Cell cycle regulators control adiposity and metabolism

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）的核心表现。脂肪组织控制着新陈代谢、胰岛素敏感性和温度调节，是创伤的缓冲，也是繁殖和饱腹感的调节者。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，脂肪量可以从体重的2-3%增加到体重的60-70%。脂肪组织由两种类型的细胞组成：储存脂肪的细胞，脂肪细胞和脂肪干细胞，脂肪干细胞可以分裂并有可能产生新的脂肪细胞。脂肪的积累有两种方式，一种是增加现有脂肪细胞中的脂质储存，另一种是扩大脂肪干细胞的数量，从而产生新的脂肪细胞。尽管肥胖和代谢综合征具有重要的健康意义，但我们对脂肪细胞数量和大小的决定、脂肪的发育和沉积（肥胖）以及这些参数与代谢功能障碍之间的联系的了解有限。我们的实验室最近发现并定位脂肪干细胞到脂肪组织的血管壁上，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的增殖，还有很多未知之处。为了研究这个问题和其他问题，在小鼠脂肪干细胞中，两个参与控制细胞增殖的重要基因p16Ink4a/p19Arf被特异性地删除。我的假设是增加脂肪干细胞的数量可以防止脂肪的形成，防止代谢失调，促进血管的形成。初步发现，删除p16Ink4a/p19Arf可增加脂肪干细胞的增殖，阻断脂肪细胞的形成，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，增加热量摄入促进脂肪细胞形成，重建脂肪库。从脂肪组织中分离p16Ink4a/p19Arf脂肪干细胞并进行细胞培养

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.