Kynurenic Acid and Gpr35 Regulate Adipose Tissue Energy Homeostasis and Inflammation

Leandro Z Agudelo; Duarte M S Ferreira; Igor Cervenka; Galyna Bryzgalova; Shamim Dadvar; Paulo R Jannig; Amanda T Pettersson-Klein; Tadepally Lakshmikanth; Elahu G Sustarsic; Margareta Porsmyr-Palmertz; Jorge C Correia; Manizheh Izadi; Vicente Martínez-Redondo; Per M Ueland; Øivind Midttun; Zachary Gerhart-Hines; Petter Brodin; Teresa Pereira; Per-Olof Berggren; Jorge L Ruas

doi:10.1016/j.cmet.2018.01.004

Kynurenic Acid and Gpr35 Regulate Adipose Tissue Energy Homeostasis and Inflammation

Leandro Z Agudelo, Duarte M S Ferreira, Igor Cervenka, Galyna Bryzgalova, Shamim Dadvar, Paulo R Jannig, Amanda T Pettersson-Klein, Tadepally Lakshmikanth, Elahu G Sustarsic, Margareta Porsmyr-Palmertz, Jorge C Correia, Manizheh Izadi, Vicente Martínez-Redondo, Per M Ueland, Øivind Midttun, Zachary Gerhart-Hines, Petter Brodin, Teresa Pereira, Per-Olof Berggren, Jorge L Ruas

63 Citations (Scopus)

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. Kynurenine is a neurotoxic metabolite detoxified to kynurenic acid by exercised skeletal muscle. Now, Agudelo et al. show that the rise in circulating kynurenic acid activates Gpr35 in adipose tissue and increases energy expenditure. This improves the metabolic consequences of high-fat diet feeding in mice. Gpr35 deletion causes progressive weight gain.

Original language	English
Journal	Cell Metabolism
Volume	27
Issue number	2
Pages (from-to)	378-392.e5
ISSN	1550-4131
DOIs	https://doi.org/10.1016/j.cmet.2018.01.004
Publication status	Published - 6 Feb 2018

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Journal Article

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10.1016/j.cmet.2018.01.004

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Agudelo, L. Z., Ferreira, D. M. S., Cervenka, I., Bryzgalova, G., Dadvar, S., Jannig, P. R., Pettersson-Klein, A. T., Lakshmikanth, T., Sustarsic, E. G., Porsmyr-Palmertz, M., Correia, J. C., Izadi, M., Martínez-Redondo, V., Ueland, P. M., Midttun, Ø., Gerhart-Hines, Z., Brodin, P., Pereira, T., Berggren, P-O., & Ruas, J. L. (2018). Kynurenic Acid and Gpr35 Regulate Adipose Tissue Energy Homeostasis and Inflammation. Cell Metabolism, 27(2), 378-392.e5. https://doi.org/10.1016/j.cmet.2018.01.004

Agudelo, LZ, Ferreira, DMS, Cervenka, I, Bryzgalova, G, Dadvar, S, Jannig, PR, Pettersson-Klein, AT, Lakshmikanth, T, Sustarsic, EG, Porsmyr-Palmertz, M, Correia, JC, Izadi, M, Martínez-Redondo, V, Ueland, PM, Midttun, Ø, Gerhart-Hines, Z, Brodin, P, Pereira, T, Berggren, P-O & Ruas, JL 2018, 'Kynurenic Acid and Gpr35 Regulate Adipose Tissue Energy Homeostasis and Inflammation', Cell Metabolism, vol. 27, no. 2, pp. 378-392.e5. https://doi.org/10.1016/j.cmet.2018.01.004

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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. Kynurenine is a neurotoxic metabolite detoxified to kynurenic acid by exercised skeletal muscle. Now, Agudelo et al. show that the rise in circulating kynurenic acid activates Gpr35 in adipose tissue and increases energy expenditure. This improves the metabolic consequences of high-fat diet feeding in mice. Gpr35 deletion causes progressive weight gain.",

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T1 - Kynurenic Acid and Gpr35 Regulate Adipose Tissue Energy Homeostasis and Inflammation

AU - Agudelo, Leandro Z

AU - Ferreira, Duarte M S

AU - Cervenka, Igor

AU - Bryzgalova, Galyna

AU - Dadvar, Shamim

AU - Jannig, Paulo R

AU - Pettersson-Klein, Amanda T

AU - Lakshmikanth, Tadepally

AU - Sustarsic, Elahu G

AU - Porsmyr-Palmertz, Margareta

AU - Correia, Jorge C

AU - Izadi, Manizheh

AU - Martínez-Redondo, Vicente

AU - Ueland, Per M

AU - Midttun, Øivind

AU - Gerhart-Hines, Zachary

AU - Brodin, Petter

AU - Pereira, Teresa

AU - Berggren, Per-Olof

AU - Ruas, Jorge L

PY - 2018/2/6

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N2 - 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. Kynurenine is a neurotoxic metabolite detoxified to kynurenic acid by exercised skeletal muscle. Now, Agudelo et al. show that the rise in circulating kynurenic acid activates Gpr35 in adipose tissue and increases energy expenditure. This improves the metabolic consequences of high-fat diet feeding in mice. Gpr35 deletion causes progressive weight gain.

AB - 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. Kynurenine is a neurotoxic metabolite detoxified to kynurenic acid by exercised skeletal muscle. Now, Agudelo et al. show that the rise in circulating kynurenic acid activates Gpr35 in adipose tissue and increases energy expenditure. This improves the metabolic consequences of high-fat diet feeding in mice. Gpr35 deletion causes progressive weight gain.

KW - Journal Article

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DO - 10.1016/j.cmet.2018.01.004

M3 - Journal article

C2 - 29414686

SN - 1550-4131

VL - 27

SP - 378-392.e5

JO - Cell Metabolism

JF - Cell Metabolism

IS - 2

ER -

Kynurenic Acid and Gpr35 Regulate Adipose Tissue Energy Homeostasis and Inflammation

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