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

  • Mol Metab. 2018 Mar:9:28-42. doi: 10.1016/j.molmet.2018.01.017.
A T Pettersson-Klein  1 ,  M Izadi  1 ,  D M S Ferreira  1 ,  I Cervenka  1 ,  J C Correia  1 ,  V Martinez-Redondo  1 ,  M Southern  2 ,  M Cameron  2 ,  T Kamenecka  2 ,  L Z Agudelo  1 ,  M Porsmyr-Palmertz  1 ,  U Martens  3 ,  B Lundgren  3 ,  M Otrocka  4 ,  A Jenmalm-Jensen  4 ,  P R Griffin  2 ,  J L Ruas  5
Affiliations
  • 1. Molecular and Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
  • 2. Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA.
  • 3. Science for Life Laboratory, RNAi Cell Screening Facility, Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden.
  • 4. Chemical Biology Consortium Sweden, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • 5. Molecular and Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address: [email protected].
PMID: 29428596 DOI: 10.1016/j.molmet.2018.01.017
Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords
Brown adipose tissue; Mitochondrial respiration; PGC-1a; PGC-1alpha; PGC-1alpha1; Protein stabilization; Small molecule screening; UCP1.
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