| Several lines of evidence show that obesity results in marked alterations in energy metabolism that contribute to the pathophysiology of several cardiovascular and metabolic disorders. As aging is an important risk factor for the development of these obesity-related diseases, this thesis demonstrated that there are physiological and metabolic changes that predispose middle-aged mice to developing insulin resistance and cardiomyopathy. We show that overall metabolic rate is reduced with aging and this is associated with impaired skeletal muscle activation of AMP-activated protein kinase (AMPK), a key regulator of energy metabolism. Furthermore, middle-aged mice fed a high fat diet develop more dramatic insulin resistance, as well as cardiac hypertrophy, than young mice. We show that these effects are due in part to increased skeletal muscle and heart expression of CD36, a key fatty acid transport protein. Indeed, ablation of CD36 can prevent middle-aged mice from developing these conditions. Moreover, increased CD36 levels in the heart and skeletal muscle were correlated with accumulation of potentially toxic lipid derivatives. These data support a link between lipotoxicity and skeletal muscle insulin resistance and cardiac hypertrophy. In addition to the role of AMPK in energy metabolism, it is also a known negative regulator of cardiac hypertrophy and we show that AMPK activation is markedly reduced in the hypertrophic middle-aged heart following high fat diet. Therefore, reduced AMPK activity may create a permissive environment for the activation of pro-hypertrophic signaling pathways in the middle-aged heart. While calorie reduction is beneficial to combat the effects of obesity, reduced caloric intake also has been shown to be cardioprotective against myocardial ischemia-reperfusion injury. In this thesis we also show that promoting glucose metabolism may contribute to improved ischemic tolerance and functional recovery of hearts from mice following short-term calorie restriction. Together, these studies suggest that perturbations in energy metabolism are important contributing factors to the etiology of a number of cardiovascular and metabolic disorders and that strategies aimed at optimizing energy metabolism may have significant therapeutic potential in the treatment of these conditions. |
