The Role of C/EBP Genes in Adipocyte Differentiation

Abstract

uncoupling protein 1 CCAAT/enhancer-binding protein peroxisome proliferator-activated receptor phosphoenolpyruvate carboxykinase untranslated region upstream stimulatory factor insulin-responsive glucose transporter stearoyl-CoA desaturase I adipocyte lipid-binding protein dexamethasone methylisobutylxanthine fatty acid synthase lipoprotein lipase. One of the central problems facing higher animals is that cells require a continuous source of energy; however, it is impractical for organisms to meet this need by supplying a constant external source of calories. Two specialized tissues, brown and white adipose tissues, have evolved to meet the ongoing requirement for energy. White adipose tissue is able to store excess calories in the form of triacylglycerol. When cells require energy, such as during periods of fasting, these needs are largely met by fatty acids and glycerol formed from lipolysis of stored triacylglycerol. Brown adipose tissues use stored triacylglycerols to maintain body temperature. In particular, these cells convert energy from fatty acid metabolism to heat through the action of uncoupling protein 1 (UCP1),1 a mitochondrial protein found only in brown adipose tissue. Brown adipocytes contain less triacylglycerol and many more mitochondria than white adipocytes, resulting in their characteristic color. Humans and rats develop brown adipose tissue depots prenatally, and although these depots largely disappear in humans during childhood, some brown adipocytes likely remain interspersed in white adipose tissue throughout adulthood (1Garruti G. Ricquier D. Int. J. Obes. Relat. Metab. Disord. 1992; 16: 383-390PubMed Google Scholar). In view of the prevalence of obesity and obesity-related diseases, such as type II diabetes, it is important to understand how white and brown adipose tissues develop and how the activities of these tissues are regulated. Many factors are important for normal adipocyte development and function. In this minireview, we explore the role of one family of transcription factors, the CCAAT/enhancer-binding proteins (C/EBPs), in inducing preadipocyte differentiation and in modulating gene expression in the fully differentiated adipocyte. Analyses of cultured cell lines, and more recently, genetically altered mice have contributed significantly to our understanding of the way in which adipose-specific gene expression is directed by C/EBPs. These models have also elucidated some of the molecular mechanisms that regulate the expression of the C/EBP genes themselves. A variety of pluripotent and preadipocyte cell lines that have been developed from mouse embryonic tissue are useful for analysis of the adipocyte differentiation program (reviewed in Ref. 2Cornelius P. MacDougald O.A. Lane M.D. Annu. Rev. Nutr. 1994; 14: 99-129Crossref PubMed Scopus (592) Google Scholar). NIH 3T3 and C3H10T1/2 are two well characterized pluripotent cell lines, which are maintained as fibroblast-like cells, but which are capable of differentiation into multiple cell types (e.g. myocytes, adipocytes, or chondrocytes (2Cornelius P. MacDougald O.A. Lane M.D. Annu. Rev. Nutr. 1994; 14: 99-129Crossref PubMed Scopus (592) Google Scholar)). Two widely studied models, 3T3-L1 and 3T3-F442A, are already committed to the adipocyte lineage and are thus considered preadipocyte cell lines. Analyses of the differentiation program in these cell lines have shown that C/EBP and PPAR transcription factors work sequentially and cooperatively to stimulate the genetic events that result in differentiation. 2A detailed account of the important role of PPARγ in preadipocyte differentiation is outside the purview of this paper; however, it has been reviewed elsewhere (3Mandrup S. Lane M.D. J. Biol. Chem. 1997; 272: 5367-5370Abstract Full Text Full Text PDF PubMed Scopus (416) Google Scholar, 4Spiegelman B.M. Diabetes. 1998; 47: 507-514Crossref PubMed Scopus (1655) Google Scholar). The molecular events associated with preadipocyte differentiation have been most thoroughly studied in 3T3-L1 cells, because they differentiate in a synchronous manner in response to dexamethasone (DEX), methylisobutylxanthine (MIX), insulin, and fetal bovine serum (Fig. 1and see Ref. 5MacDougald O.A. Lane M.D. Annu. Rev. Biochem. 1995; 64: 345-373Crossref PubMed Scopus (947) Google Scholar). This differentiation scheme routinely results in >90% of preadipocytes accumulating triacylglycerol 5 days after differentiation is initiated. Differentiation of brown adipocytes in culture has been investigated using two systems: primary brown preadipocytes (6Yubero P. Manchado C. Cassard-Doulcier A.-M. Mampel T. Vinas O. Iglesias R. Giralt M. Villarroya F. Biochem. Biophys. Res. Commun. 1994; 198: 653-659Crossref PubMed Scopus (63) Google Scholar) and HIB-1B cells, which were derived from SV40-induced brown fat tumors (7Ross S.R. Choy L. Graves R.A. Fox N. Solevjeva V. Klaus S. Ricguier D. Spiegelman B.M. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 7561-7565Cr