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: 6401132
• 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/6401132
• 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）会增加哺乳动物的寿命。尽管尚不清楚CR如何延长寿命，但已经提出了神经内分泌的参与。 瘦素是参与能量稳态的主要激素。 CR抑制瘦素。将瘦素添加到CR动物中，消除了CR对代谢率，免疫功能以及促性腺激素，甲状腺和糖皮质激素轴的影响。此外，喂食非次症（Al）和正常CR小鼠的瘦素无效的ob/ob小鼠相似，因为两者的特征都具有抑制的促性腺激素，甲状腺和体状轴和活化的糖皮质激素轴的特征。该提案解决的主要问题是，CR诱导的瘦素的减少本身可以解释CR对神经内分泌系统，与年龄相关的病理和寿命的影响。通过将瘦素从正常瘦小小鼠中产生脂肪的瘦素中，我们可以创建动物，其食物摄入的动物与Al Fed正常小鼠的食物摄入量相匹配，其瘦素水平与Cr小鼠的瘦素水平相匹配。 因此，我们可以评估在正常食品摄入量下瘦素减少的影响。具体的目标1将测试在维持正常食物摄入的同时，将血浆瘦素降低到CR水平是否会模仿对神经内分泌系统的影响，特别是对促性腺激素，促促性促促性肌，促甲状腺，促甲状腺，大理和糖皮质激素。特定的目标2将测试将血浆瘦素降低为CR水平，在正常食物摄入量中可以减少和推迟与年龄相关的病理并延长寿命。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和脂肪移植的其他方面是否足以模仿Cr，我们将创建表达低水平瘦素的瘦素转基因小鼠，并接受与特定目标1和2中相同的测试。 3将检验以下假设：在两种不同的瘦素缺乏模型，脂肪移植的ob/ob/ob/ob小鼠和瘦素转基因学模型中，与血浆瘦素水平相同，将在两种不同的瘦素缺乏模型，脂肪移植的OB/OB小鼠和瘦素转基因中类似地影响。