-fat (46 energy %) diet for 20 weeks. After 20 weeks of high-fat feeding, apoc3–/– mice showed decreased plasma triglyceride levels (0.11 ± 0.02 vs. 0.29 ± 0.04 mmol, P < 0.05) and were more obese (42.8 ± 3.2 vs. 35.2 ± 3.3 g; P < 0.05) compared with wild-type littermates. This increase in body weight was entirely explained by increased body lipid mass (16.2 ± 5.9 vs. 10.0 ± 1.8 g; P < 0.05). LPL-dependent uptake of triglyceride-derived fatty acids by adipose tissue was significantly higher in apoc3–/– mice. LPL-independent uptake of albumin-bound fatty acids did not differ. It is interesting that whole-body insulin sensitivity using hyperinsulinemic-euglycemic clamps was decreased by 43% and that suppression of endogenous glucose production was decreased by 25% in apoc3–/– mice compared with control mice. Absence of apoC3, the natural LPL inhibitor, enhances fatty acid uptake from plasma triglycerides in adipose tissue, which leads to higher susceptibility to diet-induced obesity followed by more severe development of insulin resistance. Therefore, apoC3 is a potential target for treatment of obesity and insulin resistance.

Address correspondence and reprint requests to Peter J. Voshol, Leiden University Medical Center, Department of Endocrinology and Metabolic Diseases, C4R P.O. Box 9600, NL-2300 RC Leiden, Netherlands. E-mail: p.j.voshol{at}lumc.nl


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