Cardiovascular diseases (CVD) are the leading cause of mortality worldwide. Approximately 17 million people die of CVD. Obesity is considered to be a major risk factor which predisposes an individual to an increased risk of cardiovascular disease mortality. A clustering of risk factors such as obesity, insulin resistance and dyslipidemia results in the metabolic syndrome (MetS) which has a high prevalence rate of 23.7 percent of the US population. Several studies have shown that cellular autophagy is altered in the setting of metabolic syndrome and may contribute to cardiac dysfunction. However, the status of cardiac autophagic flux and autophagy-regulating pathways in the setting of MetS is unknown. The current literature implicates AMPK and mTOR, the key cellular energy sensors in the homeostatic regulation of autophagy. To test the hypothesis that cardiac autophagy is impaired in the setting of MetS mediated by changes in the upstream regulators-AMPK and mTOR, I used the diet-induced obese (DIO) mice and Zucker obese (ZO) rats (genetic model of obesity) as models of MetS. Under baseline conditions, the DIO mice showed impaired cardiac autophagic flux, a hyper-activated state of mTOR and a repressed state of AMPK. Under a physiological stress such as a fast, DIO mice showed impaired activation of cardiac autophagy despite intact responsiveness of the upstream regulators and intact gene expression. To examine the responsiveness of autophagy and that of its upstream regulators in cardiomyocytes sequestered from the extracellular milieu, I used adult rat ventricular cardiomyocytes (ARVM) isolated from ZO rats subjected to autophagy-inducing interventions. The ARVM from ZO rat hearts showed an impaired activation of autophagy despite intact responsiveness of the upstream regulators, similar to the profile observed in vivo. Overall, my results show that cardiac autophagy is indeed impaired in the setting of MetS despite the responsiveness of its regulatory pathways, AMPK and mTOR.