Physiological Responses to Activation of Human Brown Adipose Tissue

对人类棕色脂肪组织激活的生理反应

• 批准号: 10919509
• 负责人: Aaron Cypess
• 金额: $ 61.51万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10919509
• 关键词: Acute; Adipose tissue; Adrenergic Agonists; Adrenergic Receptor; Adult; Adverse effects; Advisory Committees; Anti-Inflammatory Agents; Antidiabetic Drugs; Antioxidants; Atlases; Axilla; Basal metabolic rate; Bile Acids; Binding; Biological Markers; Bladder; Blood; Body Composition; Body Weight; Body mass index; Brown Fat; COVID-19 treatment; Cardiovascular system; Catecholamines; Cervical; Chronic; Clinical; Clinical Trials; Collaborations; Development; Diabetes Mellitus; Diastolic blood pressure; Dose; Effectiveness; Energy Metabolism; FDA approved; Fatty Acids; Fatty acid glycerol esters; Future; Gallbladder; Glucose; High Density Lipoproteins; Hormones; Hour; Human; Individual; Inflammation; Insulin; Investigation; Label; Lipolysis; Lipoproteins; Measures; Mediastinal; Metabolic; Metabolic Diseases; Metabolism; Methods; Obesity; Oral; Overactive Bladder; Paper; Patients; Pharmaceutical Preparations; Phase; Physiological; Physiology; Pilot Projects; Placebos; Plasma; Polycystic Ovary Syndrome; Positron-Emission Tomography; Publishing; Regional Anatomy; Relaxation; Reporting; Reproductive Health; Resistance; Resolution; Risk; Rodent; Series; Supraclavicular; Thermogenesis; Thinness; Thioctic Acid; Tissues; Woman; X-Ray Computed Tomography; adiponectin; bile acid metabolism; clinically relevant; effectiveness study; experience; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; improved; insulin secretion; insulin sensitivity; interest; intravenous glucose tolerance test; male; meetings; men; metabolomics; microbiome; pharmacologic; primary endpoint; response; uptake; young man

Increasing energy expenditure through activation of endogenous brown adipose tissue (BAT) is a potential approach to treat obesity and diabetes. The class of beta3-adrenergic receptor (AR) agonists stimulates rodent BAT, but this activity has never been demonstrated in humans. This past year we published findings in which we determined the ability of 200 mg oral mirabegron (Myrbetriq, Astellas Pharma, Inc.), a beta3-AR agonist currently approved to treat overactive bladder, to stimulate BAT as compared to placebo. Mirabegron led to higher BAT metabolic activity as measured via 18F-fluorodeoxyglucose (18F-FDG) using positron emission tomography (PET) combined with computed tomography (CT) in all twelve healthy male subjects (p = 0.001), and it increased resting metabolic rate (RMR) by 203 40 kcal/day (+13%; p = 0.001). BAT metabolic activity was also a significant predictor of the changes in RMR (p = 0.006). Therefore, a 3-AR agonist can stimulate human BAT thermogenesis and may be a promising treatment for metabolic disease. We recently published the first atlas of human BAT, the BATlas 1.0. In collaboration with Kong Chen, we studied 20 healthy young men 12 lean, mean body mass index (BMI) 23.2 1.9 kg/m2; 8 obese, BMI 34.8 3.3 kg/m2 after 5 h of tolerable cold exposure. We measured BAT volume and activity by 18F-labeled fluorodeoxyglucose positron emission tomography/computerized tomography (PET/CT). Obese men had less activated BAT than lean men (mean, 130 vs. 334 mL) but more fat in BAT-containing depots (mean, 1,646 vs. 855 mL) with a wide range (0.171%) in the ratio of activated BAT to inactive fat between individuals. Six anatomic regions had activated BAT: cervical, supraclavicular, axillary, mediastinal, paraspinal, and abdominalwith 67 20% of all activated BAT concentrated in a continuous fascial layer comprising the first three depots in the upper torso. These nonsubcutaneous fat depots amounted to 1.5% of total body mass (4.3% of total fat mass), and up to 90% of each depot could be activated BAT. The amount and activity of BAT was significantly influenced by region of interest selection methods, PET threshold criteria, and PET resolutions. The present study suggests that active BAT can be found in specific adipose depots in adult humans, but less than one-half of the fat in these depots is stimulated by acute cold exposure, demonstrating a previously underappreciated thermogenic potential. We also published the results of the dose response study in which we included exploratory metabolomics in collaboration with BERG Pharma. We showed that besides urinary bladder relaxation, the human beta3-AR contributes to white adipose tissue lipolysis, BAT thermogenesis, gallbladder relaxation, and bile acid metabolism. This physiology should be considered in the development of more selective beta3-AR agonists to treat obesity-related complications. Beyond these projects, we are utilizing the curated blood and tissue collected during our clinical trials to support exploratory and mechanistic studies by our colleagues. For example, Yu-Hua Tseng has shown in a series of papers that the BAT-derived hormones 12,13-diHOME and 12-HEPE increase tissue uptake of fatty acids and glucose, while MaR2 reduces inflammation.

