Role of perinatal diet in developmental programming of skeletal strength

描述（由申请人提供）：本项目测试产妇围产期饮食对骨骼获得的影响。围产期热量限制或高脂肪饮食引发的围产期发育规划是成人神经内分泌、免疫、生殖和代谢疾病（包括肥胖、动脉粥样硬化和II型糖尿病）的已知危险因素。然而，人们对生命早期营养如何影响骨骼发育知之甚少。一般的假设是围产期热量限制（CR）或高脂肪（HF）饮食会启动发育程序，从而降低出生后的骨骼生长和骨密度的获得。为了测试围产期能量状态是否会影响骨骼生长，将在妊娠/哺乳期暴露于母体CR或HF饮食的小鼠与出生后暴露的小鼠进行比较。先前的研究表明，CR和HF饮食对成年啮齿动物的骨骼有负面影响，但没有测试对幼年骨骼获得的影响。我们的具体目标包括确定骨骼生长期间的热量供应（自由与限制）和常量营养素来源（高脂肪与高碳水化合物）和/或母亲在怀孕和哺乳期间的饮食是否会影响骨量、微结构和强度。我们还将测试产前饮食是否会影响骨骼对产后饮食的反应。这些骨与环境相互作用的假设机制涉及瘦素的能量状态信号，瘦素是一种脂肪来源的能量状态信号，通过骨中的ß -肾上腺素能受体传递。因此，我们的实验将比较正常小鼠和ss-肾上腺素能受体2敲除（ss2-AR KO）小鼠的骨骼和激素对产前和产后能量可用性的反应。通过将瘦素对骨的直接作用与成骨细胞中枢性瘦素信号的作用（在ss2-AR KO小鼠中不存在）分离，我们将获得关于中枢性和外周性瘦素信号对小梁骨和皮质骨的影响的独特数据。

DESCRIPTION (provided by applicant): This project tests the effects of maternal perinatal diet on skeletal acquisition. Perinatal developmental programming, triggered by perinatal caloric restriction or high fat diet, is a known risk factor for adult neuroendocrine, immune, reproductive, and metabolic disease, including obesity, atherosclerosis, and type II diabetes. However, little is known about how early life nutrition impacts skeletal development. The general hypothesis is that perinatal caloric restriction (CR) or high fat (HF) diet will initiate developmental programming that decreases postnatal bone growth and acquisition of bone mineral density. To test whether perinatal energetic status affects bone growth, mice exposed to maternal CR or HF diet during gestation/lactation will be compared to postnatally exposed mice. Previous studies have shown negative effects of CR and HF diets on bone in adult rodents, but did not test for effects on juvenile skeletal acquisition. Our specific aims include determining whether caloric availability (ad lib vs. restricted) and macronutrient source (high fat vs. high carbohydrate) during skeletal growth and/or maternal diet during pregnancy and lactation affect bone mass, microarchitecture and strength. We will also test whether prenatal diet affects the skeletal response to postnatal diet. The hypothesized mechanism for these bone-environment interactions involves signaling of energetic status by leptin, a fat-derived signal of energetic status, via ss-adrenergic receptors in bone. Thus our experiments will compare skeletal and hormonal response to prenatal and postnatal energy availability in normal mice and ss-adrenergic receptor2 knockout (ss2-AR KO) mice. By separating the effects of direct leptin action on bone from the effects of central leptin signaling in osteoblasts (absent in ss2-AR KO mice), we will generate unique data on the effects of central vs. peripheral leptin signaling on trabecular and cortical bone. PUBLIC HEALTH RELEVANCE: This project has several applications to human health. Osteoporosis and obesity are increasing markedly in society, and understanding how interactions between prenatal and postnatal nutrition affect the skeleton may help to identify mechanisms underlying attainment of bone mass and strength during growth.