Objective: We recently described that hypertriglyceridemic apolipoprotein (apo) CIII transgenic mice show increased whole body metabolic rate. In this study, we used these apo CIII-expressing mice, combined or not with the expression of the natural promoter-driven CETP gene, to test the hypothesis that both proteins modulate diet-induced obesity. Measurements and results: Mice expressing apo CIII, CIII/CETP, CETP and nontransgenic (NonTg) mice were maintained on a high-fat diet (14% fat by weight) during 20 weeks after weaning. At the end of this period, all groups exhibited the expected lipemic phenotype. Fasting glucose levels were neither affected by the high-fat diet nor by the distinct genotypes. However, apo CIII mice showed significantly higher glycemia (B35%) and lower insulin levels (B45%) in the fed state, compared with the NonTg mice. The apo CIII mice presented significantly increased body weight, lipid content of the carcass (B25%), visceral adipose tissue mass (about twofold) and adipocyte size (B25%) compared with the CETP and NonTg mice. The CETP expression in the apo CIII background normalized the subcutaneous adipose depot and visceral adipocyte size to the levels of NonTg mice. Plasma leptin levels were lower in CETP groups (25-50%) and higher in the apo CIII mice. Similar core body temperature in all groups and similar liver mitochondrial resting respiration rates in CIII and NonTg mice indicate no differences in basal energy expenditure rates among these mice fed a high-fat diet. Conclusion: The elevation of plasma apo CIII levels aggravates diet-induced obesity and the expression of physiological levels of circulating CETP reverses this adipogenic effect, indicating a novel role for CETP in modulating adiposity. Keywords: CETP; apolipoprotein CIII; diet-induced obesity; hypertriglyceridemia; leptin; mitochondrial respiration IntroductionHypertriglyceridemia is a common feature in the general population. Although it can be caused by many factors, including dietary habits, alcohol intake, medication and different diseases, it is clear that a large number of individuals have a genetic tendency to hypertriglyceridemia. 1,2Apolipoprotein (apo) CIII is an 8.8-kDa plasma glycoprotein constituent of the triglyceride (TG)-rich lipoproteins, synthesized mainly by the liver and to a lesser extent by the intestine.3,4 Apo CIII plays an important role in regulating plasma TG metabolism. 4-6Transgenic mice expressing human apo CIII have elevated TG levels due to the presence of enlarged TG-rich lipoproteins in plasma with increased apo CIII and decreased apo E compared with controls. 7-9 Elevation in plasma TG is proportional to the level of apo CIII gene expression and to the amount of human apo CIII in plasma. 10,11On the other hand, murine apo CIII gene deletion results in hypotriglyceridemia. 12 Apo CIII delays the clearance of TG-rich lipoproteins by two ways (i) decreasing the affinity of TG-rich lipoproteins for glycosaminoglycan-bound lipases 13 and (ii) reducing the receptor-mediated uptake of l...
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