Novel mechanisms for the stromal vascular fraction of brown adipose tissue to improve metabolic homeostasis

棕色脂肪组织基质血管部分改善代谢稳态的新机制

• 批准号: 9174098
• 负责人: Kristin I Stanford
• 金额: $ 8.27万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9174098
• 关键词: Adipocytes; Adipose tissue; Blood Vessels; Body Weight decreased; Body mass index; Brown Fat; Cardiovascular Diseases; Cell Count; Cell Therapy; Cells; Chemicals; Data; Development; Diet; Disease; Endocrine; Energy Metabolism; Epidemic; Exercise; FGF21 gene; Fatty acid glycerol esters; Genetic; Glucose; Goals; Health; Heating; Homeostasis; Human; Immune; Incidence; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Insulin-Like Growth Factor I; Interleukin-6; Laboratories; Lead; Lipids; Malignant Neoplasms; Mediating; Mesenchymal Stem Cells; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Plasma; Population; Prevalence; Property; Research; Risk; Risk Factors; Role; Stimulus; Therapeutic; Tissue Transplantation; Tissues; Training; Transplantation; Weight Gain; Wild Type Mouse; abdominal fat; base; blood glucose regulation; cell type; combat; comorbidity; diabetes risk; feeding; genetic manipulation; glucose metabolism; glucose tolerance; improved; insulin sensitivity; macrophage; mortality; mouse model; nerve supply; novel; novel therapeutics; obesity treatment; oxidation; public health relevance; stem; stem cells; tool; tool development

 DESCRIPTION (provided by applicant): Obesity and type 2 diabetes and are increasing dramatically worldwide. The increasing rates of obesity and type 2 diabetes have increased the importance of elucidating the molecular basis for obesity, as well as determining potential therapeutic treatments for this condition. Brown adipose tissue (BAT) is a thermogenic tissue that contains large amounts of mitochondria to dissipate chemical energy as heat. BAT has a high capacity for both glucose and lipid oxidation, making BAT a potential target to decrease plasma glucose and lipids, and a potential target to protect against obesity and lower the risk of diabetes. Transplantation of BAT improves glucose homeostasis in normal chow-fed mice, in a model of diet-induced obesity, and in a model of type 1 diabetes, and these improvements in glucose homeostasis are mediated by increases in circulating IL-6 and FGF21. An increase in brown-adipocytes in white adipose tissue (WAT) through environmental (i.e. cold, exercise) or genetic manipulation results in increased energy expenditure, improved glucose tolerance, and protection against weight gain. It is currently unclear if BAT transplantation confers metabolic benefits due to certain cell types being transplanted, or whether the mature brown adipocytes are required as appears to be the case with `browning' of WAT. Our exciting preliminary data show that transplantation of isolated human progenitor cells differentiated into brown adipocytes decreases body weight and improves insulin sensitivity and a mouse model. We have also shown that transplantation of the total stromal vascular fraction (SVF) of mouse BAT improves glucose tolerance, suggesting that the SVF of BAT is essential to the improvement in metabolic homeostasis after transplantation, although the mechanism for this improvement, and the cell-type responsible for this improved glucose homeostasis, are unclear. We have also generated preliminary data that demonstrate that the cell distribution of the SVF compartment of BAT is altered with exercise-training, although the functional consequence of this change is not understood. There are two specific aims: 1) Determine if transplantation of the specific cell-types of BAT SVF improve glucose homeostasis, if a specific cell-type is required for this effect, and whether IL-6 or FGF21 are required for this effect; and 2) Determine if the metabolic function of the SVF population of BAT is altered after exercise-training. This project will establish the role of specific components of the BAT SVF in improvements in glucose metabolism, how these components function to mediate the beneficial effects of BAT on glucose homeostasis, and if exercise improves the metabolic capacity of specific components of the SVF. These studies have the potential to lead to the development of a novel cell-based therapy to combat type 2 diabetes and obesity and, if translatable to humans, have great therapeutic implications.

 描述（由适用提供）：肥胖和2型糖尿病，在全球范围内急剧增加。肥胖和2型糖尿病的速度的提高提高了阐明肥胖的分子基础的重要性，并确定了这种疾病的潜在治疗治疗方法。棕色脂肪组织（BAT）是一种热组织，其中包含大量的线粒体，以将化学能作为热量散发。 BAT具有葡萄糖和脂质氧化的高容量，使BAT成为降低血浆葡萄糖和脂质的潜在目标，并且是预防肥胖和降低糖尿病风险的潜在靶标。在饮食诱导的肥胖症的模型和1型糖尿病模型中，蝙蝠的移植可改善正常食用小鼠的葡萄糖稳态，在循环IL-6和FGF21中的增加，葡萄糖稳态的这些改善是通过增加葡萄糖稳态的。通过环境（即寒冷，运动）或遗传操作的白色脂肪细胞（WAT）中棕色脂肪细胞的增加会导致能量消耗增加，葡萄糖耐受性的提高以及防止体重增加。目前尚不清楚由于某些细胞类型的移植而导致的BAT移植贡献是代谢益处，还是WAT的“ Browning”似乎是这样的，是否需要成熟的棕色脂肪细胞。我们令人兴奋的初步数据表明，分化为棕色脂肪细胞的分离的人类祖细胞的移植会减轻体重，并提高胰岛素敏感性和小鼠模型。我们还表明，小鼠蝙蝠的总基质血管分数（SVF）的移植提高了葡萄糖耐量，这表明蝙蝠的SVF对于移植后代谢稳态的改善至关重要，尽管这种改进的改进机制，并且负责这种改善的Glucose Hissostasiss，对这种改进的glucose type造成了不明智的措施。我们还产生了初步数据，表明蝙蝠的SVF隔室的细胞分布会随着运动训练而改变，尽管该变化的功能后果尚不清楚。有两个具体的目的：1）确定BAT SVF的特定细胞类型的移植是否改善了葡萄糖稳态，如果需要特定的细胞类型，则该作用是否需要特定的细胞类型，以及是否需要IL-6或FGF21。 2）确定运动训练后BAT SVF群体的代谢功能是否改变。该项目将确定BAT SVF特定组成部分在葡萄糖代谢的改善中的作用，这些成分如何发挥作用以介导BAT对葡萄糖稳态的有益作用，如果运动提高了SVF特定成分的代谢能力。这些研究有可能导致开发基于细胞的新型治疗，以打击2型糖尿病和肥胖症，如果可以翻译为人类，则具有很大的治疗意义。