The adipocyte specific transcription factor C/EBP alpha modulates human ob gene expression

被引:145
作者
Miller, SG
DEVos, P
GuerreMillo, M
Wong, K
Hermann, T
Staels, B
Briggs, MR
Auwerx, J
机构
[1] INST PASTEUR, INSERM, U325, F-59019 LILLE, FRANCE
[2] LIGAND PHARMACEUT INC, SAN DIEGO, CA 92121 USA
[3] INST BIOMED CORDELIERS, INSERM, U177, F-75006 PARIS, FRANCE
关键词
3T3-L1; preadipocytes and adipocytes; leptin; obesity; C/EBP;
D O I
10.1073/pnas.93.11.5507
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The ob gene product, leptin, apparently exclusively expressed in adipose tissue, is a signaling factor regulating body weight homeostasis and energy balance. ob gene expression is increased in obese rodents and regulated by feeding, insulin, and glucocorticoids, which supports the concept that ob gene expression is under hormonal control, which is expected for a key factor controlling body weight homeostasis and energy balance. In humans, ob mRNA expression is increased in gross obesity; however, the effects of the above factors on human ob expression are unknown. We describe the structure of the human ob gene and initial functional analysis of its promoter. The human ob gene's three exons cover approximate to 15 kb of genomic DNA. The entire coding region is contained in exons 2 and 3, which are separated by a 2-kb intron. The first small 30-bp untranslated exon is located >10.5 kb upstream of the initiator ATG codon. Three kilobases of DNA upstream of the transcription start site has been cloned and characterized. Only 217 bp of 5' sequence are required for basal adipose tissue-specific expression of the ob gene as well as enhanced expression by C/EBP alpha. Mutation of the single C/EBP alpha site in this region abolished inducibility of the promoter by C/EBP alpha in cotransfection assays. The gene structure will facilitate our analysis of ob mutations in human obesity, whereas knowledge of sequence elements and factors regulating ob gene expression should be of major importance in the prevention and treatment of obesity.
引用
收藏
页码:5507 / 5511
页数:5
相关论文
共 32 条
[1]   RECOMBINANT MOUSE OB PROTEIN - EVIDENCE FOR A PERIPHERAL SIGNAL LINKING ADIPOSITY AND CENTRAL NEURAL NETWORKS [J].
CAMPFIELD, LA ;
SMITH, FJ ;
GUISEZ, Y ;
DEVOS, R ;
BURN, P .
SCIENCE, 1995, 269 (5223) :546-549
[2]   REGULATED EXPRESSION OF 3 C/EBP ISOFORMS DURING ADIPOSE CONVERSION OF 3T3-L1 CELLS [J].
CAO, ZD ;
UMEK, RM ;
MCKNIGHT, SL .
GENES & DEVELOPMENT, 1991, 5 (09) :1538-1552
[3]   DIFFERENTIATION-INDUCED GENE-EXPRESSION IN 3T3-L1 PREADIPOCYTES - CCAAT ENHANCER BINDING-PROTEIN INTERACTS WITH AND ACTIVATES THE PROMOTERS OF 2 ADIPOCYTE-SPECIFIC GENES [J].
CHRISTY, RJ ;
YANG, VW ;
NTAMBI, JM ;
GEIMAN, DE ;
LANDSCHULZ, WH ;
FRIEDMAN, AD ;
NAKABEPPU, Y ;
KELLY, TJ ;
LANE, MD .
GENES & DEVELOPMENT, 1989, 3 (09) :1323-1335
[4]   NUMBER AND EVOLUTIONARY CONSERVATION OF ALPHA-TUBULIN AND BETA-TUBULIN AND CYTOPLASMIC BETA-ACTIN AND GAMMA-ACTIN GENES USING SPECIFIC CLONED CDNA PROBES [J].
CLEVELAND, DW ;
LOPATA, MA ;
MACDONALD, RJ ;
COWAN, NJ ;
RUTTER, WJ ;
KIRSCHNER, MW .
CELL, 1980, 20 (01) :95-105
[5]   OBESE AND DIABETES - 2 MUTANT-GENES CAUSING DIABETES-OBESITY SYNDROMES IN MICE [J].
COLEMAN, DL .
DIABETOLOGIA, 1978, 14 (03) :141-148
[6]  
DESVERGNE B, 1995, INDUCIBLE GENE EXPRE, V1, P142
[7]   INDUCTION OF OB GENE-EXPRESSION BY CORTICOSTEROIDS IS ACCOMPANIED BY BODY-WEIGHT LOSS AND REDUCED FOOD-INTAKE [J].
DEVOS, P ;
SALADIN, R ;
AUWERX, J ;
STAELS, B .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (27) :15958-15961
[8]   EXPRESSION OF OB MESSENGER-RNA AND ITS ENCODED PROTEIN IN RODENTS - IMPACT OF NUTRITION AND OBESITY [J].
FREDERICH, RC ;
LOLLMANN, B ;
HAMANN, A ;
NAPOLITANOROSEN, A ;
KAHN, BB ;
LOWELL, BB ;
FLIER, JS .
JOURNAL OF CLINICAL INVESTIGATION, 1995, 96 (03) :1658-1663
[9]   RECIPROCAL REGULATION OF ADIPOGENESIS BY MYC AND C/EBP-ALPHA [J].
FREYTAG, SO ;
GEDDES, TJ .
SCIENCE, 1992, 256 (5055) :379-382
[10]   ECTOPIC EXPRESSION OF THE CCAAT ENHANCER-BINDING PROTEIN-ALPHA PROMOTES THE ADIPOGENIC PROGRAM IN A VARIETY OF MOUSE FIBROBLASTIC CELLS [J].
FREYTAG, SO ;
PAIELLI, DL ;
GILBERT, JD .
GENES & DEVELOPMENT, 1994, 8 (14) :1654-1663