UC Merced

Cardiovascular disease (CVD) is the leading cause of death among individuals with Type II diabetes (T2D) with approximately 30 million people afflicted within the United States. Metabolic Syndrome (MetS) is a contributing cause of T2D and CVD. MetS is defined by the simultaneous presence of at least three of the following conditions: (I) abdominal obesity/increased adiposity, (II) atherogenic dyslipidemia, (III) hypertension, (IV) hyperglycemia with or without insulin resistance, (V) prothrombotic state, and (VI) proinflammatory state. Thus, targeting MetS in its early stages may help prevent the later onset of CVD and T2D. During insulin resistance the heart undergoes a metabolic shift in which fatty acids (FA) accounts for about 99% of the ATP production, greatly reducing the contribution of glucose to cardiac metabolism. This metabolic shift is indicative of impaired glucose metabolism. A shift in FA metabolism with impaired glucose tolerance can progressively increase tissue and cellular damage, leading to oxidative stress as the rate of oxidant production surpasses the cell's antioxidant capacity. Increases in reactive oxygen species (ROS) and lipotoxicity ultimately lead to impaired mitochondrial function. Thyroid hormones (TH) may improve the glucose intolerance by increasing glucose reabsorption and metabolism in peripheral tissues but its effects on cardiac tissue during insulin resistance is not well known. Exogenous TH (T3 and T4) treatments have been shown to consistently protect the heart from oxidative and/or inflammatory injury following induced acute myocardial infarct (AMI). However, the effects of TH on redox biology and oxidative stress are incongruent and warrant further investigation. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an obese, hypertensive, translational model of MetS that closely mimics the human condition. With this model, we probed the effects of exogenous thyroxine (T4) on cardiac metabolism and function during MetS. We found that: (1) exogenous thyroxine increased glucose transporter (GLUT4) translocation, phosphorylation of AKT substrate 160 (p-AS160), and hexokinase expression, all crucial proteins responsible for glucose uptake and metabolism, while simultaneously decreasing carnitine palmitoyltransferase II (CPT2), an enzyme responsible for FA oxidation, suggesting the potential to upregulate glucose uptake and metabolism during insulin resistance and T2DM, (2) increased cardiac nuclear factor erythroid 2-related factor 2 (Nrf2), thioredoxin (TRX), and mitofusin 2 (Mfn2) suggesting the potential to stimulate antioxidant properties and mitochondrial function, (3) normalized left ventricular end-systolic pressure, and (4) corrected cardiac glucose turnover rates in insulin resistant OLETF rats. Our findings give insight to the ongoing investigation on the potential cardioprotective effects of thyroid hormone treatments during insulin resistance and MetS.