P2Y<sub>13</sub> receptor deficiency favors adipose tissues lipolysis and worsens insulin resistance and fatty liver disease

Thibaut Duparc; Emilia Gore; Guillaume Combes; Diane Beuzelin; Julie Pires Da Silva; Vanessa Bouguetoch; Marie-Adeline Marquès; Ana Velazquez; Nathalie Viguerie; Geneviève Tavernier; Peter Arner; Mikael Rydén; Dominique Langin; Nabil Sioufi; Mohamad Nasser; Cendrine Cabou; Souad Najib; Laurent O. Martinez

doi:10.1172/jci.insight.175623

¹LiMitAging, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

²Lifesearch SAS, Toulouse, France

³MetaDiab, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

⁴Department of Medicine (H7), Karolinska Institute, Stockholm, Sweden

⁵IHU HealthAge, Inserm, Toulouse University Hospital, Toulouse, France

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¹LiMitAging, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

²Lifesearch SAS, Toulouse, France

³MetaDiab, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

⁴Department of Medicine (H7), Karolinska Institute, Stockholm, Sweden

⁵IHU HealthAge, Inserm, Toulouse University Hospital, Toulouse, France

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¹LiMitAging, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

²Lifesearch SAS, Toulouse, France

³MetaDiab, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

⁴Department of Medicine (H7), Karolinska Institute, Stockholm, Sweden

⁵IHU HealthAge, Inserm, Toulouse University Hospital, Toulouse, France

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¹LiMitAging, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

²Lifesearch SAS, Toulouse, France

³MetaDiab, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

⁴Department of Medicine (H7), Karolinska Institute, Stockholm, Sweden

⁵IHU HealthAge, Inserm, Toulouse University Hospital, Toulouse, France

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¹LiMitAging, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

²Lifesearch SAS, Toulouse, France

³MetaDiab, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

⁴Department of Medicine (H7), Karolinska Institute, Stockholm, Sweden

⁵IHU HealthAge, Inserm, Toulouse University Hospital, Toulouse, France

Find articles by Pires Da Silva, J. in: JCI | PubMed | Google Scholar

¹LiMitAging, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

²Lifesearch SAS, Toulouse, France

³MetaDiab, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

⁴Department of Medicine (H7), Karolinska Institute, Stockholm, Sweden

⁵IHU HealthAge, Inserm, Toulouse University Hospital, Toulouse, France

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¹LiMitAging, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

²Lifesearch SAS, Toulouse, France

³MetaDiab, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

⁴Department of Medicine (H7), Karolinska Institute, Stockholm, Sweden

⁵IHU HealthAge, Inserm, Toulouse University Hospital, Toulouse, France

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¹LiMitAging, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

²Lifesearch SAS, Toulouse, France

³MetaDiab, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

⁴Department of Medicine (H7), Karolinska Institute, Stockholm, Sweden

⁵IHU HealthAge, Inserm, Toulouse University Hospital, Toulouse, France

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¹LiMitAging, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

