Obesity is considered a global pandemic and obesity-associated diseases, such as atherosclerotic cardiovascular disease (asCVD), are on the rise. In the past century, 2,4-dinitrophenol (DNP) was developed as weight loss strategy, through inducing mitochondrial uncoupling, but was rapidly banned due to toxic side effects. Recently, BAM15 was identified as a mitochondria-targeted small molecule protonophore, with much wider tolerability in vitro compared to DNP, and potency to reverse diet-induced obesity in mice. Here, we investigated the effects BAM15 on dyslipidemia and asCVD in APOE*3-Leiden.CETP mice, a well-established model for human-like cardiometabolic diseases.

Female APOE*3-Leiden.CETP mice were fed a Western-type diet (containing 16% fat, 0.15% cholesterol, +/- 0.1% w/w BAM15). In all experiments, body weight, body composition, and 4h-fasted plasma total cholesterol (TC) and triglyceride (TG) levels were monitored. Very-low-density lipoprotein (VLDL) production and VLDL catabolism were assessed after 4 and 6 weeks of treatment, respectively, and atherosclerotic lesion size was quantified within the aortic valve area after 12 weeks of treatment.

In all experiments, BAM15 prevented body weight gain by preventing accumulation of fat mass. Moreover, BAM15 consistently lowered plasma TC levels (approx. -50%) as explained by decreased VLDL-cholesterol production (-52%), without lowering plasma TG levels. While VLDL-TG-derived fatty acid uptake was increased by subcutaneous white adipose tissue (+36%) and gonadal white adipose tissue (+85%), fatty acid uptake was strongly decreased by subcapsular brown adipose tissue (-46%) and interscapular brown adipose tissue (-36%). Collectively, BAM15 attenuated atherosclerosis development by decreasing the atherosclerotic lesion size in the aortic root area (-34%).

BAM15 lowers the circulating cholesterol levels, resulting in attenuated atherosclerosis in APOE*3-Leiden.CETP mice, without apparent adverse side effects as observed for DNP. Therefore, BAM15 is a promising therapeutic strategy to combat obesity and asCVD.