Role of autophagy in the progression from obesity to diabetes and in the control of energy balance

Autophagy plays a crucial role in cellular homeostasis through the degradation and recycling of organelles such as mitochondria or endoplasmic reticulum (ER) that are closely related to the pathogenesis of diabetes. In pancreatic beta-cells producing insulin, autophagy helps maintain beta-cell mass, structure and function. In mice with beta-cell-specific deletion of Atg7 (autophagy-related 7), a critical autophagy gene, reduction of beta-cell mass and pancreatic insulin content were observed together with impaired insulin secretory function. Because of such structural and functional defects, beta-cell-specific Atg7-null mice showed hypoinsulinemia and hyperglycemia. However, those mice never developed diabetes. Obesity and lipids are physiological ER stressors that can precipitate beta-cell dysfunction and insulin resistance. Recent studies showed that beta-cell-specific Atg7-null mice, when bred with ob/ob mice, developed severe diabetes, suggesting that autophagy-deficient beta-cells can handle basal metabolic stress but have problems dealing with increased metabolic stress. Thus, autophagy deficiency in beta-cells could be a factor in the progression from obesity to diabetes due to an inappropriate response to obesity-induced ER stress. Autophagy also appears to play a role in the hypothalamic control of energy expenditure, appetite and body weight. Thus, autophagy is important to body and nutrient metabolism in many ways, and its dysregulation could contribute to the pathogenesis of metabolic disorders and diabetes.