期刊
CELL METABOLISM
卷 27, 期 2, 页码 378-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2018.01.004
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资金
- Karolinska Institutet
- Swedish Research Council
- Novo Nordisk Foundation
- Strategic Research Program in Diabetes at Karolinska Institutet
- Strategic Research Program in Regenerative Medicine at Karolinska Institutet
- Swedish Diabetes Association
- European Research Council [ERC-2013-AdG 338936-BetaImage, aCROBAT ERC-St 639382]
- Swedish Society for Medical Research
- Family Knut and Alice Wallenberg Foundation
- Skandia Insurance Company
- Diabetes and Wellness Foundation
- Bert von Kantzow Foundation
- Stichting af Jochnick Foundation
- Family Erling-Persson Foundation
- Marie Curie Career Integration Grant
- Wenner-Gren Foundations (Sweden) [CIG-294232]
- Swedish Society for Medical Research (SSMF)
- NNF Center for Basic Metabolic Research [Gerhart-Hines Group] Funding Source: researchfish
- Novo Nordisk Fonden [NNF16OC0020804, NNF17OC0026726, NNF12OC1016557] Funding Source: researchfish
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-1 alpha 1 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.
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