The ZEB1 transcription factor is a novel repressor of adiposity in female mice.
BACKGROUND
Four genome-wide association studies mapped an "obesity" gene to human chromosome 10p11-12. As the zinc finger E-box binding homeobox 1 (ZEB1) transcription factor is encoded by the TCF8 gene located in that region, and as it influences the differentiation of various mesodermal lineages, we hypothesized that ZEB1 might also modulate adiposity. The goal of these studies was to test that hypothesis in mice.


RESULTS
To ascertain whether fat accumulation affects ZEB1 expression, female C57BL/6 mice were fed a regular chow diet (RCD) ad libitum or a 25% calorie-restricted diet from 2.5 to 18.3 months of age. ZEB1 mRNA levels in parametrial fat were six to ten times higher in the obese mice. To determine directly whether ZEB1 affects adiposity, wild type (WT) mice and mice heterozygous for TCF8 (TCF8+/-) were fed an RCD or a high-fat diet (HFD) (60% calories from fat). By two months of age on an HFD and three months on an RCD, TCF8+/- mice were heavier than WT controls, which was attributed by Echo MRI to increased fat mass (at three months on an HFD: 0.517+/-0.081 total fat/lean mass versus 0.313+/-0.036; at three months on an RCD: 0.175+/-0.013 versus 0.124+/-0.012). No differences were observed in food uptake or physical activity, suggesting that the genotypes differ in some aspect of their metabolic activity. ZEB1 expression also increases during adipogenesis in cell culture.


CONCLUSIONS
These results show for the first time that the ZEB1 transcription factor regulates the accumulation of adipose tissue. Furthermore, they corroborate the genome-wide association studies that mapped an "obesity" gene at chromosome 10p11-12.
Saykally
Jessica N
JN
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, United States of America.
Dogan
Soner
S
Cleary
Margot P
MP
Sanders
Michel M
MM
D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D000273:Adipose Tissue / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D050154:Adiposity / Q000187:drug effects / Q000235:genetics*; D000483:Alleles; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009043:Motor Activity / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects / Q000235:genetics; D000071799:Zinc Finger E-box-Binding Homeobox 1
D004041:Dietary Fats; D005947:Glucose; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D000071799:Zinc Finger E-box-Binding Homeobox 1; C519422:ZEB1 protein, mouse