The bioenergetic roles of PGC-1α1, kynurenines, and GPR35 in exercise and obesity
Author: Dadvar, Shamim
Date: 2021-12-02
Location: Eva & Georg Klein Lecture Hall, Biomedicum, Karolinska Institutet, Solna, Stockholm, Sweden
Time: 15.00
Department: Inst för fysiologi och farmakologi / Dept of Physiology and Pharmacology
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Thesis (7.176Mb)
Abstract
Obesity is a major cause of medical comorbidity with detrimental effects on health span. Fundamentally, obesity is a condition of disrupted energy metabolism, where energy intake chronically exceeds expenditure. Over time, this disruption causes a systemic low-grade inflammation and impairs energy homeostasis. Physical activity can counteract these effects by increasing energy expenditure and orchestrating a myriad of healthy molecular and cellular adaptations in skeletal muscle and other metabolic organs. Many adaptations to exericse are mediated by the transcriptional co-activator PGC-1a1.
The work presented in this thesis identifies novel roles of PGC-1a1 as a regulator of the kynurenine pathway of tryptophan degradation with important bioenergetic implications in obesity and exercise. In skeletal muscle, PGC-1a1 regulates the kynurenine pathway by increasing the levels of kynurenine aminotransferases. Kynurenine aminotransferases are enzymes that serve as an important gateway of the pathway, driving kynurenine metabolism towards the production of kynurenic acid while generating glutamate in the process. Here, we show that peripheral kynurenic acid signals through GPR35 in adipose tissue, and induces a transcriptional signature consistent with beige adipocytes and anti-inflammatory immune cells. This signaling axis sensitizes adipocytes to b-adrenergic signaling, increases systemic energy expenditure, and protects against high fat diet induced metabolic disruptions and weight gain. Conversely, we find that both whole-body and hematopoietic-specific genetic deletion of Gpr35 impairs energy homeostasis. Locally in skeletal muscle, we identify that kynurenine metabolism is an integral part of the malate aspartate shuttle through Kynurenine aminotransferase 4. Exercise, via PGC-1a1, allows trained skeletal muscle to use kynurenine as a substrate to increase bioenergetic efficiency by supporting glucose oxidation through restoring cytosolic NAD+ and anaplerotically feeding the TCA cycle via glutamate.
Importantly, we show that inhibition of the malate-aspartate shuttle and kynurenine aminotransferases with Carbidopa, a drug used in the treatment of Parkinson’s disease, mitigates exercise performance and adaptations. Collectively, the work presented in this thesis has culminated in the discovery of new bioenergetic roles of the kynurenine pathway of tryptophan degradation in adipose tissue and skeletal muscle with implications in obestiy and exercise adaptation.
The work presented in this thesis identifies novel roles of PGC-1a1 as a regulator of the kynurenine pathway of tryptophan degradation with important bioenergetic implications in obesity and exercise. In skeletal muscle, PGC-1a1 regulates the kynurenine pathway by increasing the levels of kynurenine aminotransferases. Kynurenine aminotransferases are enzymes that serve as an important gateway of the pathway, driving kynurenine metabolism towards the production of kynurenic acid while generating glutamate in the process. Here, we show that peripheral kynurenic acid signals through GPR35 in adipose tissue, and induces a transcriptional signature consistent with beige adipocytes and anti-inflammatory immune cells. This signaling axis sensitizes adipocytes to b-adrenergic signaling, increases systemic energy expenditure, and protects against high fat diet induced metabolic disruptions and weight gain. Conversely, we find that both whole-body and hematopoietic-specific genetic deletion of Gpr35 impairs energy homeostasis. Locally in skeletal muscle, we identify that kynurenine metabolism is an integral part of the malate aspartate shuttle through Kynurenine aminotransferase 4. Exercise, via PGC-1a1, allows trained skeletal muscle to use kynurenine as a substrate to increase bioenergetic efficiency by supporting glucose oxidation through restoring cytosolic NAD+ and anaplerotically feeding the TCA cycle via glutamate.
Importantly, we show that inhibition of the malate-aspartate shuttle and kynurenine aminotransferases with Carbidopa, a drug used in the treatment of Parkinson’s disease, mitigates exercise performance and adaptations. Collectively, the work presented in this thesis has culminated in the discovery of new bioenergetic roles of the kynurenine pathway of tryptophan degradation in adipose tissue and skeletal muscle with implications in obestiy and exercise adaptation.
List of papers:
I. 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. Kynurenic Acid and Gpr35 Regulate Adipose Tissue Energy Homeostasis and Inflammation. Cell Metab. 2018 Feb 6;27(2):378-392.e5.
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II. Agudelo, L.Z.*, Ferreira, D.M.S.*, DADVAR, S.*, Cervenka, I., Ketsher, L., Izadi, M., Zhengye, L., Handschin, C., Venckunas, T., Brazaitis, M., Kamandulis, S., Lanner, J.T., Ruas, J.L. Skeletal Muscle PGC-1a1 Reroutes Kynurenine Metabolism to Increase Energy Efficiency and Fatigue-Resistance. Nat Commun. 2019. Jun 24;10(1):2767. *These authors contributed equally.
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II. DADVAR, S., Ferrerira, D.M.S., Porsmyr-Palmertz, M., Cervenka, I., Monasterio, G., Diaz, O.E., Castillo, F., Emont, M., Rosen, E., Villablanca, E., Ruas, J.L. Loss of Immune Cell Gpr35 Induces Insulin Resistance. [Manuscript]
I. 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. Kynurenic Acid and Gpr35 Regulate Adipose Tissue Energy Homeostasis and Inflammation. Cell Metab. 2018 Feb 6;27(2):378-392.e5.
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II. Agudelo, L.Z.*, Ferreira, D.M.S.*, DADVAR, S.*, Cervenka, I., Ketsher, L., Izadi, M., Zhengye, L., Handschin, C., Venckunas, T., Brazaitis, M., Kamandulis, S., Lanner, J.T., Ruas, J.L. Skeletal Muscle PGC-1a1 Reroutes Kynurenine Metabolism to Increase Energy Efficiency and Fatigue-Resistance. Nat Commun. 2019. Jun 24;10(1):2767. *These authors contributed equally.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. DADVAR, S., Ferrerira, D.M.S., Porsmyr-Palmertz, M., Cervenka, I., Monasterio, G., Diaz, O.E., Castillo, F., Emont, M., Rosen, E., Villablanca, E., Ruas, J.L. Loss of Immune Cell Gpr35 Induces Insulin Resistance. [Manuscript]
Institution: Karolinska Institutet
Supervisor: L. Ruas, Jorge
Co-supervisor: Schulte, Gunnar
Issue date: 2021-11-09
Rights:
Publication year: 2021
ISBN: 978-91-8016-416-0
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