Circadian Genes and Adipose Function: Impact of Chronotype, Obesity and Race

描述（由申请人提供）：在美国，肥胖的流行率正以惊人的速度增长，但女性，尤其是非洲裔美国人，尤其难以忍受。因此，确定介导与肥胖相关的胰岛素抵抗患病率增加的新途径至关重要。外周组织生物钟系统的紊乱已被认为是体重增加和胰岛素抵抗的一个新的危险因素。虽然昼夜节律系统和新陈代谢之间的相互作用在夜间动物模型中得到了充分的证明，但与人类相反，在夜间动物模型中，活跃期与高褪黑激素水平和视交叉上核神经元活动升高相一致。脂肪组织外周时钟功能改变在促进女性肥胖相关胰岛素抵抗中的潜在作用尚未阐明。此外，减肥手术已经成为一线治疗方法，每年在美国进行的手术超过20万例。在与一名减肥外科医生的持续合作中，我们已经获得了初步证据，表明减肥手术可以迅速改善胰岛素在原发性人类脂肪细胞中的作用。该应用的中心假设是脂肪组织中胰岛素敏感性的降低是由生物钟和代谢基因的昼夜节律表达改变介导的，这些紊乱在肥胖的AA女性中比非西班牙裔白人（NHW）女性更明显。将在手术前2周收集肥胖AA和NHW人类志愿者以及匹配的瘦对照女性的皮下脂肪活检。将在培养脂肪组织中测量24小时内的昼夜节律基因表达，并与每个个体的全身胰岛素敏感性和时间型进行比较。在手术前一周，一半肥胖受试者的就寝时间和用餐时间将被标准化，以确定中心昼夜节律对齐对减肥手术开始时收集的皮下和肠系膜脂肪中外周昼夜节律基因表达的影响。最后，手术患者将在术后2周和12周返回，在长期体重减轻之前，并收集皮下脂肪活检。在2周时，我们将确定脂肪组织中胰岛素敏感性的快速改善是否与NHW和AA女性昼夜节律基因表达的阶段和幅度的改善相称。在12周时，当正常饮食计划恢复，但患者仍然肥胖时，我们将阐明减肥手术是否会导致更早的时型，这与保护代谢疾病的发展有关。在这两个时间点，我们将确定AA女性减肥手术的长期疗效下降是否伴随着脂肪组织中周围昼夜节律基因表达恢复的减少。这些研究应该为外周昼夜节律基因表达和胰岛素敏感性变化的相互作用提供新的和重要的见解，这些变化发生在NHW和AA女性肥胖中，也可能导致新的治疗干预措施，以扭转目前在患病率上的种族差异

DESCRIPTION (provided by applicant): There has been an alarming increase in the prevalence of obesity in the United States, but women, in particular African Americans, have been especially hard it. It is thus crucial to identify novel pathways that mediate the increase prevalence of insulin resistance associated with obesity. Disturbances of the circadian clock system in peripheral tissues have emerged as a putative novel risk factor for weight gain and insulin resistance. While the cross-talk between the circadian system and metabolism has been well-documented in nocturnal animal models, in which, contrary to the human, the active period is aligned with high melatonin levels and elevated neuronal activity in the suprachiasmatic nucleus. The potential role of alterations in peripheral clock function in adipose tissue in promoting adiposity-related insulin resistance in women has not been elucidated. Additionally, bariatric surgery has emerged as a frontline treatment with over 200,000 procedures being performed in the US annually. In an ongoing collaboration with a bariatric surgeon, we have obtained preliminary evidence that bariatric surgery rapidly improves insulin action in primary human adipocytes. The central hypothesis of this application is that the reduction in insulin sensitivity in adipose tissue is mediated by alterations in the circadian expression of clock and metabolic genes, and that these disturbances are more pronounced in obese AA women versus non-Hispanic white (NHW) women. Subcutaneous fat biopsies from obese AA and NHW human volunteers will be collected 2 weeks prior to surgery, as well as from matched lean control women. Circadian gene expression will be measured in cultured adipose tissue over a 24 hr period and compared to the systemic insulin sensitivity and chronotype of each individual. During the week prior to surgery, bedtimes and mealtimes will be standardized for half of the obese subjects to determine the impact of central circadian alignment on peripheral circadian gene expression in subcutaneous and mesenteric fat collected at the start of the bariatric procedure. Finally, surgical patients will return 2 and 12 weeks post-surgery before long term weight loss has occurred and subcutaneous fat biopsies will be collected. At 2 weeks, we will determine if the rapid improvement in insulin sensitivity in adipose tissue is commensurate with improvement in the phase and amplitude of circadian gene expression in NHW and AA women. At 12 weeks, when normal meal schedules have resumed but patients remain obese, we will elucidate if bariatric surgery causes an earlier chronotype, which is associated with protection from the development of metabolic disease. At both time points, we will determine if the decreased long term efficacy of bariatric surgery in AA women is concomitant with a reduction in the restoration of peripheral circadian gene expression in adipose tissue. These studies should provide novel and important insights into the interplay of changes in peripheral circadian gene expression and insulin sensitivity that occurs in obesity in NHW and AA women, and may also lead to novel therapeutic interventions to reverse the current racial disparities in the prevalence of metabolic disease in women.