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- Pettersson-Klein, A. T., et al.
(author)
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Small molecule PGC-1 alpha 1 protein stabilizers induce adipocyte Ucp1 expression and uncoupled mitochondrial respiration
- 2018
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In: Molecular metabolism. - : Elsevier BV. - 2212-8778. ; 9, s. 28-42
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Journal article (peer-reviewed)abstract
- Objective: The peroxisome proliferator-activated receptor-gamma coactivator-1 alpha 1 (PGC-1 alpha 1) regulates genes involved in energy metabolism. Increasing adipose tissue energy expenditure through PGC-1 alpha 1 activation is potentially beneficial for systemic metabolism. Pharmacological PGC-1 alpha 1 activators could be valuable tools in the fight against obesity and metabolic disease. Finding such compounds has been challenging partly because PGC-1 alpha 1 is a transcriptional coactivator with no known ligand-binding properties. While, PGC-1 alpha 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 alpha 1 protein stabilizers. Positive hits were tested for their ability to induce endogenous PGC-1 alpha 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 alpha 1 protein accumulation, target gene expression, and uncoupled mitochondrial respiration in brown adipocytes.Conclusions: We identify compounds that induce PGC-1 alpha 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.
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