부산대학교 도서관

The cardiovascular (CV) benefits of the CETP inhibitor dalcetrapib (DAL) are dependent on ADCY9 genotype. We also observed genotype-dependent changes in body weight (BW) in DAL-treated patients that were directionally opposite to the effects on CV outcomes in the dal-OUTCOMES study and atherosclerosis imaging in dal-PLAQUE-2. Our goal was to study the effect of Adcy9 inactivation on BW and body adipose tissue volume (ATV) in mice. Adcy9-inactivated (Adcy9) and wild-type (WT) mice (n=8), that do not express CETP, were first infected with an adeno-associated virus expressing a gain-of-function (D377Y) Pcsk9 and exposed to a high-fat, high-cholesterol diet (HFD) for 16 weeks before sacrifice. We have previously shown that Adcy9 mice have significantly less aortic atherosclerosis than WT mice (9 vs 4%, P=0.01). At the start of HFD, BW of Adcy9 mice (24.6±0.5 g) and WT mice (26.1±0.8 g) were similar. At 14 weeks of HFD, BW of Adcy9 mice (43.6±2.4 g) was greater than that of WT (34.1±1.3 g, P<0.01). At 14 weeks, ATV determined by MRI was higher in Adcy9 (9.5±1.2 cm) compared to WT (4.3±0.4 cm) mice (P<0.01). At sacrifice, interscapular, inguinal, perirenal and epididymal fat depots showed macroscopically increased volume in Adcy9 versus WT. We then studied the effect of Adcy9 inactivation on BW and ATV in mice transgenic for human CETP (tgCETP). tgCETP-Adcy9 mice (n=11) and tgCETP mice (n=7) had similar BW (34.4±1.0 and 32.2±0.9 g) and ATV (5.4±0.7 and 4.4±0.4 cm) at 14 weeks of HFD. These results demonstrate that Adcy9 regulates BW and adipose tissue in mice only in the absence of CETP. As was previously observed in patients, the effects of Adcy9 on weight and adiposity were directionally opposite to that on atherosclerosis.