The treatment of obesity and diabetes remains a challenge and the biological mechanisms of these diseases are still not fully understood. Diabetes and obesity are associated with increased risk of the development of cardiovascular complications and there is an urgent need to find novel therapeutic approaches for treating obesity and diabetes. Currently there are several approaches to treat these diseases. Among them chemical uncouplers could be used as an effective treatment for obesity but the dangerous side effects of these compounds has limited their use in vivo. Here we propose a novel theoretical model based on the mechanism of action of chemical uncouplers: the thermogenin-like system (TLS). The TLS may be used in vivo to reproduce the mechanism of action of chemical uncouplers but without their dangerous side effects.
The treatment of obesity remains a challenge and it is reported that increased brown fat activity could be an efficient way to treat obesity by inducing thermogenesis, enhancing metabolism through glucose uptake, oxygen consumption and decreasing adipose tissue triglyceride content through lipolysis. After the recent discovery of the presence of active brown fat in human adults, the study of brown fat has gained interest because its activation could increase weight loss. Additionally, there is growing evidence that white adipocytes can be converted into brown fat-like adipocytes [1], [2] in order to enhance thermogenesis and triglyceride utilization to further promote weight loss [3]. However, the mechanisms involved in this conversion remain unknown in part. For this reason, the amount of active brown fat is insufficient to induce an effective weight loss in human adults. An alternative approach is the use of chemical uncouplers in vivo such as FCCP. These compounds induce weight loss, thermogenesis, triglyceride utilization and glucose uptake in white adipocytes [4]. However, the use of chemical uncouplers in vivo is limited since these compounds have significant side effects like hyperthermia, tachycardia, diaphoresis, eventually leading to death [5]. Another study shows that certain chemical uncouplers have a dynamic range and can be safely used in vivo because they induce a limited uncoupling [6]. Nevertheless, these compounds may have limited effects on weight loss. Here we describe a novel theoretical method to induce an autoregulated artificial uncoupling in vivo, potentially resulting in safe and effective thermogenesis, glucose uptake, lipolysis and subsequent weight loss: a thermogenin-like system (TLS). Because the TLS may induce thermogenesis, glucose uptake, oxygen consumption and triglyceride utilization from most adult tissues, it may be used as an interesting alternative treatment for obesity. Because glucose uptake reduces blood glucose levels, the TLS could decrease insulin production and subsequent lipogenesis, suggesting that the TLS could constitute an interesting approach to the treatment of obesity and diabetes. Thus, we propose the TLS as an alternative treatment for obesity in vivo. Indeed, the fact that the TLS requires ATP is remarkable, the system will stop if the level of ATP dramatically decreases, preventing both the uncoupling-induced proton leak and the cell death or cell dysfunction in vivo. Moreover, the TLS is designed to function in a specific tissue and not at the whole-organism level in contrast to an intravenous injection of chemical uncouplers. For example, the TLS may be used in white adipocytes to induce thermogenesis from these cells. The system may also be used in endothelial cells because there are large numbers of endothelial cells in an adult organism and there is a large amount of oxygen in this tissue, allowing for efficient thermogenesis from these cells. We think that the TLS could be used in combination with approaches that increase brown fat activity to treat obesity but further studies are needed.
Another way to promote uncoupling in vivo is the thermogenin (also called UCP1) system. This protein is naturally present in the mitochondria of brown adipose tissue and it is used to produce heat by non-shivering thermogenesis. UCP1 is activated by fatty acids in the brown fat in mammals. Therefore, it is not possible to express UCP1 in other cells in order to induce an effective thermogenesis since most cells may not possess the machinery required for fatty acids uptake and the molecular mechanisms underlying fatty acids transport remain elusive in part. Furthermore, even if white adipocytes possess a large amount of fatty acids, this system would be ineffective because it is necessary to induce lipolysis to stimulate UCP1 and to promote uncoupling. Lipolysis is induced by a sympathetic stimulation in vivo in the brown fat and white adipocytes don’t possess an adequate sympathetic innervation in vivo to support an effective thermogenesis in vivo. Although an artificial injection of norepinephrine could be used to stimulate engineered white adipocytes in vivo (UCP1 and norepinephrinelipolysis pathways double positives fat cells), it could induce major side effects like tachycardia and death. For these reasons it is possible to establish a theoretical experimental model based on the thermogenin system: the TLS (or UCP1-like system).
The first step of this model is the in vivo transduction of adipose tissue with adeno-associated viral (AAV) vectors. The following transgenic DNA constructs are used in vivo: the light-driven inward H+ pump PoXeR targeted to the inner mitochondrial membrane, firefly luciferase, luciferin-regenerating enzyme (LRE), cysteine racemase and thioesterase. Now, we describe the function of each actor. PoXeR is a natural light-driven inward proton pump found in Parvularcula oceani, a deep-ocean marine bacterium. This pump controls the u
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