²Lifesearch SAS, Toulouse, France

³MetaDiab, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

⁴Department of Medicine (H7), Karolinska Institute, Stockholm, Sweden

⁵IHU HealthAge, Inserm, Toulouse University Hospital, Toulouse, France

Find articles by Viguerie, N. in: JCI | PubMed | Google Scholar |

¹LiMitAging, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

²Lifesearch SAS, Toulouse, France

³MetaDiab, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

⁴Department of Medicine (H7), Karolinska Institute, Stockholm, Sweden

⁵IHU HealthAge, Inserm, Toulouse University Hospital, Toulouse, France

Find articles by Tavernier, G. in: JCI | PubMed | Google Scholar |

¹LiMitAging, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

²Lifesearch SAS, Toulouse, France

³MetaDiab, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

⁴Department of Medicine (H7), Karolinska Institute, Stockholm, Sweden

⁵IHU HealthAge, Inserm, Toulouse University Hospital, Toulouse, France

Find articles by Arner, P. in: JCI | PubMed | Google Scholar

¹LiMitAging, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

²Lifesearch SAS, Toulouse, France

³MetaDiab, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

⁴Department of Medicine (H7), Karolinska Institute, Stockholm, Sweden

⁵IHU HealthAge, Inserm, Toulouse University Hospital, Toulouse, France

Find articles by Rydén, M. in: JCI | PubMed | Google Scholar |

¹LiMitAging, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

²Lifesearch SAS, Toulouse, France

³MetaDiab, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

⁴Department of Medicine (H7), Karolinska Institute, Stockholm, Sweden

⁵IHU HealthAge, Inserm, Toulouse University Hospital, Toulouse, France

Find articles by Langin, D. in: JCI | PubMed | Google Scholar |

¹LiMitAging, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

²Lifesearch SAS, Toulouse, France

³MetaDiab, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

⁴Department of Medicine (H7), Karolinska Institute, Stockholm, Sweden

⁵IHU HealthAge, Inserm, Toulouse University Hospital, Toulouse, France

Find articles by Sioufi, N. in: JCI | PubMed | Google Scholar

¹LiMitAging, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

²Lifesearch SAS, Toulouse, France

³MetaDiab, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

⁴Department of Medicine (H7), Karolinska Institute, Stockholm, Sweden

⁵IHU HealthAge, Inserm, Toulouse University Hospital, Toulouse, France

Find articles by Nasser, M. in: JCI | PubMed | Google Scholar

¹LiMitAging, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

²Lifesearch SAS, Toulouse, France

³MetaDiab, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

⁴Department of Medicine (H7), Karolinska Institute, Stockholm, Sweden

⁵IHU HealthAge, Inserm, Toulouse University Hospital, Toulouse, France

Find articles by Cabou, C. in: JCI | PubMed | Google Scholar |

¹LiMitAging, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

²Lifesearch SAS, Toulouse, France

³MetaDiab, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

⁴Department of Medicine (H7), Karolinska Institute, Stockholm, Sweden

⁵IHU HealthAge, Inserm, Toulouse University Hospital, Toulouse, France

Find articles by Najib, S. in: JCI | PubMed | Google Scholar

¹LiMitAging, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

²Lifesearch SAS, Toulouse, France

³MetaDiab, Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III (UPS) UMR1297, Toulouse, France

⁴Department of Medicine (H7), Karolinska Institute, Stockholm, Sweden

⁵IHU HealthAge, Inserm, Toulouse University Hospital, Toulouse, France

Find articles by Martinez, L. in: JCI | PubMed | Google Scholar |

JCI Insight. https://doi.org/10.1172/jci.insight.175623.
Copyright © 2024, Duparc et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published March 12, 2024 - Version history

Excessive lipolysis in white adipose tissues (WAT) leads to insulin resistance (IR) and ectopic fat accumulation in insulin-sensitive tissues. However, the impact of G_i-coupled receptors in restraining adipocyte lipolysis through inhibition of cAMP production remained poorly elucidated. Given that the G_i-coupled P2Y₁₃ receptor (P2Y₁₃-R) is a purinergic receptor expressed in WAT, we investigated its role in adipocyte lipolysis and its effect on IR and metabolic dysfunction-associated steatotic liver disease (MASLD). In human, mRNA expression of P2Y₁₃-R in WAT was negatively correlated to adipocytes lipolysis. In mice, adipocytes lacking P2Y₁₃-R displayed higher intracellular cAMP levels, indicating impaired G_i signaling. Consistently, the absence of P2Y₁₃-R was linked to increased lipolysis in adipocytes and WAT explants via hormone-sensitive lipase activation. Metabolic studies indicate that mice lacking P2Y₁₃-R show a greater susceptibility to diet-induced IR, systemic inflammation, and MASLD compared to their wild-type counterparts. Assays conducted on precision-cut liver slices exposed to WAT conditioned medium and on liver-specific P2Y₁₃-R knockdown mice suggested that P2Y₁₃-R activity in WAT protects from hepatic steatosis, independently of liver P2Y₁₃-R expression. In conclusion, our findings support the idea that targeting adipose P2Y₁₃-R activity may represent a pharmacological strategy to prevent obesity-associated disorders, including type 2 diabetes and MASLD.

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Version 2 (April 22, 2024): Electronic publication

P2Y₁₃ receptor deficiency favors adipose tissues lipolysis and worsens insulin resistance and fatty liver disease

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P2Y13 receptor deficiency favors adipose tissues lipolysis and worsens insulin resistance and fatty liver disease

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P2Y₁₃ receptor deficiency favors adipose tissues lipolysis and worsens insulin resistance and fatty liver disease