Elsevier

Molecular Metabolism

Volume 8, February 2018, Pages 77-85
Molecular Metabolism

Original Article
Degradation of brown adipocyte purine nucleotides regulates uncoupling protein 1 activity

https://doi.org/10.1016/j.molmet.2017.12.010Get rights and content
Under a Creative Commons license
open access

Highlights

  • The total concentration of purine nucleotides is lower in brown than in white adipocytes.

  • Upon adrenergic activation, brown adipocytes decrease purine nucleotide concentrations and release degradation products.

  • Upon adrenergic activation, free purine nucleotide concentrations are further decreased by complexation to imported calcium.

  • Full thermogenic activity of uncoupling protein 1 requires remodeling of purine pool sizes.

  • Decreased free purine nucleotide concentrations contribute to full uncoupling protein 1 activity.

Abstract

Objective

Non-shivering thermogenesis in mammalian brown adipose tissue depends on thermogenic uncoupling protein 1. Its activity is triggered by free fatty acids while purine nucleotides mediate inhibition. During activation, it is thought that free fatty acids overcome purine-mediated inhibition. We measured the cellular concentration and the release of purine nucleotide metabolites to uncover a possible role of purine nucleotide degradation in uncoupling protein 1 activation.

Methods

With mass spectrometry, purine nucleotide metabolites were quantified in cellular homogenates and supernatants of cultured primary brown adipocytes. We also determined oxygen consumption in response to a β-adrenergic agonist.

Results

Upon adrenergic activation, brown adipocytes decreased the intracellular concentration of inhibitory nucleotides (ATP, ADP, GTP and GDP) and released the respective degradation products. At the same time, an increase in cellular calcium occurred. None of these phenomena occurred in white adipocytes or myotubes. The brown adipocyte expression of enzymes implicated in purine metabolic remodeling is altered upon cold exposure. Pharmacological and genetic interference of purine metabolism altered uncoupling protein 1 mediated uncoupled respiration.

Conclusion

Adrenergic stimulation of brown adipocytes lowers the intracellular concentration of purine nucleotides, thereby contributing to uncoupling protein 1 activation.

Keywords

Purine nucleotides
Uncoupling protein 1
Brown adipose tissue
Non-shivering thermogenesis
HILIC-MS/MS
Guanosine monophosphate reductase

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