Small molecule PGC-1?1 protein stabilizers induce adipocyte Ucp1 expression and uncoupled mitochondrial respiration.

ABSTRACT: OBJECTIVE:The peroxisome proliferator-activated receptor-? coactivator-1?1 (PGC-1?1) regulates genes involved in energy metabolism. Increasing adipose tissue energy expenditure through PGC-1?1 activation is potentially beneficial for systemic metabolism. Pharmacological PGC-1?1 activators could be valuable tools in the fight against obesity and metabolic disease. Finding such compounds has been challenging partly because PGC-1?1 is a transcriptional coactivator with no known ligand-binding properties. While, PGC-1?1 activation is regulated by several mechanisms, protein stabilization is a crucial limiting step due to its short half-life under unstimulated conditions. METHODS:We designed a cell-based high-throughput screening system to identify PGC-1?1 protein stabilizers. Positive hits were tested for their ability to induce endogenous PGC-1?1 protein accumulation and activate target gene expression in brown adipocytes. Select compounds were analyzed for their effects on global gene expression and cellular respiration in adipocytes. RESULTS:Among 7,040 compounds screened, we highlight four small molecules with high activity as measured by: PGC-1?1 protein accumulation, target gene expression, and uncoupled mitochondrial respiration in brown adipocytes. CONCLUSIONS:We identify compounds that induce PGC-1?1 protein accumulation and show that this increases uncoupled respiration in brown adipocytes. This screening platform establishes the foundation for a new class of therapeutics with potential use in obesity and associated disorders.

SUBMITTER: Pettersson-Klein AT 

PROVIDER: S-EPMC5870114 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature