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. Epub 2018 Feb 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes, Brown / drug effects*
  • Adipocytes, Brown / metabolism
  • Animals
  • Anti-Obesity Agents / chemistry
  • Anti-Obesity Agents / pharmacology*
  • Cell Respiration
  • HEK293 Cells
  • Humans
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism*
  • Protein Stability
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Uncoupling Agents / chemistry
  • Uncoupling Agents / pharmacology*
  • Uncoupling Protein 1 / genetics
  • Uncoupling Protein 1 / metabolism*

Substances

  • Anti-Obesity Agents
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Small Molecule Libraries
  • Ucp1 protein, mouse
  • Uncoupling Agents
  • Uncoupling Protein 1