Defining Adipocyte Progenitors and their Developmental Origins

描述（由申请人提供）：适当控制能量和营养稳态对生长、发育和预防代谢疾病至关重要。脂肪组织在能量平衡的调节中起着关键作用，作为控制能量储存、能量利用和食物摄入的代谢传感器。病理性脂肪组织分布和脂肪细胞功能障碍与肥胖和肥胖相关疾病如2型糖尿病、心血管疾病和癌症密切相关。肥胖症的日益流行和与治疗代谢疾病相关的成本上升增加了了解脂肪组织生物学各个方面的紧迫性，包括脂肪细胞如何形成。我的实验室主要研究脂肪细胞的祖细胞，或称“前脂肪细胞”。这是一种定义不明确的细胞类型，其调控机制尚不完全清楚。我资助的K01奖项中描述的研究发现，前脂肪细胞决定因子Zfp423在脂肪组织血管的内皮周围间充质细胞（周细胞）亚群中活跃表达。在这个R03提案中，我们将通过测试Zfp423+血管周围细胞代表一种独特的细胞类型，作为脂肪细胞谱系的发育前体，扩展K01资助的研究结果。在具体目标1中，我们将对表达Zfp423的分离的脂肪来源的周细胞进行功能和分子分析。在具体目标2中，我们将采用遗传谱系追踪来确定这些细胞在脂肪谱系中的确切作用。了解脂肪前体的生物学特性将有助于深入了解脂肪组织的发育起源和脂肪组织分布的生理调节。

DESCRIPTION (provided by applicant): Proper control of energy and nutrient homeostasis is crucial for growth, development, and the prevention of metabolic disease. Adipose tissue plays a critical role in the regulation of energy balance, functioning as a metabolic sensor that control energy storage, energy utilization, and food intake. Pathological adipose tissue distribution and adipocyte dysfunction are intimately linked to obesity and obesity-associated diseases such as type 2 diabetes, cardiovascular disease, and cancer. The growing epidemic of obesity and rising costs associated with treating metabolic disease has increased the urgency for understanding all aspects of adipose tissue biology, including how adipocytes are formed. My laboratory focuses on the adipocyte progenitor, or "preadipocyte". This is a cell type poorly defined, whose regulation is incompletely understood. The studies described in my funded K01 award led to the discovery that the preadipocyte determination factor, Zfp423, is actively expressed in a subset of peri-endothelial mesenchymal cells (pericytes) of adipose tissue blood vessels. In this R03 proposal, we will extend the findings from the K01-funded studies by testing the hypothesis that Zfp423+ perivascular cells represent a unique cell type, serving as developmental precursors in the adipocyte lineage. In Specific Aim 1 we will perform functional and molecular analyses of isolated adipose- derived pericytes expressing Zfp423. In Specific Aim 2 we will employ genetic lineage tracing to determine the precise role of these cells in the adipose lineage. Understanding the biology of adipose precursors will shed tremendous insight into the developmental origin of fat tissue and physiological regulation of adipose tissue distribution.