Developmental Genes and the Origin of Fat

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DESCRIPTION (provided by applicant): The development of obesity depends in part on the balance between food intake and caloric utilization; but also on the balance between white adipose tissue, which is the primary site of energy storage, and brown adipose tissue, which is specialized for energy expenditure. In addition, white fat in different depots is heterogeneous with respect to its metabolic functions and impact on overall glucose and lipid homeostasis. Accumulation of excess visceral fat (central or "apple-shaped" obesity) is associated with insulin resistance and increased risk of type 2 diabetes and metabolic syndrome, whereas accumulation of subcutaneous adipose (peripheral or "pear-shaped" obesity) does not have such a risk. Both obesity and body fat distribution are heritable traits, however little is known about the developmental origins of adipose tissue; the control of brown versus white preadipocyte commitment; the control of relative amounts and functional differences between white fat cells in different depots; the heterogeneity and intrinsic differences of white fat cells in different depots; and the exact pathways and intermediates between the embryonic stem cell, the mesodermal/mesenchymal stem cell, the preadipocyte (or preadipocytes) and the mature fat cell. Recently, we and others have begun to gain some insights into early adipose development and patterning. By comparing gene expression patterns of adipocytes and stromovascular fraction containing preadipocytes from different depots, we identified a potentially important role for fundamental developmental and patterning genes in this process, including a number of Hox genes, Shox2, T-box-15 (Tbx15), Engrailed-1, Glypican-4, and others. For three of these genes (Tbx15, Glypican-4, and HoxA5), the level of expression in humans is highly correlated with the level of obesity, as measure by BMI, and the fat distribution as measured by waist- hip ratio (WHR), suggesting that developmental and patterning genes may play important roles in determination of adipose mass and distribution. In this grant, we propose to directly address the question of the origin of adipose tissue, as well as how developmental and patterning genes may play important roles in determining number and distribution of adipocytes in different fat depots, and the differential function of adipocytes in these depots, which leads to their differential association with diabetes and metabolic syndrome. The specific aims of this grant are to: Determine the role of developmental and patterning genes in adipocyte determination, differentiation and differential function of adipocytes from visceral and subcutaneous depots, through in vitro and in vivo over- and under-expression, including conditional knockout by homologous recombination in mice. In addition, we will identify the true developmental origins of adipocytes in different depots using lineage tracing experiments in vivo. Finally, we will determine how microRNA expression differs between adipocytes and preadipocytes from different depots, and how microRNAs might play a role in development, differentiation and function of adipocytes in different depots. PUBLIC HEALTH RELEVANCE: Accumulation of excess visceral fat (central or "apple-shaped" obesity) is associated with increased risk of type 2 diabetes and metabolic syndrome, whereas accumulation of subcutaneous adipose (peripheral or "pear- shaped" obesity) does not have such a risk. Recently, we have demonstrated that certainly fundamental developmental genes may play a role in this process. In this study we will determine the role of these genes in adipocyte determination and differential function of adipocytes from visceral and subcutaneous depots through studies over-expressing or knocking out there expression in preadipocytes in culture and in genetically engineered mice in vivo.