Small molecule PGC-1α1 protein stabilizers induce adipocyte Ucp1 expression and uncoupled mitochondrial respiration

The peroxisome proliferator-activated receptor-γ coactivator-1α1 (PGC-1α1) regulates genes involved in energy metabolism. Increasing adipose tissue energy expenditure through PGC-1α1 activation is potentially beneficial for systemic metabolism. Pharmacological PGC-1α1 activators could be valuable to...

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Published in:	Molecular metabolism (Germany) Vol. 9; pp. 28 - 42
Main Authors:	Pettersson-Klein, A.T., Izadi, M., Ferreira, D.M.S., Cervenka, I., Correia, J.C., Martinez-Redondo, V., Southern, M., Cameron, M., Kamenecka, T., Agudelo, L.Z., Porsmyr-Palmertz, M., Martens, U., Lundgren, B., Otrocka, M., Jenmalm-Jensen, A., Griffin, P.R., Ruas, J.L.
Format:	Journal Article
Language:	English
Published:	Germany Elsevier GmbH 01-03-2018 Elsevier
Subjects:	Adipocytes, Brown - drug effects Adipocytes, Brown - metabolism Animals Anti-Obesity Agents - chemistry Anti-Obesity Agents - pharmacology Brown adipose tissue Cell Respiration HEK293 Cells Humans Medicin och hälsovetenskap Mice Mitochondria - drug effects Mitochondria - metabolism Mitochondrial respiration Original Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism PGC-1a PGC-1alpha PGC-1alpha1 Protein Stability Protein stabilization Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Small molecule screening UCP1 Uncoupling Agents - chemistry Uncoupling Agents - pharmacology Uncoupling Protein 1 - genetics Uncoupling Protein 1 - metabolism MEF2 C/EBP HNF XBP1 UCP1 PTM Brown adipose tissue FCCP HPRT PGC Small molecule screening Protein stabilization HEK PGC-1alpha PGC-1alpha1 IDP NRF2 PPAR ROS Mitochondrial respiration PGC-1a SREBP1
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Summary:	The peroxisome proliferator-activated receptor-γ coactivator-1α1 (PGC-1α1) regulates genes involved in energy metabolism. Increasing adipose tissue energy expenditure through PGC-1α1 activation is potentially 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 properties. While, PGC-1α1 activation is regulated by several mechanisms, protein stabilization is a crucial limiting step due to its short half-life under unstimulated conditions. We designed a cell-based high-throughput screening system to identify PGC-1α1 protein stabilizers. Positive hits were tested for their ability to induce endogenous PGC-1α1 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. Among 7,040 compounds screened, we highlight four small molecules with high activity as measured by: PGC-1α1 protein accumulation, target gene expression, and uncoupled mitochondrial respiration in brown adipocytes. We identify compounds that induce PGC-1α1 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. [Display omitted] •A high-throughput platform to identify PGC-1α1 activators.•PGC-1α1 protein stabilizers work as activators in brown adipocytes.•Small molecule PGC-1α1 activators induce Ucp1 expression and cellular respiration.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally.
ISSN:	2212-8778 2212-8778
DOI:	10.1016/j.molmet.2018.01.017