Cell cycle regulators control adiposity and metabolism

细胞周期调节剂控制肥胖和新陈代谢

基本信息

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
项目类别：
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

项目摘要

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）是伴随的代谢综合征（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、胰岛素敏感性和温度调节，是对抗创伤的缓冲剂以及生殖和饱腹感的调节剂。全球肥胖患病率约为 15%，在美国，超过三分之二的人口被认为超重。由于热量过剩，脂肪量可以从总体重的 2-3% 增加到 60-70%。脂肪组织由两种细胞类型组成：储存脂质的细胞、脂肪细胞和可以分裂并有可能产生新脂肪细胞的脂肪干细胞。脂肪堆积以两种方式发生，一是增加现有脂肪细胞中的脂质储存，二是扩大脂肪干细胞群，进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决定、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仍然有限。我们的实验室最近发现脂肪干细胞并将其定位到脂肪组织的血管壁，从而充当微环境。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，在小鼠脂肪干细胞中专门删除了两个参与控制细胞增殖的重要基因，p16Ink4a/p19Arf。我假设增加脂肪干细胞数量将阻止脂肪形成，防止代谢失调并促进血管形成。初步研究结果显示，删除p16Ink4a/p19Arf会增加脂肪干细胞的增殖并阻止脂肪细胞的形成，从而导致脂肪含量降低；然而，这些小鼠表现出更好的胰岛素反应。相反，增加热量摄入会促进脂肪细胞的形成，从而重建脂肪库。从脂肪组织中分离 p16Ink4a/p19Arf 脂肪干细胞并放入细胞培养物中研究表明它们可以分化成成熟的功能性脂肪细胞。目标 1 将侧重于了解正常和肥胖环境下的肥胖和新陈代谢。目标 2 的重点将放在 p16Ink4a/p19Arf 如何控制脂肪干细胞增殖和分化的分子基础上。在这些研究结束时，我将扩大对正常生理和肥胖下脂肪干细胞数量如何控制肥胖和代谢的理解，并可能发现代谢治疗的新靶点。