Stress and Body Weight Regulation

描述（申请人提供）：社会压力在现代社会的许多方面都很普遍。流行病学数据表明，压力与超重、肥胖和代谢疾病的发展有关。我们在实验室建立了慢性社会压力的可见洞穴系统（VBS）模型。在VBS中，混合性别的大鼠群体被饲养2周，在此期间，群体中的雄性大鼠迅速形成统治等级，产生从属（SUB）和优势（DOM）动物。我们发现亚种动物在社会压力下体重减轻。在VBS中反复，间歇性地暴露于社会压力，随后是恢复期，亚鼠逐渐发展出肥胖的特征，部分是由于神经内分泌的改变和食物摄入的改变，并使动物容易出现代谢综合征的其他症状。因此，VBS模型为严格检查增强（或减弱）社会压力与代谢调节的相互作用的因果因素提供了一个自然主义范式，同时也允许对所涉及的控制系统进行复杂的分析。因此，我们建议继续利用VBS实现以下三个具体目标。具体目标是：1)；为了验证这一假设，即尽管在慢性社会压力和恢复的反复循环中肥胖程度更高，但SUB患者的葡萄糖耐量有所改善，这在一定程度上是由于血液中葡萄糖的去除量增加；而这又继发于关键组织中葡萄糖转运蛋白（GLUT）表达的改变。我们进一步假设，在最后一个社会压力周期之后的长期恢复期，SUB将变得更加肥胖，并恢复到更差的葡萄糖耐量。为了验证饮食组成，大量营养素的可用性，或膳食模式，或这些参数的组合，改变社会压力的代谢后果的假设。具体来说，假设饮食脂肪的增加会加剧亚脂肪在VBS恢复期间优先作为内脏脂肪组织重获体重的趋势。应激和能量稳态的内分泌和神经肽介质将在社会压力发作之前、期间和之后的饮食操纵中被确定；3)确定饮食诱导肥胖的遗传易感性是否影响社会压力引起的行为、神经内分泌、神经肽和代谢后果。这些研究对于理解慢性压力和从压力中恢复如何影响与肥胖及其相关代谢紊乱相关的行为、生理和代谢的变化具有直接的人类意义。社会压力在现代社会的许多方面都很普遍，社会压力的一个充分记录的后果是肥胖的发展。我们开发了一个实验室模型，可见洞穴系统（VBS），来研究啮齿动物社会压力的影响，我们发现，在从反复的社会压力中恢复的过程中，大鼠出现了与人类相似的代谢综合征症状，如内分泌测量改变和内脏脂肪增加。使用这种自然模型可以研究社会压力和新陈代谢之间的相互作用，从而为治疗和预防人类肥胖及相关疾病的疗法提供见解。

DESCRIPTION (provided by applicant): Social stress is prevalent in many facets of modern society. Epidemiological data suggest that stress is linked to the development of overweight, obesity and metabolic disease. We have established the visible burrow system (VBS) model of chronic social stress in our laboratory. In the VBS, mixed gender colonies of rats are housed for 2-week periods during which male rats of the colony quickly develop a dominance hierarchy resulting in subordinate (SUB) and dominant (DOM) animals. We found that SUB animals have reduced body weight during social stress. With repeated, intermittent exposures to social stress in the VBS followed by periods of recovery, SUB rats progressively develop characteristics of obesity that occur, in part, through neuroendocrine alterations and changes in food intake, and predispose the animals to develop other symptoms of the metabolic syndrome. Thus, the VBS model offers a naturalistic paradigm for rigorously examining causal factors that enhance (or diminish) the interaction of social stress with metabolic regulation, while also allowing sophisticated analyses of the control systems involved. We are therefore proposing to continue using the VBS with the following three specific aims. Specific aims are: 1.) To test the hypothesis that SUB have improved glucose tolerance despite having greater adiposity following repeated cycles of chronic social stress and recovery, and that this is due in part to increased glucose removal from the blood; and that this in turn is secondary to altered expression of glucose transporters (GLUT) in key tissues. We further hypothesize that over a long-term recovery period following the final cycle of social stress, SUB will become more obese and revert to worsened glucose tolerance, 2.) To test the hypothesis that diet composition, macronutrient availability, or meal patterns, or a combination of these parameters, alters the metabolic consequences of social stress. Specifically, increased dietary fat is hypothesized to exacerbate the tendency for SUB to regain body weight preferentially as visceral adipose tissue during recovery from the VBS. Endocrine and neuropeptide mediators of stress and energy homeostasis will be determined in response to dietary manipulations prior to, during, and after episodes of social stress, 3) determine whether genetic susceptibility to diet-induced obesity affects the behavioral, neuroendocrine, neuropeptide, and metabolic consequences resulting from social stress. This collection of studies have direct human significance in understanding how chronic stress and recovery from stress affects changes in behavior, physiology, and metabolism associated with obesity and its associated metabolic disorders. PUBLIC HEALTH RELEVANCE Social stress is prevalent in many facets of modern society and a well documented consequence of social stress is the development of obesity. We have developed a laboratory model, the visible burrow system (VBS), to study the effects of social stress in rodents in which we find that during recovery from repeated bouts of social stress, rats develop symptoms of metabolic syndrome similar to those observed in humans such as altered endocrine measures and increased visceral adiposity. Using this naturalistic model allows study of interactions between social stress and metabolism, thereby providing insight toward therapies used to treat and prevent obesity and related diseases in humans.