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Small molecule PGC-...
Small molecule PGC-1 alpha 1 protein stabilizers induce adipocyte Ucp1 expression and uncoupled mitochondrial respiration
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Pettersson-Klein, A. T. (author)
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Izadi, M. (author)
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Ferreira, D. M. S. (author)
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Cervenka, I. (author)
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Correia, J. C. (author)
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Martinez-Redondo, V. (author)
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Southern, M. (author)
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Cameron, M. (author)
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Kamenecka, T. (author)
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Agudelo, L. Z. (author)
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Porsmyr-Palmertz, M. (author)
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- Martens, Ulf (author)
- Stockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab)
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- Lundgren, Bo (author)
- Stockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab)
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Otrocka, M. (author)
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Jenmalm-Jensen, A. (author)
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Griffin, P. R. (author)
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Ruas, J. L. (author)
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(creator_code:org_t)
- Elsevier BV, 2018
- 2018
- English.
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In: Molecular metabolism. - : Elsevier BV. - 2212-8778. ; 9, s. 28-42
- Related links:
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https://doi.org/10.1...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Keyword
- Small molecule screening
- PGC-1a
- PGC-1alpha
- PGC-1alpha1
- Protein stabilization
- UCP1
- Mitochondrial respiration
- Brown adipose tissue
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Pettersson-Klein ...
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Izadi, M.
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Ferreira, D. M. ...
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Cervenka, I.
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Correia, J. C.
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Martinez-Redondo ...
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show more...
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Southern, M.
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Cameron, M.
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Kamenecka, T.
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Agudelo, L. Z.
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Porsmyr-Palmertz ...
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Martens, Ulf
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Lundgren, Bo
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Otrocka, M.
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Jenmalm-Jensen, ...
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Griffin, P. R.
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Ruas, J. L.
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Endocrinology an ...
- Articles in the publication
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Molecular metabo ...
- By the university
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Stockholm University