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Regulatory pathways that control adaptive metabolic responses in adipose and skeletal muscle tissues
Organisms go through cycles of metabolic activity, driven by internal cues (circadian, circannual clocks) and physiologic/behavioral inputs (e.g. feeding/fasting, physical activity/rest). In addition, organisms face environmental challenges (physical, chemical or psychological stressors) that require continual adaptation of the pathways regulating metabolism. The goal of our research is to elucidate the regulatory and transcriptional mechanisms that integrate information and enable physiologic adaptations (particularly in response to changes in physical activity, environmental temperature, nutritional state), and that, when deregulated, contribute to metabolic disease. Our studies focus on the Estrogen-Related Receptors (ERRα, ERRβ, and ERRγ), which we use as an entry point to the study of the regulatory / transcriptional networks that are important for adaptation in adipose tissue and in skeletal muscle, in response to changes in environmental temperature, physical exercise and/or diet. In past studies, we have shown that ERRs, and in particular ERRα, co-ordinate gene expression programs that regulate mitochondrial biogenesis and oxidative capacity.
Our current studies build on this past work, using mouse models with genetically modified loci for ERRs (floxed alleles) and dissecting the unique and shared roles of ERRs in adipose tissue and in skeletal muscle. We are also identifying novel mechanisms that regulate ERR activity, as well as new important downstream effectors of ERRs, thereby expanding the network of regulators of mitochondrial oxidative function. Our studies identify and probe new avenues for therapeutic intervention in states where oxidative metabolism and tissue function are compromised, such as insulin resistance and type 2 diabetes, disease-associated muscle atrophies and age-related degenerative diseases.