Acute treatment with chemical PPARGC1a1 activators in brown fat cells. Acute treatment with chemical PPARGC1a1 activators in brown fat cells

The peroxisome proliferator-activated receptor-coactivator-1α1 (PGC-1α1) regulates genes involved in energy metabolism. Increasing adipose tissue energy expenditure through PGC-1α1 activation has been suggested to be beneficial for systemic metabolism. Pharmacological PGC-1α1 activators could be valuable tools in the fight against obesity and metabolic disease. Finding such compounds has been challenging partly because PGC-1α1 is a transcriptional coactivator with no known ligand-binding activities. Importantly, PGC-1α1 activation is regulated by several mechanisms but protein stabilization is a limiting step as the protein has a short half-life under unstimulated conditions. We designed a cell-based high-throughput system to identify stabilizers of PGC-1α1 protein. Positive hits were tested for their ability to induce endogenous PGC-1α1 protein accumulation and activate target gene expression in brown adipocytes. Selected compounds were analyzed for their effects on global gene expression in brown adipocytes. Overall design: Fully differentiated brown fat cells (previously described Uldry M et al 2006 Cell Metab.; PMID16679291) were treated for 8h with 10μM of compound (AM73 or AM80) or DMSO (control), in triplicate. RNA was extracted and used for global gene expression analyzes.