17 Translational Control in Metabolic Diseases: The Role of mTOR Signaling in Obesity and Diabetes

For some time it has been recognized not only that protein synthesis is regulated by growth factors and hormonal signaling (Shi et al. 2003), but that the translation machinery is also specifically affected by nutrient levels (Clemens et al. 1980; Pain et al. 1980). These stimuli modulate both the global synthesis of proteins and the selective translation of specific mRNAs. Thus, given the impact of nutrient supply and endocrine signaling on protein synthesis, it is logical to presume that pathological conditions affecting nutrient homeostasis would result in major deregulation of protein synthesis. Currently, the most prevalent homeostatic dis-order is the metabolic syndrome, defined as a cluster of pathologies that always includes obesity, plus at least two of the following factors: raised serum triglyceride levels, reduced high-density-lipoprotein cholesterol levels, raised blood pressure, and raised fasting plasma glucose. The recent dramatic increase in the incidence of obesity has strongly contributed to an escalation of the metabolic syndrome manifestations in Western societies. It is believed that the increase in obesity derives from the fact that during evolution, food scarcity led to the development of dominant genetic traits to secure and manage caloric intake (Neel 1999). In Western societies, food availability, which increased dramatically in the 1950s, began to reveal these calorie-securing traits, and obesity emerged as a prevalent disorder that has since reached epidemic proportions. The nutrient overload resulting from increased food intake is being further accentuated by a decrease in physical activity and a demographic shift to an aging population (Pi-Sunyer 2002).