Interactions of sympathetic nervous and melanocortin systems in obesity reversal

描述（由申请人提供）：估计65%的美国成年人超重或肥胖，这一数字正在上升。有新的证据表明，大量的内脏脂肪会增加一个人患心血管疾病、高血压和糖尿病的风险。人们对从瘦到胖的转变比相反的转变了解得更多。我们使用西伯利亚仓鼠（Photopus sungorus）动物模型，因为它们在自然界中长时间的“夏季”中肥胖，在短时间的“冬季”中自然恢复到更瘦的状态。因此，这些动物可以通过改变实验室中的光照条件来研究肥胖、瘦和过渡状态，从而提供一个没有遗传操作的有生物学意义的模型。Bartness实验室的报告有助于描述身体脂肪和大脑之间的联系，并将功能归因于这些联系。神经元对交感神经系统的影响已被发现是以脂肪储存特异性方式的脂肪动员（脂解）的主要引发剂;这在仓鼠和人类中是真实的。参与脂质动员的过程的变化可以通过测量交感神经激活后的交感神经驱动和细胞内级联反应的副产物（周脂蛋白的磷酸化，脂肪甘油三酯脂肪酶）来测定。第一个具体目标提出使用新的体内磷酸化标记物-围脂蛋白（perilipin）（一种在非磷酸化状态下保护脂滴免于分解的细胞内蛋白）观察脂解的变化，以及通过去甲肾上腺素周转测量交感神经驱动，最后测量甘油和游离脂肪酸（脂解产物）在食物剥夺仓鼠血液中的浓度。据我们所知，这将是第一次在体内测量的磷脂酰肌醇磷酸化，虽然它是公认的最后一个必要的步骤，在体外脂解。第二个具体目标将使用与第一个目标相同的测量来测试涉及黑皮质素系统和交感神经系统脂肪回路的特定脑部位如何参与脂解。理解这一点很重要，因为黑皮质素肽或受体的突变占人类肥胖病例的6-8%。总的来说，这些实验将测试脂肪库的区域变化如何响应环境刺激和神经化学刺激，激活脑交感神经系统-白色脂肪连接以触发脂解，因此对于了解肥胖逆转很重要。这将使用独特的、天然存在的、完整的、肥胖的动物模型来实现，该模型采用了脂解的创新标志物。因此，这些研究的结果将有助于脂质动员的机制和肥胖逆转的过程的重要和相关的知识。

DESCRIPTION (provided by applicant): An estimated 65% of American adults are overweight or obese and this number is rising. There is emerging evidence that high amounts of visceral fat increases a person's risk for developing cardiovascular disease, hypertension and diabetes. More is known about the transition from lean to obese than the reverse. We use the Siberian hamster (Phodopus sungorus) animal model because they are obese during long 'summer-like' days in nature and naturally reverse to a leaner state in short 'winter-like' days. Therefore, these animals can be studied in the obese, lean and transition states by altering their lighting conditions in the laboratory thereby providing a biologically meaningful model without genetic manipulation. Reports from the Bartness laboratory have been instrumental in delineating connections between body fat and the brain and ascribing function to these connections. Neuronal influence on the sympathetic nervous system has been found to be the principle initiator of fat mobilization (lipolysis) in a fat depot specific manner; this is true in hamsters and humans. Changes in the processes involved in lipid mobilization can be assayed by measuring sympathetic drive and by-products of intracellular cascades (phosphorylation of perilipin, adipose triglyceride lipase) after sympathetic activation. The first specific aim proposes looking at changes in lipolysis using a new in vivo marker of phosphorylation -- perilipin, an intracellular protein that in the non-phosphorylated state protects lipid droplets from breakdown, as well as measuring sympathetic drive via norepinephrine turnover and finally glycerol and free fatty acid (products of lipolysis) concentrations in blood of food deprived hamsters. To our knowledge, this will be the first in vivo measure of phosphorylation of perilipin though it is well established as one of the last necessary steps of lipolysis in vitro. The second specific aim will test how specific brain sites involving the melanocortin system and the sympathetic nervous system circuits to fat is involved in lipolysis using the same measures as the first aim. This is important to understand because mutations of melanocortin peptides or receptors account for 6-8% cases of obesity seen in humans. Collectively, these experiments will test how regional changes in fat depots occur in response to environmental stimuli and neurochemical stimulation that activate brain-sympathetic nervous system-white fat connections to trigger lipolysis and thus are important to understand for obesity reversal. This will be accomplished using a unique, naturally occurring, intact, obese animal model employing innovative markers of lipolysis. Thus, the results of these studies will contribute important and relevant knowledge of the mechanisms of lipid mobilization and of the process of obesity reversal.