Cell cycle regulators control adiposity and metabolism

细胞周期调节剂控制肥胖和新陈代谢

• 批准号: 8784402
• 负责人: Daniel Carl Berry
• 金额: $ 5.51万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8784402
• 关键词: Adipocytes; Adipose tissue; Adult; Asses; Atherosclerosis; Attention; Biological Assay; Blood Vessels; Body Weight; Bromodeoxyuridine; Buffers; CDKN2A gene; Cardiovascular Diseases; Cell Count; Cell Culture Techniques; Cell Cycle; Cell Cycle Arrest; Cell Cycle Proteins; Cell Differentiation process; Cell Proliferation; Cell model; Cells; Cyclin D1; Data; Deposition; Development; Diabetes Mellitus; Diet; Employee Strikes; Energy Intake; Epidemic; Equilibrium; Eye; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Genes; Glucose; Health; Homeostasis; Hypertension; In Vitro; Insulin; Knock-out; Label; Link; Lipids; Location; Malignant Neoplasms; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Molecular; Morphology; Mus; Mutate; Obesity; Overweight; Pathway interactions; Phenotype; Physiology; Plasma; Population; Prevalence; Process; RNA Sequences; Regulation; Reporter; Reporting; Reproduction; Retinoblastoma; Role; Satiation; Staging; Stem cells; Technology; Temperature; Testing; Tissues; Trauma; Triglycerides; Tumor Suppressor Proteins; United States; Weight Gain; adipocyte differentiation; cancer cell; cell type; feeding; fight against; genetic analysis; improved; in vivo; insulin sensitivity; metabolic abnormality assessment; novel therapeutics; p19ARF; prevent; progenitor; public health relevance; response; self-renewal; stem cell population; tool; vasculogenesis

DESCRIPTION (provided by applicant): Obesity is of epidemic proportions and adipose tissue (fat) is central to the manifestation of the accompanying metabolic syndrome (diabetes, cardiovascular disease, atherosclerosis, and hypertension). Fat tissue controls metabolism, insulin sensitivity, and temperature regulation, and is a buffer against trauma and a regulator of reproduction and satiety. The global prevalence of obesity is approximately 15% and in the United States more than two thirds of the population is considered overweight. Fat mass can expand from 2-3% to 60-70% of overall body weight in response to caloric excess. Fat tissue is comprised of two cell types: the cells that store lipids, adipocytes, and fat stem cells which can divide and have the potential to make new adipocytes. Fat accumulation occurs in two ways, one is to increase lipid storage in existing adipocytes and the second is to expand the fat stem cell population in turn creating new adipocytes. Despite the important health implications of obesity and the metabolic syndrome our understanding about adipocyte number and size determination, fat development and deposition (adiposity) and the link between these parameters and metabolic dysfunction are limited. Our lab recently identified and localized fat stem cells to the blood vessel wall in the adipose tissue thus serving as the microenvironment. Much remains unknown about these newly identified stem cells including controlling fat stem cell proliferation. To examine this and other questions, two important genes involved in controlling cell proliferation, p16Ink4a/p19Arf, were specifically deleted in mouse fat stem cells.I hypothesis that increasing fat stem cell number will prevent fat formation, prevent metabolic dysregulation and promote blood vessel formation. Preliminary findings revealed that deleting p16Ink4a/p19Arf increased fat stem cell proliferation and blocked adipocyte formation leading to reduced fat content; however, these mice display better insulin responses. Conversely, increasing the caloric intake promoted adipocyte formation reestablishing the adipose depot. Isolation of p16Ink4a/p19Arf fat stem cells from the adipose tissue and placement into cell culture revealed that they can differentiate into mature functioning adipocytes. Aim 1 will focus on understanding adiposity and metabolism under normal and obese settings. In aim 2 the emphasis will be placed on the molecular underpinnings of how p16Ink4a/p19Arf control fat stem cell proliferation and differentiation. At the conclusion of these studies, I will have expanded ou understanding of how adipose stem cell number controls adiposity and metabolism under normal physiology and obesity and may uncover new targets for metabolic therapy.

描述（由申请人提供）：肥胖是一种流行病，脂肪组织（脂肪）是伴随代谢综合征（糖尿病、心血管疾病、动脉粥样硬化和高血压）表现的核心。脂肪组织控制新陈代谢、胰岛素敏感性和体温调节，是创伤的缓冲器，也是生殖和饱腹感的调节器。肥胖症的全球患病率约为15%，在美国，超过三分之二的人口被认为超重。脂肪量可以从总体重的2-3%增加到60-70%，以响应热量过剩。脂肪组织由两种类型的细胞组成：储存脂质的细胞，脂肪细胞和脂肪干细胞，脂肪干细胞可以分裂并具有制造新脂肪细胞的潜力。脂肪积累以两种方式发生，一种是增加现有脂肪细胞中的脂质储存，第二种是扩大脂肪干细胞群，从而产生新的脂肪细胞。尽管肥胖和代谢综合征对健康有重要影响，但我们对脂肪细胞数量和大小的确定、脂肪发育和沉积（肥胖）以及这些参数与代谢功能障碍之间的联系的理解是有限的。我们的实验室最近发现并定位脂肪干细胞在脂肪组织的血管壁，从而作为微环境。关于这些新发现的干细胞，包括控制脂肪干细胞增殖，仍有许多未知之处。为了研究这个问题和其他问题，两个重要的基因参与控制细胞增殖，p16 Ink 4a/p19 Arf，被专门删除在小鼠脂肪干细胞。我假设，增加脂肪干细胞的数量将防止脂肪形成，防止代谢失调，促进血管形成。初步研究结果显示，删除p16 Ink 4a/p19 Arf增加了脂肪干细胞的增殖，并阻止了脂肪细胞的形成，导致脂肪含量减少;然而，这些小鼠显示出更好的胰岛素反应。相反，增加热量摄入会促进脂肪细胞形成，重建脂肪库。从脂肪组织中分离p16 Ink 4a/p19 Arf脂肪干细胞并置于细胞培养物中 发现它们可以分化为成熟的功能性脂肪细胞。目标1将集中在了解肥胖和代谢下正常和肥胖的设置。 在目标2中，重点将放在p16 Ink 4a/p19 Arf如何控制脂肪干细胞增殖和分化的分子基础上。在这些研究的结论中，我将扩大我们对脂肪干细胞数量如何在正常生理和肥胖下控制肥胖和代谢的理解，并可能发现代谢治疗的新靶点。