DIET EFFECT ON ENERGY METABOLISM

这项研究的总体目标是描述神经内分泌和 负责提高膳食能量效率的细胞因子 保持在肥胖倾向的动物中。 遗传性肥胖（ob/ob）小鼠 将用于大多数拟议的研究。 这种动物有一种突变 在ob基因，导致生产的截短， 脂肪组织中的非功能性ob蛋白。 野生型ob蛋白是 由脂肪组织分泌来调节食物摄入和能量平衡。 一个有待验证的假设是，ob/ob小鼠中ob基因的突变 导致中枢神经系统的调节改变， 神经肽Y和促肾上腺皮质激素释放激素系统，这些 改变还取决于糖皮质激素的存在或所选择的 饮食因素，包括饮食中的葡萄糖或脂肪。 建议开展研究， 确定脑室内注射地塞米松和/或 将野生型ob蛋白质导入饲喂各种饮食的切除肾上腺的ob/ob小鼠中 影响神经肽V和促肾上腺皮质激素释放激素的分泌， 选择下丘脑部位。 在平行研究中， 切除肾上腺的ob/ob小鼠将在体外用地塞米松 和/或OB蛋白。 神经肽Y和促肾上腺皮质激素释放激素 将测量分泌。 另一个有待检验的假设是， ob基因突变导致胰腺癌的早期发育印记 导致胰岛素调节持续缺陷的胰岛 葡萄糖诱导的胰岛素分泌本身的远端分泌。 胰腺 培养来自2周龄ob/ob和瘦小鼠的胰岛以表征 这一缺陷的代谢基础。 来自新生儿ob/ob和+/+的胰岛 将检查小鼠以观察印记是否在出生和出生之间表达。 2周龄的ob/ob小鼠。 这些数据应该会增加我们对 饮食和神经系统依赖的代谢因素相互作用 与ob蛋白在调节身体肥胖，并应有助于定义 改善预防和控制肥胖的营养方法。

The overall goal of this research is to characterize neuroendocrine and cellular factors responsible for the enhanced efficiency of dietary energy retention in obesity-prone animals. The genetically obese (ob/ob) mouse will be used in most of the proposed studies. This animal has a mutation in the ob gene that leads to production of a truncated and presumably nonfunctional ob protein in adipose tissue. Wild-type ob protein is secreted from adipose tissue to regulate food intake and energy balance. One hypothesis to be tested is that mutation of the ob gene in ob/ob mice leads to altered regulation in the central nervous system of the neuropeptide Y and corticotropin releasing hormone systems, and that these alterations also depend on the presence of glucocorticoids or selected dietary factors including dietary glucose or fat. Studies are proposed to determine how intracerebroventricular injection of dexamethasone and/or wild-type ob protein into adrenalectomized ob/ob mice fed various diets affects neuropeptide V and corticotropin releasing hormone secretion in selected hypothalamic sites. In parallel studies hypothalamic blocks from adrenalectomized ob/ob mice will be treated in vitro with dexamethasone and/or ob protein. Neuropeptide Y and corticotropin releasing hormone secretion will be measured. Another hypothesis to be tested is that the ob gene mutation causes an early developmental imprint in pancreatic islets that leads to a persistent defect in regulation of insulin secretion distal to glucose-induced insulin secretion per se. Pancreatic islets from 2 wk old ob/ob and lean mice will be cultured to characterize the metabolic basis for this defect. Islets from neonatal ob/ob and +/+ mice will be examined to see if an imprint is expressed between birth and 2 wk of age in ob/ob mice. These data should increase our understanding of the diet and neurohormonal-dependent metabolic factors that interact with ob protein in regulation of body fatness, and should aid in defining improved nutritional approaches to the prevention and control of obesity.