Interactions of sympathetic nervous and melanocortin systems in obesity reversal

描述（由申请人提供）：据估计，65%的美国成年人超重或肥胖，而且这个数字还在上升。越来越多的证据表明，大量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了解得更多，而不是相反。我们使用西伯利亚仓鼠（Phodopus sungorus）作为动物模型，因为它们在自然界漫长的“类似夏天”的日子里是肥胖的，在短的“类似冬天”的日子里自然地恢复到更瘦的状态。因此，这些动物可以在肥胖、瘦弱和过渡状态下进行研究，通过改变实验室的光照条件，从而提供一个没有基因操纵的生物学意义的模型。Bartness实验室的报告在描述身体脂肪和大脑之间的联系以及将这些联系归因于功能方面发挥了重要作用。神经元对交感神经系统的影响已被发现是脂肪动员（脂肪分解）的主要发起者，以脂肪库的特定方式；仓鼠和人类都是如此。参与脂质动员过程的变化可以通过测量交感神经驱动和交感神经激活后细胞内级联反应的副产物（periilipin的磷酸化，脂肪甘油三酯脂肪酶）来测定。第一个具体目标是使用一种新的体内磷酸化标记物——perilipin（一种细胞内蛋白质，在非磷酸化状态下保护脂滴不被分解）来观察脂肪分解的变化，以及通过去甲肾上腺素的转换来测量交感驱动，最后测量食物剥夺仓鼠血液中的甘油和游离脂肪酸（脂肪分解的产物）浓度。据我们所知，这将是第一次在体内测量近岸磷脂磷酸化，尽管它是体外脂肪分解的最后必要步骤之一。第二个特定目标将使用与第一个目标相同的测量方法，测试涉及黑素皮质素系统和脂肪交感神经系统回路的特定大脑部位如何参与脂肪分解。理解这一点很重要，因为在人类肥胖病例中，黑色素皮质素肽或受体的突变占6-8%。总的来说，这些实验将测试脂肪库的区域变化是如何在环境刺激和神经化学刺激下发生的，这些刺激会激活大脑交感神经系统-白色脂肪连接，从而引发脂肪分解，因此对理解肥胖逆转很重要。这将完成使用一个独特的，自然发生的，完整的，肥胖的动物模型采用创新的脂肪分解标记。因此，这些研究结果将为脂质动员机制和肥胖逆转过程提供重要的相关知识。

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.