Pref-1 Expressing Cells in Embryonic Adipose Development and Adipose Expansion in Adults
Obesity has become a worldwide epidemic, which has lead to a surge of interest in therapeutics to combat this condition. Characterized by an increase in adipose tissue mass, obesity is associated with increased risk of a variety of detrimental diseases such as cardiovascular diseases and diabetes. Despite major advances in uncovering the root of this problem, the underlying basic biological process of adipose tissue development, as well as its ability to expand, is not well understood. To this end, many transcription factors have been identified to play a role in promoting the differentiation of precursor cells, or preadipocytes, into fully mature and lipid-filled adipocytes. Attempts have been made to identify early precursors of adipocytes, however the origin of these adipocytes are not clear, and classic lineage tracing has not been performed extensively. The aim of this dissertation work was to identify adipose precursor cells using the preadipocyte marker, Pref-1, to investigate adipose precursors during embryogenesis and the expansion of adipose tissue in adults.
Chapter 1 reviews the adipose tissue organ and the role of Pref-1 in the regulation of adipocyte differentiation. In addition to being the main energy storage organ, adipose tissue is now well recognized as an endocrine organ of the body, and there are a variety of hormones and cytokines that are secreted by adipose tissue for many physiological functions including energy homeostasis. Pref-1 is expressed prior to differentiation into adipocytes, and becomes extinguished during differentiation. Pref-1 activates MEK/ERK to upregulate Sox9 which binds to the promoter and blocks expression of several important transcription factors that promote adipocyte differentiation.
Chapter 2 focuses on understanding white adipose tissue development and the identification and characterization of adipose precursors. To investigate adipose tissue development, I generated transgenic mouse models to label and ablate Pref-1 expressing cells in vivo, with the overall goal of uncovering details of adipose development during embryogenesis, and diet induced expansion of adipose tissue in adults. Pref-1 expressing cells represent adipose precursors that are mesenchymal in origin, and not endothelial cells or pericytes. These precursors are capable of division and are required for the expansion of the adipose tissue both during embryogenesis and during high fat diet induced obesity.
Chapter 3 focuses on another type of fat, brown adipose tissue (BAT), which, unlike white adipose tissue (WAT), burns fatty acids to perform non-shivering thermogenesis, and which was recently recognized to be present even in adult humans. Brown adipocytes have a different morphological and gene expression profile compared to white adipocytes, and can be identified by the unique expression of Uncoupling Protein-1 (UCP-1). UCP-1 acts to uncouple respiration from ATP production, resulting in heat production. I generated transgenic mice to label UCP-1 expressing cells in vivo, and to characterize these cells during cold induced or beta-adrenergic agonist induced expansion of BAT.
Chapter 4, concludes this body of work, and discusses future directions and remaining questions. Thus, these studies provide a better understanding of both white and brown adipose tissue development and characterization of the precursors responsible for adipose tissue development, and may offer future therapeutic targets for obesity.