Twist-1 Is a PPARδ-Inducible, Negative-Feedback Regulator of PGC-1α in Brown Fat Metabolism
Open Access
- 1 April 2009
- journal article
- research article
- Published by Elsevier BV in Cell
- Vol. 137 (1), 73-86
- https://doi.org/10.1016/j.cell.2009.01.051
Abstract
Brown fat is specialized for energy expenditure, a process that is principally controlled by the transcriptional coactivator PGC-1α. Here, we describe a molecular network important for PGC-1α function and brown fat metabolism. We find that twist-1 is selectively expressed in adipose tissue, interacts with PGC-1α, and is recruited to the promoters of PGC-1α's target genes to suppress mitochondrial metabolism and uncoupling. In vivo, transgenic mice expressing twist-1 in the adipose tissue are prone to high-fat-diet-induced obesity, whereas twist-1 heterozygous knockout mice are obesity resistant. These phenotypes are attributed to their altered mitochondrial metabolism in the brown fat. Interestingly, the nuclear receptor PPARδ not only mediates the actions of PGC-1α but also regulates twist-1 expression, suggesting a negative-feedback regulatory mechanism. These findings reveal an unexpected physiological role for twist-1 in the maintenance of energy homeostasis and have important implications for understanding metabolic control and metabolic diseases.Keywords
This publication has 50 references indexed in Scilit:
- GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1αCell Metabolism, 2006
- Peroxisome-Proliferator-Activated Receptor δ Activates Fat Metabolism to Prevent ObesityCell, 2003
- PPARδ is a very low-density lipoprotein sensor in macrophagesProceedings of the National Academy of Sciences of the United States of America, 2003
- Twist Regulates Cytokine Gene Expression through a Negative Feedback Loop that Represses NF-κB ActivityCell, 2003
- SRC-1 and TIF2 Control Energy Balance between White and Brown Adipose TissuesCell, 2002
- Large-scale analysis of the human and mouse transcriptomesProceedings of the National Academy of Sciences of the United States of America, 2002
- Cooperative E‐box regulation of human GLI1 by TWIST and USFgenesis, 2002
- Effects of peroxisome proliferator-activated receptor δ on placentation, adiposity, and colorectal cancerProceedings of the National Academy of Sciences of the United States of America, 2001
- Role of Leptin in Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Expression1Endocrinology, 2000
- Activation of PPARγ Coactivator-1 Through Transcription Factor DockingScience, 1999