Mechanisms Underlying Adipose Tissue Thermogenesis

脂肪组织产热的机制

• 批准号: 9356246
• 负责人: Aaron Cypess
• 金额: $ 11.88万
• 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/9356246
• 关键词: Address; Adipocytes; Adipose tissue; Adrenergic Receptor; Agonist; Bile Acids; Biochemistry; Blood Pressure; Body fat; Boston; Brown Fat; C57BL/6 Mouse; Cardiovascular system; Cell Line; Cells; Clinical Trials; Collaborations; Collection; Corticotropin; Data; Diabetes Mellitus; Diet; Dose; Ephedrine; Experimental Models; Failure; Fatty acid glycerol esters; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Targeting; Generations; Genes; Heart Rate; Heterogeneity; High Fat Diet; Human; Human Cell Line; Human Cloning; Immune; Impairment; In Vitro; Inflammation; Insulin; Insulin Resistance; Ligand Binding; Ligands; Maps; Measures; Messenger RNA; Metabolic; Metabolic Diseases; Modeling; Neck; Norepinephrine; Nude Mice; Obesity; Oxygen Consumption; Patients; Pharmacological Treatment; Phosphorylation; Physiology; Population; Respiration; Rodent; Sampling; Sympathomimetics; TNF gene; Testing; Thermogenesis; Time; Tissue Differentiation; Transplantation; base; feeding; genetic signature; glucose tolerance; glucose uptake; impaired glucose tolerance; in vitro Model; in vivo; inflammatory marker; insulin signaling; mRNA Expression; medical schools; member; novel; receptor expression; response

In collaboration with Dr. Tseng's group at the Joslin Diabetes Center / Harvard Medical School in Boston, we generated clonal cell lines from human neck fat and characterized their adipogenic differentiation and metabolic function in vitro and in vivo after transplantation into immune deficient nude mice. Using clonal analysis and gene expression profiling, we identified unique sets of gene signatures in human preadipocytes that could predict the thermogenic potential of these cells once matured in culture into adipocytes. These data highlight the cellular heterogeneity in human BAT and WAT and provide novel gene targets to prime preadipocytes for thermogenic differentiation. This past year, we also used these immortalized human adipocytes to describe the adrenergic receptor expression and functional profiling that will guide the develop of pharmacological compounds that can be used to activate human BAT and treat obesity and metabolic disease. With ATCC, we are developing an additional collection of human adipose tissue cell populations and cell lines from additional depots. These will help enrich the functional and anatomical mapping of human adipose tissue. In parallel, we tested the effects of diet-induced obesity (DIO) on brown adipose tissue (BAT). We fed 6-week-old C57BL/6 mice either a normal chow diet (NCD) or a high-fat diet (HFD). After 16 additional weeks, we measured body fat, WAT, and BAT mRNA expression, glucose tolerance, and rates of glucose uptake in response to insulin and the beta3-AR agonist mirabegron. We saw that compared with NCD, HFD increased body fat and impaired glucose tolerance. Both WAT and BAT had higher mRNA levels of markers of inflammation, including TNF and F4/80. Insulin signaling in BAT and WAT was reduced, with decreased Akt phosphorylation. Diet-normalized BAT glucose uptake rates were lower in response to mirabegron. These results support a model in which DIO leads to BAT inflammation and insulin resistance, leading to a broader impairment of BAT function.

与波士顿Joslin糖尿病中心/哈佛医学院的Tseng博士团队合作，我们从人颈部脂肪中克隆出细胞系，并在移植到免疫缺陷裸鼠体内后，在体外和体内研究了它们的成脂分化和代谢功能。通过克隆分析和基因表达谱分析，我们在人类前脂肪细胞中发现了一组独特的基因特征，这些基因特征可以预测这些细胞在培养中成熟为脂肪细胞后的生热潜力。这些数据突出了人类BAT和WAT的细胞异质性，并为启动前脂肪细胞的产热分化提供了新的基因靶点。在过去的一年里，我们还使用这些永生化的人类脂肪细胞来描述肾上腺素能受体的表达和功能图谱，这将指导开发可用于激活人类BAT和治疗肥胖和代谢性疾病的药物化合物。 通过ATCC，我们正在从更多的仓库中开发更多的人类脂肪组织细胞群和细胞系的集合。这些将有助于丰富人类脂肪组织的功能和解剖图谱。 同时，我们测试了饮食诱导肥胖(DIO)对棕色脂肪组织(BAT)的影响。我们用普通饲料(NCD)和高脂饲料(HFD)喂养6周龄C57BL/6小鼠。另外16周后，我们测量了体脂、WAT和BAT基因的表达，糖耐量，以及胰岛素和β3-AR激动剂米雷贝格隆对葡萄糖摄取率的影响。我们看到，与NCD相比，HFD增加了体内脂肪，损害了糖耐量。WAT和BAT的炎症标志物包括肿瘤坏死因子和F4/80的mRNA水平均较高。BAT和WAT的胰岛素信号转导减少，Akt磷酸化减少。饮食标准化的蝙蝠对米拉贝格隆的葡萄糖摄取率较低。这些结果支持一种模型，在该模型中，DIO导致BAT炎症和胰岛素抵抗，导致BAT功能更广泛的损害。