Cold Induced Changed in Human Subcutaneous White Adipose

 描述(申请人提供)：最近通过PET-CT重新发现人类棕色脂肪组织，启动了更多关于产热和肥胖防御的研究。许多研究已经证明，小鼠的白色脂肪组织(WAT)具有上调其生热能力并变成“米色”的能力。除了我们最近的研究外，还没有研究表明典型的人类水库会发生褐变。我们最近研究了人类的皮下(SC)Wat，发现对寒冷和季节的反应有相当大的能力上调UCP1和其他线粒体基因，我们在培养的人类脂肪细胞中证明了这一现象。WAT的季节性变化特别令人感兴趣，因为这表明了对较冷天气的生理反应，没有挑衅性和非生理性的实验条件。此外，我们发现，SC Wat巨噬细胞负荷高的肥胖者也不上调SC Wat UCP1，这表明脂肪炎症抑制了Wat生热能力的增加。许多免疫调节功能参与了这一过程。基于这些数据，我们提出了以下假设。假设1.反复暴露在寒冷的温度下会放大人类皮下水分的变化。这些浅褐色的影响随着季节的变化而强烈地表现出来，并涉及到免疫介质的激活。假设2。SC Wat的褐变涉及脂肪组织免疫介质的急剧增加，这可能是激活蛋白激酶A(PKA)的儿茶酚胺的来源之一。这一过程在体内被β阻滞剂抑制。假设3：肥胖的胰岛素抵抗受试者对冷诱导的WAT变化具有抵抗力，这是因为促炎环境抑制了局部的褐变介质。假设4.寒冷和季节诱导的SC Wat的变化将导致组织的功能变化，其特征是线粒体解偶联增加，甘油三酯转化(脂解)增加和静息代谢率增加。 公共健康：肥胖与胰岛素抵抗、糖尿病和心脏病密切相关。最近的研究集中在人类的棕色脂肪组织上，这可能会增加能量消耗，有助于预防肥胖。这项建议考察了皮下白色脂肪变成棕色或米色的程度。我们将确定肥胖/代谢综合征的炎症状态是否抑制了这一过程，并将表征寒冷对脂肪甘油三酯转化的影响。

 DESCRIPTION (provided by applicant): The recent rediscovery of human brown adipose tissue through PET-CT has initiated more research on thermogenesis and defense defense against obesity. Many studies have demonstrated that white adipose tissue (WAT) in mice has the ability to upregulate its thermogenic capacity and become "beige". No studies have demonstrated browning of typical human WAT depots, except for our recent studies. We have recently examined the subcutaneous (SC) WAT of humans and found a considerable ability to upregulate UCP1 and other mitochondrial genes in response to cold and to seasons, and we have demonstrated this phenomenon with human adipocytes in culture. The seasonal changes in WAT are of particular interest, since this indicates a physiologic response to colder weather, without provocative and unphysiologic experimental conditions. In addition, we found that obese humans with a high SC WAT macrophage burden do not upregulate SC WAT UCP1 as well, suggesting that adipose inflammation inhibits the increased thermogenic capacity of WAT. A number of immune-mediate functions are involved in this process. Based on these data, we propose the following hypotheses. Hypothesis 1. Repeated exposure to cold temperatures will amplify changes in human subcutaneous WAT beiging. These beiging effects are seen acutely, in response to seasons and involve an activation of immune mediators. Hypothesis 2. The beiging of SC WAT involves an acute increase in adipose tissue immune mediators, which may be a source of catecholamines that activate protein kinase A (PKA). This process is inhibited by β-blockers in vivo. Hypothesis 3. Obese insulin resistant subjects are resistant to cold induced changes in WAT due to the proinflammatory milieu which inhibits local mediators of beiging. Hypothesis 4. Cold- and season-induced changes in SC WAT will lead to functional changes in the tissue, characterized by increased mitochondrial uncoupling, increased TG turnover (lipolysis) and increased resting metabolic rate. PUBLIC HEALTH: Obesity is closely linked with insulin resistance, diabetes and heart disease. Recent studies have focused on brown adipose tissue in humans, which may increase energy expenditure and help prevent obesity. This proposal examines the extent to which subcutaneous white adipose can become brown-like, or beige. We will determine whether this process is inhibited by the inflammatory state of obesity/metabolic syndrome, and we will characterize the effects of cold on adipose triglyceride turnover.