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

昼夜节律基因和脂肪功能：睡眠时间型、肥胖和种族的影响

• 批准号: 8766025
• 负责人: Matthew J Brady
• 金额: $ 45.1万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8766025
• 关键词: Address; Adipocytes; Adipose tissue; African American; Americas; Animal Model; Bariatrics; Behavior; Behavior Therapy; Behavioral; Biochemical; Biopsy; Body Weight decreased; Circadian Rhythms; Clinical; Collaborations; Data; Development; Energy Intake; Energy Metabolism; Epidemic; Fatty acid glycerol esters; Feedback; Gene Expression; Genes; Goals; High Risk Woman; Human; Human Volunteers; Individual; Insulin; Insulin Resistance; Intervention; Laboratories; Lead; Life Style; Measurement; Measures; Mediating; Mediator of activation protein; Medical center; Melatonin; Mesentery; Metabolic; Metabolic Diseases; Metabolism; Molecular; Morbid Obesity; Neurons; Non obese; Not Hispanic or Latino; Obesity; Operative Surgical Procedures; Pacemakers; Pathway interactions; Patients; Periodicity; Peripheral; Phase; Prevalence; Procedures; Race; Randomized; Recruitment Activity; Regulation; Reporting; Research; Research Personnel; Risk Factors; Rodent; Role; Schedule; Severities; Signal Transduction; Site; Sleep; Surgeon; System; Testing; Time; Tissue Sample; Tissues; Transgenic Organisms; United States; Weight Gain; Woman; bariatric surgery; circadian pacemaker; combinatorial; design; experience; health disparity; improved; insight; insulin sensitivity; insulin signaling; new therapeutic target; novel; novel therapeutic intervention; obesity risk; public health relevance; racial difference; response; restoration; subcutaneous; suprachiasmatic nucleus

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.

描述（申请人提供）：在美国，肥胖症的流行率有惊人的增长，但女性，特别是非洲裔美国人，尤其难以控制。外周组织中生物钟系统的紊乱已经成为体重增加和胰岛素抵抗的一个假定的新风险因素。虽然昼夜节律系统和代谢之间的串扰已经在夜间动物模型中得到了很好的证明，其中与人类相反，活跃期与高褪黑激素水平和视交叉上核中升高的神经元活动一致。脂肪组织外周生物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，减肥手术已成为一线治疗，每年在美国进行超过20万例手术。在与减肥外科医生的持续合作中，我们已经获得了初步证据，减肥手术迅速改善了胰岛素在原代人脂肪细胞中的作用。本申请的中心假设是脂肪组织中胰岛素敏感性的降低是由时钟和代谢基因的昼夜节律表达的改变介导的，并且这些紊乱在肥胖AA女性中比非西班牙裔白色（NHW）女性更明显。将在手术前2周收集来自肥胖AA和NHW人类志愿者以及来自匹配的瘦对照女性的皮下脂肪活检。将在24小时的时间段内在培养的脂肪组织中测量昼夜节律基因表达，并与每个个体的全身胰岛素敏感性和时辰型进行比较。在手术前一周内，将对一半肥胖受试者的就寝时间和进餐时间进行标准化，以确定中央昼夜节律调整对在减肥手术开始时收集的皮下和肠系膜脂肪中的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，然后进行长期体重减轻，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女性中昼夜节律基因表达的相位和幅度的改善相称。12周后，当恢复正常膳食安排但患者仍然肥胖时，我们将阐明减肥手术是否会导致更早的时钟型，这与防止代谢疾病的发展有关。在这两个时间点，我们将确定减肥手术在AA女性中的长期疗效降低是否伴随着脂肪组织中外周昼夜节律基因表达恢复的减少。这些研究应该为NHW和AA女性肥胖患者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重要见解，也可能导致新的治疗干预措施，以扭转目前患病率的种族差异 代谢性疾病。