THE PANCREATIC POLYPEPTIDE FAMILY IN OBESITY

胰多肽、神经肽Y和多肽YY是第三个家族 从大脑-肠轴提取的结构相关的多肽。 本提案的目标是通过以下方式澄清这些机制 这些多肽控制营养的摄取和利用，并 确定它们在肥胖发病机制中的作用。我们将研究 同源胰多肽对糖代谢的影响 葡萄糖钳夹技术及其在大鼠脂肪分解中的应用 脂肪细胞。其他研究将确定脑池内注射 注射神经肽Y对食物摄取、胃排空、 体温调节、胰岛素分泌和内脏血流 标记微球技术。我们还将确定多肽YY是否 通过脂肪沐浴释放回肠粘膜，使回肠制动 通过减缓肠道转运来增加营养物质的吸收。在这些 我们将研究YY肽对胃排空的影响， 肠道转运和空肠水、电解质和 营养素。初步研究表明，胰腺淀粉酶和DNA 用YY多肽慢性治疗可降低其含量。饱满 将进行剂量-反应研究，该多肽对 肠道生长情况已确定。在老鼠身上进行这些实验后，我们将 探讨胰腺缺损的原因及意义 最近在先天性肥胖小鼠中发现了多肽释放。我们会 观察PANCREATION之间的超微结构关系 肥大胰岛内的多肽细胞和其他内分泌细胞 测定胰岛素对肥胖小鼠的降糖和降糖作用。 肾上腺切除对此动物模型中泛素释放的影响。 其他研究将确定胰腺多肽是否会逆转 通过抑制胆汁和胆汁分泌而导致吸收不良的先天性肥胖 胰腺血流。最后，我们将扩大对异常情况的调查 肥胖小鼠脑内神经肽含量的观察。尤其是我们 将比较神经肽Y在肥胖和瘦小鼠中的分布 强调神经肽Y在脑内的区域分布。这些 研究将确定这个家族控制的机制 为营养素的摄取和利用提供实验依据 为今后胰多肽在肥胖症治疗中的应用奠定基础。

Pancreatic Polypeptide, Neuropeptide Y and Peptide YY are the third family of structurally related peptides to be extracted from the brain-gut axis. The objectives of the present proposal are to clarify the mechanisms by which these peptides control nutrient intake and utilization and to determine their role in the pathogenesis of obesity. We will examine the effects of isologous pancreatic polypeptide upon glucose metabolism using the glucose clamp technique and upon lipolysis using isolated rat adipocytes. Other studies will determine the effects of intracisternal injections of Neuropeptide Y on food intake, gastric emptying, thermoregulation, insulin secretion and splanchnic blood flow using the labelled microsphere technique. We will also determine if Peptide YY released by fat bathing the ileal mucosa engages the ileal-brake which increases absorption of nutrients by slowing intestinal transit. In these studies we will examine the effects of Peptide YY on gastric emptying, intestinal transit and jejunal fluxes of water, electrolytes and nutrients. Preliminary studies demonstrate that pancreatic amylase and DNA contents are reduced by chronic treatment with peptide YY. Full dose-response studies will be performed and the effects of this peptide on intestinal growth determined. Following these experiments in rat, we will investigate the cause and significance of the defect in pancreatic polypeptide release recently decribed in congenitally obese mice. We will examine the ultrastructural relationships between the pancreated polypeptide cell and other endocrine cells within the hypertrophic islet of the obese mouse and determine the effects of insulin hypoglycemia and adrenalectomy on pancreated polypeptide release in this animal model. Other studies will determine whether pancreatic polypeptide reverses congenital obesity by inducing malabsorption through inhibition of bile and pancreatic flow. Finally we will expand our investigations on the abnormal brain content of the neuropeptide observed in obese mice. In particular we will compare the distribution of neuropeptide Y in obese and lean mice emphasizing the regional distribution of neuropeptide Y in brain. These studies will determine the mechanisms by which this family controls nutrient intake and utilization and could provide the experimental basis for the future use of pancreatic polypeptide in the treatment of obesity.