Molecular bases of the regulation of energy expenditure by bone

项目摘要-项目#4 骨源性激素骨钙素（OCN）在骨重建过程中释放，这一过程随着骨密度的降低而下降。 年龄由OCN调节的生理功能，如生育能力、葡萄糖耐量和认知能力， 与OCN活性形式的循环水平平行。在这里，我们探讨的可能性， OCN通过对棕色脂肪组织（BAT）的影响调节另一个年龄依赖性过程，产热。 我们认为两种类型的体温调节功能障碍的老龄化人口：冷不耐受和潮热。 BAT是一种产热器官，氧化脂肪酸和葡萄糖产生热量。感冒或药物 BAT的刺激诱导小鼠和人的产热并改善葡萄糖耐量。衰老是 与BAT功能减弱以及体温过低和代谢功能障碍风险增加相关。之甚少 由于大多数在动物身上进行的研究， 模型只评估年轻人。交感神经系统（SNS）紧张，BAT的主要驱动力 活动，在老年人中升高。因此，衰老过程中BAT活性的降低反映了对寒冷的低反应性 和SNS信令。可以增强对SNS信号的敏感性或调节BAT功能的因素， SNS具有改善伴随衰老的代谢和体温调节功能障碍的潜力。 OCN水平在衰老中降低，与BAT对冷和交感神经信号的响应性降低平行。 相反，OCN处理足以刺激体外棕色脂肪细胞中的产热基因程序 并通过增加体内能量消耗和BAT能力来防止饮食诱导的肥胖（DIO）。 目标1中的研究将探索内源性OCN的丧失是否通过以下途径增加对寒冷和DIO的易感性： Ocn-/-突变体和老年野生型小鼠中BAT功能减弱。目标2中的研究将调查 外源性OCN保护免受DIO的机制，并询问是否恢复生理水平， OCN可通过激活BAT提高衰老小鼠的代谢功能和耐寒能力。目标3中的研究将 考虑OCN和体温调节失调的另一种情况，围绝经期潮热。 围绝经期或卵巢切除术后雌激素耗竭与骨破裂有关 吸收和活性OCN水平的短暂增加。这一时期往往伴随着热 调节异常和血管痉挛症状（VMS），形式为潮热。与减少相关的条件 骨吸收和OCN，包括抗再吸收化合物治疗和肥胖，与 减少潮热的风险。我们将研究OCN在小鼠潮热模型中的作用。如果成功， 这项研究将为老年人对寒冷和DIO敏感性的机制提供新的见解。 个体和潮热在围绝经期妇女understudied具有广泛影响的问题。

PROJECT SUMMARY-Project #4 The bone-derived hormone osteocalcin (OCN) is released during bone remodeling, a process that declines with age. Physiological functions regulated by OCN, such as fertility, glucose tolerance, and cognition, deteriorate over the lifespan in parallel with circulating levels of the active form of OCN. Here we explore the possibility that OCN regulates another age-dependent process, thermogenesis, through effects on brown adipose tissue (BAT). We consider two types of thermoregulatory dysfunction in aging populations: cold intolerance and hot flashes. BAT is a thermogenic organ that oxidizes fatty acids and glucose to produce heat. Cold or pharmacological stimulation of BAT induces thermogenesis and improves glucose tolerance in mice and humans. Aging is associated with diminished BAT function and increased risks of hypothermia and metabolic dysfunction. Little is known about the causes and consequences of impaired BAT function in aging because most studies in animal models exclusively evaluate young adults. Sympathetic nervous system (SNS) tone, the primary driver of BAT activity, is elevated in aged individuals. Thus, reduced BAT activity in aging reflects hyporesponsiveness to cold and SNS signaling. Factors that can enhance sensitivity to SNS signals or regulate BAT function independent of the SNS have the potential to improve metabolic and thermoregulatory dysfunction that accompanies aging. OCN levels decrease in aging, in parallel with reduced responsiveness of BAT to cold and sympathetic signaling. Conversely, OCN treatment is sufficient to stimulate a thermogenic gene program in brown adipocytes in vitro and to protect against diet-induced obesity (DIO) by increasing energy expenditure and BAT capacity in vivo. Studies in Aim 1 will explore whether loss of endogenous OCN increases susceptibility to cold and DIO via diminished BAT function in Ocn-/- mutants and aged wild-type mice. Studies in Aim 2 will investigate the mechanism by which exogenous OCN protects against DIO and ask whether restoring physiological levels of OCN to aged mice will improve metabolic function and cold tolerance by activating BAT. Studies in Aim 3 will consider another situation where OCN and thermoregulation are dysregulated, peri-menopausal hot flashes. Estrogen depletion in the peri-menopausal period or following ovariectomy is associated with a burst of bone resorption and a transient increase in active OCN levels. This period is often accompanied by thermal dysregulation and vasomotor symptoms (VMS) in the form of hot flashes. Conditions associated with reduced bone absorption and OCN, including treatment with anti-resorptive compounds and obesity, are associated with reduced risk of hot flashes. We will investigate the role of OCN in a mouse model of hot flashes. If successful, this research will provide novel insights into the mechanism underlying sensitivity to cold and DIO in aged individuals and hot flashes in peri-menopausal women understudied issues with widespread effects.