Sympathetic Regulation of AMPK in the control of non-shivering thermogenesis

AMPK 的交感神经调节控制非颤抖生热作用

• 批准号: 8117484
• 负责人: KURT William SAUPE
• 金额: $ 29.11万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-17 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117484
• 关键词: Adenosine Monophosphate; Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic Agonists; Adrenergic Receptor; Age; Autonomic nervous system; Biogenesis; Biological Process; Biopsy; Blood; Body Temperature; Body Weight; Brown Fat; Calories; Centrifugation; Chronic; Data; Development; Diet; Down-Regulation; Energy Intake; Epidemic; Equilibrium; Esthesia; Expenditure; Fatty acid glycerol esters; Goals; Health; Heating; Human; Hunger; Hypothalamic structure; In Vitro; Insulin; Knockout Mice; Leptin; Link; Liver; Measures; Mediating; Metabolic syndrome; Mitochondria; Molecular; Mus; Muscle; Obesity; Patients; Phosphorylation; Play; Production; Protein Kinase; Publishing; Pump; Regulation; Research; Role; Signal Transduction; Sympathetic Nervous System; System; Temperature; Testing; Thermogenesis; Tissues; Transgenic Mice; Up-Regulation; Weight Gain; adiponectin; adrenergic; cell type; clinical application; combat; desensitization; diet and exercise; energy balance; in vivo; insulin sensitivity; novel; prevent; sex

DESCRIPTION (provided by applicant): While a role for adenosine monophosphate activated protein kinase (AMPK) in regulating body energy balance via effects in non-adipose tissues has gained acceptance, little is known about the biological function of AMPK in white and brown adipose tissues. The proposed studies will test two hypotheses, the first being that adrenergic signaling regulates AMPK activity in white adipose tissue, which in turn plays a role in controlling white adipocyte insulin sensitivity and adipokine production. The second hypothesis is that AMPK contributes to the regulation of body weight and temperature by controlling the thermogenic potential and amount of non-shivering thermogenesis in brown adipose. To test these hypotheses, three specific aims will be accomplished. First, the adrenergic receptor sub-type(s) necessary and sufficient to upregulate 11 AMPK activity in white adipose tissue, as well as the cell type(s) in which this occurs, will be determined. This will be done in vivo by exposing wildtype and 23-adrenergic receptor knockout mice to 14 days of cold exposure or adrenergic receptor agonists administered via micro-osmotic pumps, and fractionating the white adipose tissue using differential centrifugation. The second aim is to determine what role sympathetic modulation of 11 AMPK activity has in "healthful" and "harmful" remodeling of white adipose tissue. In mice, the extent to which 23-adrenergic induced healthful remodeling of WAT occurs in AMPK knockout mice will be determined. In metabolic syndrome patients and age/sex matched controls, the hypothesis that desensitization of adrenergic signaling in white adipocytes is associated with a downregulation of 11 AMPK activity will be tested. The third aim is to test the hypothesis that chronic weight gain increases caloric expenditure of BAT via an AMPK-mediated increase in brown adipocyte mitochondrial biogenesis. This will be tested in wildtype and 11 AMPK knockout mice in vivo, as well as in vitro using pharmacological activation and inhibition of 11 AMPK in primary cultures of brown adipocytes. The long term goal of this research is to manipulate the amount, and "health" of white adipose tissue by targeting the AMPK signaling system in white and brown adipocytes. PUBLIC HEALTH RELEVANCE: Efforts to combat the "obesity epidemic" by encouraging exercise and dieting have been largely unsuccessful. Our studies examine a way of metabolizing calories into heat instead of storing them as fat, and the possibility that the "health" of fat is regulated by a branch of the autonomic nervous system.

描述（由申请人提供）：虽然腺苷一磷酸活化蛋白激酶（AMPK）通过在非脂肪组织中的作用调节身体能量平衡的作用已被接受，但对AMPK在白色和棕色脂肪组织中的生物学功能知之甚少。拟议的研究将测试两个假设，第一个是肾上腺素能信号调节白色脂肪组织中的AMPK活性，这反过来又在控制白色脂肪细胞胰岛素敏感性和脂肪因子产生中起作用。第二个假设是AMPK通过控制棕色脂肪中的产热潜能和非颤抖性产热的量来调节体重和体温。为了检验这些假设，将完成三个具体目标。首先，将确定上调白色脂肪组织中11 AMPK活性所必需和足够的肾上腺素能受体亚型，以及发生这种情况的细胞类型。这将通过将野生型和23-肾上腺素能受体敲除小鼠暴露于14天的冷暴露或通过微渗透泵施用肾上腺素能受体激动剂，并使用差速离心分离白色脂肪组织来体内完成。第二个目的是确定11 AMPK活性的交感神经调节在白色脂肪组织的“健康”和“有害”重塑中的作用。在小鼠中，将确定23-肾上腺素能诱导的WAT的健康重塑在AMPK敲除小鼠中发生的程度。在代谢综合征患者和年龄/性别匹配的对照中，将检验白色脂肪细胞中肾上腺素能信号传导的脱敏与11 AMPK活性下调相关的假设。第三个目的是检验慢性体重增加通过AMPK介导的棕色脂肪细胞线粒体生物合成增加BAT的热量消耗的假设。这将在野生型和11 AMPK敲除小鼠体内进行测试，以及在棕色脂肪细胞原代培养物中使用11 AMPK的药理学激活和抑制进行体外测试。这项研究的长期目标是通过靶向白色和棕色脂肪细胞中的AMPK信号系统来操纵白色脂肪组织的数量和“健康”。公共卫生相关性：通过鼓励锻炼和节食来对抗“肥胖流行病”的努力基本上没有成功。我们的研究考察了一种将卡路里代谢成热量而不是将它们储存成脂肪的方式，以及脂肪的“健康”受到自主神经系统分支调节的可能性。