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Cell Metab. 2018 Feb 6;27(2):378-392.e5. doi: 10.1016/j.cmet.2018.01.004.

Kynurenic Acid and Gpr35 Regulate Adipose Tissue Energy Homeostasis and Inflammation.

Author information

1
Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, 17177 Stockholm, Sweden.
2
Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden.
3
Science for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Department of Newborn Medicine, Karolinska University Hospital, Stockholm, Sweden.
4
Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
5
Department of Clinical Science, University of Bergen, Bergen, Norway; Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway.
6
Bevital A/S, Laboratoriebygget, 5021 Bergen, Norway.
7
Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: jorge.ruas@ki.se.

Abstract

The role of tryptophan-kynurenine metabolism in psychiatric disease is well established, but remains less explored in peripheral tissues. Exercise training activates kynurenine biotransformation in skeletal muscle, which protects from neuroinflammation and leads to peripheral kynurenic acid accumulation. Here we show that kynurenic acid increases energy utilization by activating G protein-coupled receptor Gpr35, which stimulates lipid metabolism, thermogenic, and anti-inflammatory gene expression in adipose tissue. This suppresses weight gain in animals fed a high-fat diet and improves glucose tolerance. Kynurenic acid and Gpr35 enhance Pgc-1α1 expression and cellular respiration, and increase the levels of Rgs14 in adipocytes, which leads to enhanced beta-adrenergic receptor signaling. Conversely, genetic deletion of Gpr35 causes progressive weight gain and glucose intolerance, and sensitizes to the effects of high-fat diets. Finally, exercise-induced adipose tissue browning is compromised in Gpr35 knockout animals. This work uncovers kynurenine metabolism as a pathway with therapeutic potential to control energy homeostasis.

KEYWORDS:

Gpr35; Rgs14; adipose tissue; beige fat; brown fat; energy expenditure; exercise; inflammation; kynurenic acid

PMID:
29414686
DOI:
10.1016/j.cmet.2018.01.004
[Indexed for MEDLINE]
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