Brain Mechanisms of Non-Exercise Activity Thermogenesis

描述（由申请人提供）：肥胖是一个日益严重的健康问题。随着肥胖症的增加，人口中的体育活动量减少了。在我们这个久坐不动的社会里，低水平的身体活动对体重增加有很大的影响。尽管能量摄入的神经、激素、分子和遗传机制都得到了很好的研究，但对能量通过身体活动消耗的机制却知之甚少。人类的非运动活动产热（NEAT）包括意志运动以外的所有身体活动的能量消耗; NEAT显著有助于抵抗过度喂养时体重增加的能力。我们以前已经证明，中枢管理的神经肽食欲素A增加NEAT大鼠。此外，与肥胖抵抗大鼠相比，肥胖倾向大鼠在获得高脂肪饮食后，对下丘脑室旁核（PVN）中食欲素的NEAT激活作用不太敏感。在这里，我们建议系统地研究PVN食欲素差异影响NEAT在肥胖和瘦动物的机制。我们假设食欲素诱导的NEAT的能量消耗导致体重减轻。因此，我们将确定每天两次中枢食欲素治疗是否会降低大鼠的体重并增加NEAT。接下来，我们假设食欲素诱导的NEAT减少有助于肥胖倾向大鼠的体重增加。因此，在第二项研究中，我们将确定高脂肪饮食如何有助于食欲素刺激肥胖倾向大鼠、肥胖抵抗大鼠和对照大鼠的NEAT的能力。第三，我们将确定高碳水化合物饮食如何改变肥胖倾向大鼠、肥胖抵抗大鼠和对照大鼠的每日NEAT，以及饮食如何影响食欲素诱导的NEAT。最后，我们将通过比较食欲素合成和食欲素含量在这些动物的靶向脑区中来检查食欲素对肥胖倾向大鼠、肥胖抵抗大鼠和对照大鼠的NEAT的不同作用的神经机制。通过这些研究，我们希望描述食欲素如何影响NEAT变化的神经机制，以及评估食欲素如何与饮食相互作用以影响NEAT和肥胖。了解身体活动的能量消耗影响NEAT的机制是开发有效的行为和药理学策略以对抗肥胖的关键一步。

DESCRIPTION (provided by applicant): Obesity is a growing health concern. As obesity has increased, the amount of physical activity in the population has decreased. In our sedentary society, low levels of physical activity have a significant impact on weight gain. Whereas the neural, hormonal, molecular, and genetic mechanisms of energy intake are well studied, very little is known about the mechanisms through which energy is expended through physical activity. Non-exercise activity thermogenesis (NEAT) in humans is comprised of the energy expenditure of all physical activity outside of volitional exercise; NEAT contributes significantly to the ability to resist weight gain in the face of overfeeding. We have previously demonstrated that central administration of the neuropeptide orexin A increases NEAT in rats. Moreover, obesity-prone rats are less sensitive to the NEAT-activating effects of orexin in the paraventricular hypothalamic nucleus (PVN) after access to a high-fat diet compared to obesity-resistant rats. Here, we propose to systematically examine the mechanisms through which PVN orexin differentially affects NEAT in obese and lean animals. We hypothesize that the energy expenditure from orexin-induced NEAT induces weight loss. Therefore, we will determine if twice-daily central orexin treatment decreases body weight and increases NEAT in rats. Next, we hypothesize that decreases in orexin-induced NEAT contribute to weight gain in obesity-prone rats. Therefore, in the second study, we will determine how the high-fat diet contributes to the ability of orexin to stimulate NEAT in the obesity-prone, obesity-resistant, and control rats. Third, we will determine how a high-carbohydrate diet alters daily NEAT in obesity-prone, obesity-resistant, and control rats, as well as how the diet affects orexin-induced NEAT. Lastly, we will examine the neural mechanisms of the differential effects of orexin on NEAT in obesity-prone, obesity- resistant, and control rats by comparing orexin synthesis and orexin content in targeted brain regions in these animals. With these studies, we hope to delineate the neural mechanisms of how orexin affects changes in NEAT, as well as to assess how orexin interacts with diet to affect NEAT and obesity. Understanding the mechanisms through which the energy expenditure of physical activity affects NEAT is a critical step in developing effective behavioral and pharmacological strategies to combat obesity.