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: 10697844
• 负责人: Aaron Cypess
• 金额: $ 83.23万
• 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/10697844
• 关键词: Acute; Adipose tissue; Adrenergic Agonists; Adrenergic Receptor; Adult; Adverse effects; Advisory Committees; Anatomy; 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; Emission-Computed Tomography; 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; Pharmacology; Phase; Physiological; Physiology; Pilot Projects; Placebos; Plasma; Polycystic Ovary Syndrome; Positron-Emission Tomography; Publishing; Relaxation; Reporting; Reproductive Health; Resistance; Resolution; Risk; Rodent; Series; Supraclavicular; Thermogenesis; Thinness; Thioctic Acid; Time; 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; 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）来增加能量消耗是治疗肥胖和糖尿病的潜在方法。β -肾上腺素能受体（AR）激动剂类刺激啮齿动物的BAT，但这种活性从未在人类中得到证实。在过去的一年里，我们发表了研究结果，我们确定了200mg口服mirabegron （Myrbetriq, Astellas Pharma, Inc.）的能力，这是一种β - ar激动剂，目前被批准用于治疗膀胱过度活动，与安慰剂相比，可以刺激BAT。在所有12名健康男性受试者中，Mirabegron通过正电子发射断层扫描（PET）结合计算机断层扫描（CT）使用18f -氟脱氧葡萄糖（18F-FDG）测量了更高的BAT代谢活性（p = 0.001），并使静息代谢率（RMR）提高203,40 kcal/天（+13%;p = 0.001）。BAT代谢活性也是RMR变化的重要预测因子（p = 0.006）。因此，3-AR激动剂可以刺激人BAT产热，可能是代谢性疾病的一种有希望的治疗方法。