Metabolismo energético de animais knockout induzidos para Acetil-CoA Carboxilase 2 (ACC2) específica de coração: ACC2 como gene alvo na hipertrofia cardíaca induzida por obesidade

Abstract

Increased fatty acid (FA) oxidation and elevated lipid accumulation has been observed in many chronic diseases such as diabetes and obesity and they are closely associated with cardiac dysfunction. This study was undertaken to elucidate the mechanisms underlying the chronic substrate switch in obese adult hearts and to determine the functional consequences of increasing FA oxidation simultaneously with the development of obesity. We sought to test whether inducible cardiac-specific deletion of ACC2 in mice with diet induced obesity would facilitate long chain fatty acid (FA) entry into the mitochondria, leading to an increase in FA oxidation and ultimately restoring the balance between lipid supply and oxidation in the heart. Inducible cardiac-specific ACC2 knockout mice (ICKO) were used to facilitate long chain FA entry into the mitochondria. A high-fat diet was used to increase FA supply to the heart and to develop obesity in these mice. A total dose of 100mg/Kg of tamoxifen for 5 days was enough to delete ACC2 protein and to increase FA oxidation 4 weeks after the start of tamoxifen protocol in ACC2 F/F-MerCreMer+ without imparing the cardiac function as shown by Echocardiography measurements. Once the animal model was stablished, a high-fat diet (HFD) (60% das kcal derived by milk fat) was given for 12 weeks to increase AG supply to the heart developing a state of obesity with increased body weight, adipose tissue content, non sterified fatty acids levels (NEFA) and glucose intolerance in control (CONT) and inducible cardiac specific knockout mice for ACC2 (ICKO). Moreover, a high-fat diet resulted in increased heart weight to tibia length ratio in CONT mice when compared to CONT and ICKO mice fed with a control diet and ICKO in the same high-fat diet protocol, characterizing the development of cardiac hypertrophy in CONT+HFD and a protective effect in ICKO+HFD mice. These data were followed by a reduction in mRNA levels for PPAR-α and PGC-1α in CONT+HFD animals when compared with ICKO+HFD. As expected, a high-fat diet increased mRNA levels for UCP3 in CONT e ICKO mice. No effect was observed for mRNA levels of CD36, SOD2, Bax and BNP. Differently, ANP mRNA levels were reduced in CONT+HFD when compared to CONT+CD. These data suggest that an increase in FA oxidation, resulting from ACC2 an inducible inactivation counteracted the elevated FA availability during HFD resulting in a balanced lipid metabolism and protect against cardiac hypertrophy.