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Small molecule PGC-1 alpha 1 protein stabilizers induce adipocyte Ucp1 expression and uncoupled mitochondrial respiration
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Number of Authors: 172018 (English)In: Molecular metabolism, ISSN 2212-8778, Vol. 9, p. 28-42Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2018. Vol. 9, p. 28-42
Keywords [en]
Small molecule screening, PGC-1a, PGC-1alpha, PGC-1alpha1, Protein stabilization, UCP1, Mitochondrial respiration, Brown adipose tissue
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:su:diva-155973DOI: 10.1016/j.molmet.2018.01.017ISI: 000429085000004PubMedID: 29428596OAI: oai:DiVA.org:su-155973DiVA, id: diva2:1206201
Available from: 2018-05-16 Created: 2018-05-16 Last updated: 2018-05-16Bibliographically approved

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Martens, UlfLundgren, Bo
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