通过激活内源性棕色脂肪组织（BAT）来增加能量消耗是一种治疗肥胖症和糖尿病的潜在方法。 Beta3-肾上腺素受体（AR）激动剂的类别刺激了啮齿动物的蝙蝠，但是这种活动在人类中从未得到证明。 在过去的一年中，我们发表了研究结果，在这些发现中，我们确定了200 mg口服Mirabegron（Myrbetriq，Astellas Pharma，Inc。），这是一种目前批准的Beta3-AR激动剂，以治疗过度活跃的膀胱，可以刺激与安慰剂相比。 Mirabegron通过正电子发射断层扫描（PET）与18F氟脱氧葡萄糖（18F-FDG）进行了较高的BAT代谢活性，并在所有十二个健康的男性受试者（P = 0.001）中结合了计算机断层扫描（CT）（PET）（P = 0.001），并将静止的代谢率（RMR）提高到203 40 kcal/kcal day（+13％）。 BAT代谢活性也是RMR变化的重要预测指标（P = 0.006）。 因此，3-AR激动剂可以刺激人类BAT的热发生，并且可能是代谢疾病的有前途的治疗方法。 我们最近发表了人类蝙蝠的第一个地图集，即Batlas 1.0。 在与Kong Chen合作的情况下，我们研究了20名健康的年轻男子12瘦，平均体重指数（BMI）23.2 1.9 kg/m2； 8肥胖，BMI 34.8 3.3 kg/m2，5小时可容忍的冷暴露。 我们通过18F标记的氟脱氧葡萄糖正电子发射断层扫描/计算机断层扫描（PET/CT）测量了BAT的体积和活性。肥胖的男性的活性蝙蝠比瘦男人（平均130 vs. 334毫升）的蝙蝠少，但在含蝙蝠的仓库中（平均为1,646 vs. 855毫升）的脂肪含量更高，其范围很广（0.171％），而活性蝙蝠与个人之间的无效脂肪的比率更高。六个解剖区域已经激活了蝙蝠：颈椎，上锁骨，腋窝，纵隔，脊柱和腹部和腹部With 67 20％的所有活化的蝙蝠集中在连续的筋膜层中，其中包括上躯干中前三个仓库。这些非肌脂肪仓库占体重的1.5％（占总脂肪质量的4.3％），每个仓库中最多90％可以激活蝙蝠。蝙蝠的数量和活动受到关注区域选择方法，PET阈值标准和PET分辨率的显着影响。本研究表明，在成年人的特定脂肪仓库中可以找到活跃的蝙蝠，但是急性冷暴露刺激了这些仓库中脂肪的一半，这表明先前未被低估的热潜能。 我们还发表了剂量反应研究的结果，其中我们与Berg Pharma合作纳入了探索性代谢组学。 我们表明，除了膀胱松弛外，人beta3-ar还有助于白色脂肪组织脂解，蝙蝠的热生成，胆囊松弛和胆汁酸代谢。在开发更有选择性的beta3-ar激动剂以治疗与肥胖相关的并发症时，应考虑这种生理学。 除了这些项目之外，我们还利用临床试验期间收集的策划的血液和组织来支持同事的探索性和机械研究。 例如。

项目成果

Correction: Effect of Chronic Athletic Activity on Brown Fat in Young Women.

• DOI: 10.1371/journal.pone.0160129
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Singhal V;Maffazioli GD;Ackerman KE;Lee H;Elia EF;Woolley R;Kolodny G;Cypess AM;Misra M
• 通讯作者: Misra M

RNA polymerase II-associated factor 1 regulates the release and phosphorylation of paused RNA polymerase II.

RNA 聚合酶 II 相关因子 1 调节暂停的 RNA 聚合酶 II 的释放和磷酸化。

• DOI: 10.1126/science.aad2338
• 发表时间: 2015-12-11
• 期刊: Science (New York, N.Y.)
• 作者: Yu M;Yang W;Ni T;Tang Z;Nakadai T;Zhu J;Roeder RG
• 通讯作者: Roeder RG

Automatic Segmentation and Quantification of White and Brown Adipose Tissues from PET/CT Scans.

• DOI: 10.1109/tmi.2016.2636188
• 发表时间: 2017-03
• 期刊: IEEE transactions on medical imaging
• 影响因子: 10.6
• 作者: Hussein S;Green A;Watane A;Reiter D;Chen X;Papadakis GZ;Wood B;Cypess A;Osman M;Bagci U
• 通讯作者: Bagci U

Brown fat in humans: consensus points and experimental guidelines.

• DOI: 10.1016/j.cmet.2014.07.025
• 发表时间: 2014-09-02
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Cypess AM;Haft CR;Laughlin MR;Hu HH
• 通讯作者: Hu HH