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- Title
ERRα Agonists Regulate PGC-1α/ERRα Pathways in Mouse Myotubes Resulting in Enhanced Oxygen Consumption Rates.
- Authors
Otto, Keith A.; Bramlett, Kelli S.; Gernert, Douglas L.; Reifel-Miller, Anne
- Abstract
Estrogen related receptor (ERR) a is a constitutively active orphan receptor with no known physiological ligand. PGC-1α has been shown to interact with ERRα to regulate fatty acid oxidation, oxidative phosphorylation, and mitochondrial biogenesis pathways. Identification of small molecules capable of stimulating ERRα could be used to treat metabolic diseases such as type 2 diabetes. We recently identified several selective ERRα agonists that regulate the interaction with PGC-1α resulting in alterations in PGC-1α/ERRα pathways in mouse myotubes. Compounds from a acylhydrazone scaffold were identified as selective ERRα agonists based on their ability to recruit PGC-1α to ERRα in a biochemical assay. In mouse C2C12 myotubes, the ERRα agonists increased mRNA expression of pdk4 mnf1 mnf2 mead and cact, genes know to be activated through PGC-1α/ERRα pathways. In addition, the oxygen consumption rate (OCR) was increased in mouse myotubes following incubation with the ERRα agonists, which is a direct indication of enhanced fatty acid oxidation. A standard ERRα inverse agonist, XCT790, was also evaluated in vitro and in the mouse myotubes. XCT790 inhibited PGC-1α recruitment to ERRα, decreased mRNA expression of PGC-1α/ERRα regulated genes, and decreased the OCR in mouse myotubes. These data demonstrate that ERRα agonists stimulate fatty acid oxidation in a mouse, muscle cell line, and thus could be beneficial for the treatment of insulin resistance and potentially type 2 diabetes.
- Subjects
ESTROGEN receptors; ESTROGEN agonists; OXYGEN; FATTY acids; INSULIN resistance; TYPE 2 diabetes; LABORATORY mice
- Publication
Diabetes, 2007, Vol 56, pA282
- ISSN
0012-1797
- Publication type
Article