Study on the development and microenvironment of adipose tissue

Abstract

Part I. Identification and characterization of perilipin-positive proliferating pre-natal pre-adipocytes

The significance of the obesity epidemic necessitates a profound understanding of adipose development and expansion. Still, the definition and regulators of preadipocytes during de-velopment remain unclear. Herein, I highlight prenatal preadipocytes, residing in embryonic inguinal mesodermal tissue, as a tool for tracing adipogenesis. On the contrary to consensus that perilipin is expressed exclusively in differentiated adipocytes, I show that perilipin-positive prenatal preadipocytes proliferate as clusters along the vasculature. These prenatal preadipocytes have distinct expressions of stem cell markers and cellular lineage compared to adult preadipocytes. Moreover, the percentage of proliferating preadipocytes decreased ab-ruptly after birth, which was regulated by lipid influx and intracellular accumulation. Intri-guingly, through genetic manipulation of adipose-lineage and vasculature, I revealed that re-ciprocal interactions of both components were critical to proper adipose development. Taken together, our spatiotemporal studies during perinatal adipogenesis unraveled the characteristics of prenatal preadipocytes and the regulators affecting this dynamic process.

Part II. The roles of Ang1 in modulating adipose vasculature for adipose tissue expansion and remodeling

Adipose tissue is a highly vascularized organ. Recent studies demonstrated that obesity and related metabolic diseases are associated with vascular rarefaction and hypoxia, which leads to adipose inflammation, fibrosis and finally insulin resistance. With genetically modified mouse model modulating adipocyte-specific Ang1 expressions, I examined the roles of adi-pose vasculature in adipose tissue expansion and remodeling in response to high-fat diet challenge. Ang1 depletion reduced vascular density, showed lesser body weight gain, in-creased adipose inflammation, and led to metabolic dysfunction. In contrast, Ang1 overex-pression caused an increase in vascular density, leading to higher energy expenditure, lesser body weight gain, alleviated adipose hypoxia and inflammation, and metabolic improve-ments. These data indicate that modulated adipose vasculature exert critical roles by chang-ing hypoxic state in adipose tissue and affecting proper adipose function for metabolic ho-meostasis. This study sheds light to adipose Ang1 as a therapeutic potential to treat and prevent obesity and concomitant metabolic diseases.