脂肪細胞分化初期の分子機構及び新規分化制御因子の有する多彩な生理機能に関する研究

摘要

Obesity is a major risk factor for diabetes, hypertension, hyperlipidemia, and arteriosclerosis. Although the middle and late stages of adipocyte differentiation are well characterized, the earliest step in the differentiation process has remained largely unknown. We isolated102 genes expressed at the beginning of the differentiation of a mouse preadipo-cyte cell line, 3T3-L1 cells. Because approximately half of these genes were unknown, we named them factor for adipocyte differentiation (fad) genes, I first show how these genes regulate the early stage of adipocyte differentiation. We next generated fadl04-deficient mice, and demonstrated that fad104-deficient mice died due to cyanosis-associated lung dysplasia with atelectasis. We also found that fad104 positively regulated adipocyte differentiation and negatively regu-lated and that FAD24 contributed to the regulation of DNA replication by recruiting histone acetyltransferase binding to ORC1 (HBO1) to DNA replication origins. In vitro culture experiments revealed that fad24-null embryos developed normally to the morula stage, but acquired growth defects in subsequent stages. These results strongly suggest that fad24 is essential for pre-implantation in embryonic development, particularly for progression to the blastocyst stage. These findings together indicate that both fad104 and fad24 contribute not only to adipogenesis but also to other physiological events. The multi-functional roles of these genes are discussed.