The activation of brown and beige fat and role in insulin sensitivity

棕色和米色脂肪的激活及其在胰岛素敏感性中的作用

• 批准号: 9241565
• 负责人: Philip A Kern
• 金额: $ 54.41万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241565
• 关键词: Adipocytes; Adipose tissue; Adrenergic Receptor; Adverse effects; Agonist; Basal metabolic rate; Biogenesis; Brown Fat; CREB1 gene; Cells; Chronic; Combined Modality Therapy; Cyclic AMP-Dependent Protein Kinases; Development; Diabetes Mellitus; Dose; Energy Metabolism; Fatty acid glycerol esters; Figs - dietary; Functional disorder; Gene Expression Profile; Heart Diseases; Heating; Human; Individual; Inflammation; Insulin Resistance; Lead; Link; Lipids; Lipolysis; Mammals; Marketing; Metabolic; Metabolism; Mitochondria; Mus; Obesity; Overactive Bladder; Oxidative Phosphorylation; PET/CT scan; PPAR gamma; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Pioglitazone; Respiration; Role; Skeletal Muscle; Sympathetic Nervous System; Thermogenesis; Tissues; cell type; flexibility; improved; insulin sensitivity; interest; natural hypothermia; obesity treatment; prevent; therapeutic target; transcription factor; uncoupling protein 1

There has been much interest in exploiting brown adipose tissue (BAT) and beige adipose tissue for the treatment of obesity and related complications. Although brown and beige adipocytes are derived from different precursors and display unique patterns of gene expression markers, both cells have increased mitochondrial content and express UCP1, which uncouples oxidative respiration to generate heat. In addition, both brown and beige adipocytes require PPARγ for their development, and both cell types are induced through the ß-adrenergic receptor (βAR)/PKA pathway. BAT and beige fat are activated through the sympathetic nervous system or by the use of βAR agonist drugs. Adipose tissue contains β3AR, and there have been attempts to treat obesity with β3 agonists. Currently, mirabegron (Myrbetriq®, Astellas) is a highly specific β3 agonist marketed for overactive bladder with minimal side effects at the recommended dose. In addition, the diabetes drug pioglitazone is a PPARγ agonist which reduces inflammation and improves insulin sensitivity. We hypothesize that the combination of pioglitazone and mirabegron will be more effective than either drug alone at activating both BAT and beige adipose tissue and in improving insulin sensitivity. We hypothesize that the mechanism of this improvement in insulin sensitivity will result from an increased partitioning of lipid into oxidative pathways, improved metabolic flexibility and decreased adipose inflammation. Hypothesis 1. Chronic treatment of insulin resistant subjects with a β3 agonist will result in increased mass and activity of BAT and beige adipose tissue along with increased resting metabolic rate. Hypothesis 2. The combined treatment with both a TZD (PPARγ agonist) and a β3 agonist will result in an additional stimulation of BAT and beige adipose mass and activity. Hypothesis 3. The activation of BAT and beige adipose tissue will be associated with reduced skeletal muscle lipotoxicity and improvements in adipose tissue inflammation. Hypothesis 4. The activation of BAT and beige adipose tissue by combined TZD and β3 agonists will result in a greater improvement in insulin sensitivity than by monotherapy alone. These studies are important because the repurposing of these common drugs could synergistically improve many of the metabolic dysfunctions in obese individuals.

人们对开发棕色脂肪组织(BAT)和米色脂肪很感兴趣 用于治疗肥胖和相关并发症的组织。虽然是棕色和米色 脂肪细胞来源于不同的前体细胞，并表现出独特的基因表达模式 标志，两种细胞都增加了线粒体含量，表达了解偶联的UCP1 氧化呼吸产生热量。此外，棕色和米色脂肪细胞都需要 PPARγ促进它们的发育，两种类型的细胞都是通过β-肾上腺素能受体诱导的 (βAR)/PKA通路。蝙蝠和米色脂肪通过交感神经系统被激活。 或通过使用βAR激动剂药物。脂肪组织含有β3AR，已经有 尝试使用β3激动剂治疗肥胖症。目前，mirabegron(Myrbetriq®，Astellas)是一家 高度特异的β3激动剂用于治疗膀胱过度活跃，副作用最小 推荐剂量。此外，糖尿病药物吡格列酮是一种PPARγ激动剂， 减少炎症，改善胰岛素敏感性。我们假设这两个因素的结合 在激活两种蝙蝠方面，吡格列酮和米拉贝隆将比单独使用这两种药物更有效 和米色脂肪组织，以及改善胰岛素敏感性。我们假设 胰岛素敏感性改善的机制是由于增加了对 脂类进入氧化途径，提高代谢灵活性，降低脂肪 发炎。 假设1.长期使用β-3激动剂治疗胰岛素抵抗受试者将导致 随着休息时间的增加，蝙蝠和米色脂肪组织的质量和活性增加 代谢率。 假设2：TZD(PPARγ激动剂)和β3激动剂的联合治疗将 导致额外的刺激蝙蝠和米色脂肪的质量和活动。 假设3：蝙蝠和米色脂肪组织的激活与减少有关 骨骼肌脂毒性和改善脂肪组织炎症。 假设4.TZD和β联合应用对蝙蝠和米色脂肪组织的激活 激动剂将导致胰岛素敏感性的改善比单一疗法更大。 这些研究很重要，因为这些常见药物的再利用可能 协同改善肥胖者的许多代谢功能障碍。