Cardiovascular Abnormalities in Transgenic Mice With Reduced Brown Fat

Abstract

Background —A new model of murine obesity has recently been developed through transgenic ablation of brown adipose tissue that manifests typical metabolic complications of obesity, including insulin resistance and non–insulin-dependent diabetes mellitus. The cardiovascular phenotype has not been defined. Methods and Results —Transthoracic echocardiography, aortic catheterization, isolated whole-heart studies, and morphometric histology defined cardiac structure and function in 30 transgenic mice with reduced brown fat and 30 matched wild-type controls. Obesity was indicated by a 77% increase in body weight and was accompanied by elevated systemic pressures (mean aortic blood pressure 85±1 versus 66±2 mm Hg; P <0.01), left ventricular dilation and hypertrophy (mass/body weight 4.0±0.2 versus 2.7±0.3 mg/g; P <0.01), and high cardiac output (cardiac index 3.2±0.4 versus 2.4±0.1 mL · kg −1 · min −1 ; P <0.01). Baseline functional parameters assessed in vitro were not different, but after imposition of zero-flow ischemia, significant relaxation impairment developed in obese mice. Although morphometrically determined myocyte diameters were similar, the percentage of interstitial fibrosis was significantly increased in transgenic mice compared with wild-type controls (7.5±2% versus 4.2±0.2%; P <0.01). Conclusions —Transgenic ablation of brown adipose tissue is associated not only with obesity but also with systemic hypertension, left ventricular hypertrophy with eccentric remodeling and fibrosis, and high cardiac output, a unique constellation of findings strikingly similar to that seen in human obesity. Mice with reduced brown fat may serve as a new model for the cardiovascular morbid complications associated with obesity in humans.