1. Academic Validation
  2. Induction of UCP1 and thermogenesis by a small molecule via AKAP1/PKA modulation

Induction of UCP1 and thermogenesis by a small molecule via AKAP1/PKA modulation

  • J Biol Chem. 2020 Oct 30;295(44):15054-15069. doi: 10.1074/jbc.RA120.013322.
Laurent Vergnes 1 Jason Y Lin 2 Graeme R Davies 3 Christopher D Church 3 Karen Reue 4
Affiliations

Affiliations

  • 1 Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California USA. Electronic address: lvergnes@ucla.edu.
  • 2 Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California USA.
  • 3 Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom.
  • 4 Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California USA; Department of Medicine, and Molecular Biology Institute, University of California-Los Angeles, Los Angeles, California USA.
Abstract

Strategies to increase energy expenditure are an attractive approach to reduce excess fat storage and body weight to improve metabolic health. In mammals, uncoupling protein-1 (UCP1) in brown and beige adipocytes uncouples fatty acid oxidation from ATP generation in mitochondria and promotes energy dissipation as heat. We set out to identify small molecules that enhance UCP1 levels and activity using a high-throughput screen of nearly 12,000 compounds in mouse brown adipocytes. We identified a family of compounds that increase Ucp1 expression and mitochondrial activity (including un-coupled respiration) in mouse brown adipocytes and human brown and white adipocytes. The mechanism of action may be through compound binding to A kinase anchoring protein (AKAP) 1, modulating its localization to mitochondria and its interaction with protein kinase A (PKA), a known node in the β-adrenergic signaling pathway. In mice, the hit compound increased body temperature, UCP1 protein levels, and thermogenic gene expression. Some of the compound effects on mitochondrial function were UCP1- or AKAP1-independent, suggesting compound effects on multiple nodes of energy regulation. Overall, our results highlight a role for AKAP1 in thermogenesis, uncoupled respiration, and regulation energy balance.

Keywords

A-kinase anchoring protein (AKAP); adipocyte; mitochondrial metabolism; protein kinase A (PKA); uncoupling protein.

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