TY - JOUR
T1 - The diabetes gene and wnt pathway effector TCF7L2 regulates adipocyte development and function
AU - Chen, Xi
AU - Ayala, Iriscilla
AU - Shannon, Chris
AU - Fourcaudot, Marcel
AU - Acharya, Nikhil K.
AU - Jenkinson, Christopher P.
AU - Heikkinen, Sami
AU - Norton, Luke
N1 - Funding Information:
Acknowledgments. The authors thank David H. Wasserman, Owen McGuinness, and Louise Lantier, at Vanderbilt Mouse Metabolic Phenotyping Center, and Syann Lee, at the Metabolic Core Unit at University of Texas Southwestern Medical Center in Dallas, for help in phenotyping. Funding. This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grant KO1-DK-098314 to L.N. and was partly supported by grants DK-059637 to the Vanderbilt Mouse Metabolic Phenotyping Center and DK-88761 to the Metabolic Core Unit at University of Texas Southwestern Medical Center in Dallas. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. X.C. performed experiments, analyzed data, and reviewed and edited the manuscript. I.A., C.S., M.F., N.K.A., and C.P.J. researched data and reviewed and edited the manuscript. S.H. performed computational analysis and reviewed and edited the manuscript. L.N. planned the studies, performed experiments, analyzed all raw data, and wrote the manuscript. L.N. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented as an oral presentation at the 76th Scientific Sessions of the American Diabetes Association, New Orleans, LA, 10–14 June 2016.
Publisher Copyright:
© 2018 by the American Diabetes Association.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - The gene encoding for transcription factor 7-like 2 (TCF7L2) is the strongest type 2 diabetes mellitus (T2DM) candidate gene discovered to date. The TCF7L2 protein is a key transcriptional effector of the Wnt/b-catenin signaling pathway, which is an important developmental pathway that negatively regulates adipogenesis. However, the precise role that TCF7L2 plays in the development and function of adipocytes remains largely unknown. Using a combination of in vitro approaches, we first show that TCF7L2 protein is increased during adipogenesis in 3T3-L1 cells and primary adipocyte stem cells and that TCF7L2 expression is required for the regulation of Wnt signaling during adipogenesis. Inactivation of TCF7L2 protein by removing the high-mobility group (HMG)-box DNA binding domain in mature adipocytes in vivo leads to whole-body glucose intolerance and hepatic insulin resistance. This phenotype is associated with increased subcutaneous adipose tissue mass, adipocyte hypertrophy, and inflammation. Finally, we demonstrate that TCF7L2 mRNA expression is downregulated in humans with impaired glucose tolerance and adipocyte insulin resistance, highlighting the translational potential of these findings. In summary, our data indicate that TCF7L2 has key roles in adipose tissue development and function that may reveal, at least in part, how TCF7L2 contributes to the pathophysiology of T2DM.
AB - The gene encoding for transcription factor 7-like 2 (TCF7L2) is the strongest type 2 diabetes mellitus (T2DM) candidate gene discovered to date. The TCF7L2 protein is a key transcriptional effector of the Wnt/b-catenin signaling pathway, which is an important developmental pathway that negatively regulates adipogenesis. However, the precise role that TCF7L2 plays in the development and function of adipocytes remains largely unknown. Using a combination of in vitro approaches, we first show that TCF7L2 protein is increased during adipogenesis in 3T3-L1 cells and primary adipocyte stem cells and that TCF7L2 expression is required for the regulation of Wnt signaling during adipogenesis. Inactivation of TCF7L2 protein by removing the high-mobility group (HMG)-box DNA binding domain in mature adipocytes in vivo leads to whole-body glucose intolerance and hepatic insulin resistance. This phenotype is associated with increased subcutaneous adipose tissue mass, adipocyte hypertrophy, and inflammation. Finally, we demonstrate that TCF7L2 mRNA expression is downregulated in humans with impaired glucose tolerance and adipocyte insulin resistance, highlighting the translational potential of these findings. In summary, our data indicate that TCF7L2 has key roles in adipose tissue development and function that may reveal, at least in part, how TCF7L2 contributes to the pathophysiology of T2DM.
UR - http://www.scopus.com/inward/record.url?scp=85044481864&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044481864&partnerID=8YFLogxK
U2 - 10.2337/db17-0318
DO - 10.2337/db17-0318
M3 - Article
C2 - 29317436
AN - SCOPUS:85044481864
VL - 67
SP - 554
EP - 568
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 4
ER -