Metabolic Actions of Brain Leptin Receptors Signaling in Type 1 Diabetes

描述（由申请人提供）：根据青少年糖尿病研究基金会，在美国，1型糖尿病（T1D）折磨着1- 300万人，由于尚不清楚的原因，其发病率以每年约3%的惊人速度增长。因此，预计未来几年T1D患者数量将显著增加。T1D是胰腺细胞损失导致致命代谢失衡的结果。目前的T1D挽救生命干预措施包括每日给药胰岛素。这些疗法可降低高血糖、糖化血红蛋白、恶病质，并预防或延缓一些与t1d相关的疾病。然而，即使目前的胰岛素输送系统得到了很大的改善，T1D的继发性并发症包括使人衰弱、长期存在和经济上具有挑战性的疾病，例如心脏病、失明、肾衰竭、神经病变和高血压。可能由于胰岛素的脂肪生成作用，长期胰岛素治疗被怀疑是T1D患者中过量异位脂质沉积（即：在非脂肪组织中）和冠状动脉疾病极高发生率（55岁后bbb90 %）的基础。此外，部分由于胰岛素的强效、速效、降糖作用，强化胰岛素治疗显著增加了低血糖的风险，这是一种致残甚至致命的事件。因此，迫切需要新的和更好的抗t1d治疗方法。开发新的甚至可能不需要胰岛素的治疗方法的一个主要障碍是，没有胰岛素的生活是不相容的。然而，在Roger Unger博士及其同事最近报道瘦素单药治疗（不使用胰岛素）可以逆转T1D啮齿动物模型中由胰岛素缺乏引起的致命后果和许多代谢缺陷后，这种范式可能需要修改。因此，脂肪细胞分泌激素瘦素的缓效降糖作用可能是目前T1D治疗的一个有吸引力的替代和/或辅助治疗。本研究将直接验证大脑，特别是下丘脑神经元中的lepr介导瘦素抗t1d作用的假设。为了直接验证我们的假设，我们将在两种不同的胰岛素缺乏症小鼠模型中评估cns限制瘦素给药的代谢结果。然后，我们将

DESCRIPTION (provided by applicant): According to the Juvenile Diabetes Research Foundation, type 1 diabetes (T1D) afflicts 1-3 million of people in the United States of America and, for reasons yet to be understood, its incidence has been increasing at an alarming annual rate of ~3%. Thus, the number of T1D patients is expected to increase significantly in the next years. T1D occurs as a consequence of pancreatic ¿-cell loss leading to a lethal metabolic imbalance. Current T1D life-saving interventions include daily insulin administrations. These therapies reduce hyperglycemia, glycosylated hemoglobin, cachexia and prevent or delay some of T1D-associated morbidities. However, even with the current and much improved insulin delivery systems, T1D secondary complications include debilitating, long-lasting and economically challenging conditions as for example heart disease, blindness, kidney failure, neuropathy, and hypertension. Probably owing to insulin's lipogenic actions, long-term insulin treatment is suspected to underlie the excessive ectopic lipid deposition (i.e.: in non-adipose tissues) and the extremely high incidence of coronary artery disease (> 90% after age 55) seen in T1D subjects. Furthermore, in part due to insulin's potent, fast-acting, glycemia-lowering effects, intensive insulin therapy significantly increases the risk of hypoglycemia, an event that s disabling and can even be fatal. New and better anti-T1D therapies are therefore urgently needed. A major barrier to the development of new and potentially even insulin-free treatments has been the paradigm that life without insulin is not compatible. This paradigm may need to be revised however after Dr. Roger Unger and colleagues recently reported that leptin monotherapy (without the use of insulin) can reverse the lethal consequences and many of the metabolic defects caused by insulin deficiency in rodent models of T1D. The slow-acting, glycemia-lowering effects of the adipocyte- secreted hormone leptin may therefore represent an attractive alternative and/or adjuvant to current T1D therapies. Here, will directly test the hypothesis that LEPRs in brain and specifically in hypothalamic neurons mediate leptin's anti-T1D action. To directly test our hypothesis, we will assess the metabolic outcomes of CNS-restricted leptin administration in two different mouse models of insulin deficiency. Then, we will make use of other unique genetically-engineered mouse lines to determine the biochemical identity of the neurons mediating these actions. We strongly believe that results from the studies proposed herein will lead to a better understanding of the mechanism(s) by which leptin rescues lethality and improves metabolism in T1D. Once identified, this molecular component(s) can then be exploited to develop new and effective anti-T1D strategies without the risks of hypoglycemia and cardiovascular disease. PUBLIC HEALTH RELEVANCE: According to the Juvenile Diabetes Research Foundation, type 1 diabetes (T1D) afflicts 1-3 million of people in the United States of America and, for reasons yet to be understood, its incidence has been increasing at an alarming annual rate of ~3%. Daily insulin administrations are life-saving for people with T1D but probably owing to insulin's lipogenic actions and potent, fast-acting, glycemia- lowering effects intensive insulin therapy significantly increases the risk of coronary artery disease (> 90% after age 55) and hypoglycemia in T1D subjects. Here, we will perform experiments aimed at identifying the neurocircuitries and molecular mechanisms by which leptin administration ameliorates T1D; we believe that results from the experiments proposed in this application will pave the way to develop better therapeutic approaches against T1D without the risks of hypoglycemia and cardiovascular disease.