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.