Life Extension by Caloric Restriction: Role of Leptin

通过热量限制延长寿命：瘦素的作用

• 批准号: 6615721
• 负责人: SIMON KLEBANOV
• 金额: $ 31万
• 依托单位: ST. LUKE'S-ROOSEVELT INST FOR HLTH SCIS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-15 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6615721
• 关键词: adipose tissue; adrenocorticotropic hormone; behavioral /social science research tag; body temperature regulation; cell transplantation; corticosterone; estradiol; estrus; follicle stimulating hormone; genetically modified animals; growth /development; hormone regulation /control mechanism; inflammation; insulinlike growth factor; laboratory mouse; leptin; longevity; luteinizing hormone; nutrient intake activity; nutrition of aging; nutrition related tag; pituitary gonadal axis; thyrotropin; thyroxine; triiodothyronine

Caloric restriction (CR) increases longevity in mammals. While it is still unclear how CR extends life span, neuroendocrine involvement has been suggested. Leptin is a major hormone involved in energy homeostasis. CR suppresses leptin. Adding leptin to CR animals abolishes effect of CR on the metabolic rate, the immune function and on the gonadotropic, thyrotropic and glucocorticoid axes. Moreover, leptin null mutant ob/ob mice fed ad libitum (AL) and normal CR mice are similar in that both are characterized by suppressed gonadotropic, thyrotropic and somatotropic axes and activated glucocorticoid axis. The major question this proposal addresses is the degree to which the reduction in leptin induced by CR can by itself explain CR effects on the neuroendocrine system, age-related pathologies and life span. By transplanting leptin producing fat from normal lean mice into leptin deficient, ob/ob mice we can create animals whose food intake is matched to that of AL fed normal mice and whose leptin levels are matched to those of CR mice. Thus, we can assess the effects of reduced leptin at the normal food intake. Specific Aim 1 will test whether reducing plasma leptin to CR levels, while maintaining the normal food intake, will mimic CR effects on the neuroendocrine system, specifically on the gonadotropic, thyrotropic, somatotropic and glucocorticoid axes. Specific Aim 2 will test whether reducing plasma leptin to CR levels, at the normal food intake can reduce and postpone age- related pathologies and extend life span. In ob/ob mice, fat transplants will create plasma leptin levels matched to those of CR mice, but will not mimic paracrine and autocrine effects of leptin. To test whether a reduction in leptin PLASMA levels and not other aspects of fat transplantation is sufficient to mimic CR, we will create leptin transgenic mice expressing low levels of leptin and subject them to the same tests as in Specific Aims 1 and 2. Specific Aim 3 will test the hypothesis that the neuroendocrine system, age-related pathologies and life span will be affected similarly in two different models of leptin deficiency, fat transplanted ob/ob mice and leptin transgenics, as long as PLASMA leptin levels are the same.

热量限制 (CR) 可延长哺乳动物的寿命。虽然目前尚不清楚 CR 如何延长寿命，但有人提出神经内分泌参与。 瘦素是一种参与能量稳态的主要激素。 CR 抑制瘦素。向 CR 动物中添加瘦素可消除 CR 对代谢率、免疫功能以及促性腺、促甲状腺和糖皮质激素轴的影响。此外，随意喂养(AL)的瘦素缺失突变ob/ob小鼠和正常CR小鼠的相似之处在于，两者的特征都是抑制促性腺激素、促甲状腺激素和促生长激素轴以及激活糖皮质激素轴。该提案解决的主要问题是 CR 引起的瘦素减少在多大程度上可以单独解释 CR 对神经内分泌系统、年龄相关病理和寿命的影响。通过将产生瘦素的正常瘦小鼠的脂肪移植到瘦素缺乏的 ob/ob 小鼠中，我们可以创造出食物摄入量与 AL 喂养的正常小鼠相匹配的动物，并且其瘦素水平与 CR 小鼠的瘦素水平相匹配。 因此，我们可以评估正常食物摄入量下瘦素减少的影响。具体目标 1 将测试将血浆瘦素降低至 CR 水平，同时维持正常食物摄入量，是否会模拟 CR 对神经内分泌系统的影响，特别是对促性腺、促甲状腺、促生长和糖皮质激素轴的影响。具体目标 2 将测试在正常食物摄入量下将血浆瘦素降低至 CR 水平是否可以减少和推迟与年龄相关的病变并延长寿命。在 ob/ob 小鼠中，脂肪移植将产生与 CR 小鼠相匹配的血浆瘦素水平，但不会模仿瘦素的旁分泌和自分泌作用。 为了测试瘦素血浆水平的降低而不是脂肪移植其他方面的降低是否足以模拟 CR，我们将创建表达低水平瘦素的瘦素转基因小鼠，并对它们进行与特定目标 1 和 2 中相同的测试。 3 将检验以下假设：神经内分泌系统、年龄相关的病理学和寿命在两种不同的瘦素缺乏模型（脂肪移植的 ob/ob 小鼠和瘦素转基因小鼠）中将受到类似的影响，只要血浆瘦素水平相同。