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: 7901570
• 负责人: KURT William SAUPE
• 金额: $ 29.63万
• 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/7901570
• 关键词: Adenosine Monophosphate; Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic Agonists; Adrenergic Receptor; Age; Autonomic nervous system; Biogenesis; Biological Process; Biopsy; Blood; 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; Shivering; 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; public health relevance; 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）：虽然单磷酸腺苷激活蛋白激酶（AMPK）通过非脂肪组织中的作用调节身体能量平衡的作用已获得认可，但人们对 AMPK 在白色和棕色脂肪组织中的生物学功能知之甚少。拟议的研究将检验两个假设，第一个假设是肾上腺素信号传导调节白色脂肪组织中的 AMPK 活性，进而在控制白色脂肪细胞胰岛素敏感性和脂肪因子的产生中发挥作用。第二个假设是 AMPK 通过控制棕色脂肪的产热潜力和非颤抖产热量来调节体重和温度。为了检验这些假设，将实现三个具体目标。首先，将确定上调白色脂肪组织中 11 AMPK 活性所必需且充分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冷暴露或通过微渗透泵施用肾上腺素能受体激动剂 14 天，并使用差速离心分离白色脂肪组织来在体内完成。第二个目的是确定 11 AMPK 活性的交感调节在白色脂肪组织的“健康”和“有害”重塑中发挥什么作用。在小鼠中，将确定 AMPK 敲除小鼠中 23-肾上腺素能诱导的 WAT 健康重塑的程度。在代谢综合征患者和年龄/性别匹配的对照中，将测试白色脂肪细胞中肾上腺素能信号脱敏与 11 AMPK 活性下调相关的假设。第三个目的是检验这样的假设：慢性体重增加通过 AMPK 介导的棕色脂肪细胞线粒体生物发生的增加来增加 BAT 的热量消耗。这将在野生型和 11 AMPK 敲除小鼠体内进行测试，并在体外使用棕色脂肪细胞原代培养物中 11 AMPK 的药理激活和抑制进行测试。这项研究的长期目标是通过针对白色和棕色脂肪细胞中的 AMPK 信号系统来控制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”的努力基本上不成功。我们的研究探讨了一种将卡路里代谢为热量而不是将其储存为脂肪的方法，以及脂肪的“健康”受到自主神经系统分支调节的可能性。