Research ArticleHepatologyMetabolism Open Access | 10.1172/jci.insight.175623

Thibaut Duparc,1 Emilia Gore,1 Guillaume Combes,1,2 Diane Beuzelin,1,3 Julie Pires Da Silva,1 Vanessa Bouguetoch,1,2,3 Marie-Adeline Marquès,4 Ana Velazquez,1 Nathalie Viguerie,4 Geneviève Tavernier,4 Peter Arner,5 Mikael Rydén,5 Dominique Langin,2,4,6,7 Nabil Sioufi,2,3 Mohamad Nasser,1,2 Cendrine Cabou,1,2 Souad Najib,1,2 and Laurent O. Martinez1,2

1LiMitAging, Institute of Metabolic and Cardiovascular Diseases (I2MC), University of Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.

2Institut Hospitalo-Universitaire HealthAge, (IHU HealthAge), INSERM, Toulouse University Hospital, Toulouse, France.

3Lifesearch SAS, Toulouse, France.

4MetaDiab, I2MC, University of Toulouse, INSERM, UPS, UMR1297, Toulouse, France.

5Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

6Biochemistry Laboratory, Toulouse University Hospital, Toulouse, France.

7Institut Universitaire de France (IUF), Paris, France.

Address correspondence to: Laurent Martinez, INSERM, UMR 1297, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. Phone: 33.5.62.74.86.70; Email: Laurent.Martinez@inserm.fr.

Authorship note: CC and SN contributed equally to this work.

Find articles by Duparc, T. in: JCI | PubMed | Google Scholar

1LiMitAging, Institute of Metabolic and Cardiovascular Diseases (I2MC), University of Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.

2Institut Hospitalo-Universitaire HealthAge, (IHU HealthAge), INSERM, Toulouse University Hospital, Toulouse, France.

3Lifesearch SAS, Toulouse, France.

4MetaDiab, I2MC, University of Toulouse, INSERM, UPS, UMR1297, Toulouse, France.

5Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

6Biochemistry Laboratory, Toulouse University Hospital, Toulouse, France.

7Institut Universitaire de France (IUF), Paris, France.

Address correspondence to: Laurent Martinez, INSERM, UMR 1297, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. Phone: 33.5.62.74.86.70; Email: Laurent.Martinez@inserm.fr.

Authorship note: CC and SN contributed equally to this work.

Find articles by Gore, E. in: JCI | PubMed | Google Scholar

1LiMitAging, Institute of Metabolic and Cardiovascular Diseases (I2MC), University of Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.

2Institut Hospitalo-Universitaire HealthAge, (IHU HealthAge), INSERM, Toulouse University Hospital, Toulouse, France.

3Lifesearch SAS, Toulouse, France.

4MetaDiab, I2MC, University of Toulouse, INSERM, UPS, UMR1297, Toulouse, France.

5Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

6Biochemistry Laboratory, Toulouse University Hospital, Toulouse, France.

7Institut Universitaire de France (IUF), Paris, France.

Address correspondence to: Laurent Martinez, INSERM, UMR 1297, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. Phone: 33.5.62.74.86.70; Email: Laurent.Martinez@inserm.fr.

Authorship note: CC and SN contributed equally to this work.

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

1LiMitAging, Institute of Metabolic and Cardiovascular Diseases (I2MC), University of Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.

2Institut Hospitalo-Universitaire HealthAge, (IHU HealthAge), INSERM, Toulouse University Hospital, Toulouse, France.

3Lifesearch SAS, Toulouse, France.

4MetaDiab, I2MC, University of Toulouse, INSERM, UPS, UMR1297, Toulouse, France.

5Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

6Biochemistry Laboratory, Toulouse University Hospital, Toulouse, France.

7Institut Universitaire de France (IUF), Paris, France.

Address correspondence to: Laurent Martinez, INSERM, UMR 1297, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. Phone: 33.5.62.74.86.70; Email: Laurent.Martinez@inserm.fr.

Authorship note: CC and SN contributed equally to this work.

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

1LiMitAging, Institute of Metabolic and Cardiovascular Diseases (I2MC), University of Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.

2Institut Hospitalo-Universitaire HealthAge, (IHU HealthAge), INSERM, Toulouse University Hospital, Toulouse, France.

3Lifesearch SAS, Toulouse, France.

4MetaDiab, I2MC, University of Toulouse, INSERM, UPS, UMR1297, Toulouse, France.

5Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

6Biochemistry Laboratory, Toulouse University Hospital, Toulouse, France.

7Institut Universitaire de France (IUF), Paris, France.

Address correspondence to: Laurent Martinez, INSERM, UMR 1297, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. Phone: 33.5.62.74.86.70; Email: Laurent.Martinez@inserm.fr.

Authorship note: CC and SN contributed equally to this work.

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

1LiMitAging, Institute of Metabolic and Cardiovascular Diseases (I2MC), University of Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.

2Institut Hospitalo-Universitaire HealthAge, (IHU HealthAge), INSERM, Toulouse University Hospital, Toulouse, France.

3Lifesearch SAS, Toulouse, France.

4MetaDiab, I2MC, University of Toulouse, INSERM, UPS, UMR1297, Toulouse, France.

5Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

6Biochemistry Laboratory, Toulouse University Hospital, Toulouse, France.

7Institut Universitaire de France (IUF), Paris, France.

Address correspondence to: Laurent Martinez, INSERM, UMR 1297, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. Phone: 33.5.62.74.86.70; Email: Laurent.Martinez@inserm.fr.

Authorship note: CC and SN contributed equally to this work.

Find articles by Bouguetoch, V. in: JCI | PubMed | Google Scholar

1LiMitAging, Institute of Metabolic and Cardiovascular Diseases (I2MC), University of Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.

2Institut Hospitalo-Universitaire HealthAge, (IHU HealthAge), INSERM, Toulouse University Hospital, Toulouse, France.

3Lifesearch SAS, Toulouse, France.

4MetaDiab, I2MC, University of Toulouse, INSERM, UPS, UMR1297, Toulouse, France.

5Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

6Biochemistry Laboratory, Toulouse University Hospital, Toulouse, France.

7Institut Universitaire de France (IUF), Paris, France.

Address correspondence to: Laurent Martinez, INSERM, UMR 1297, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. Phone: 33.5.62.74.86.70; Email: Laurent.Martinez@inserm.fr.

Authorship note: CC and SN contributed equally to this work.

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

1LiMitAging, Institute of Metabolic and Cardiovascular Diseases (I2MC), University of Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.

2Institut Hospitalo-Universitaire HealthAge, (IHU HealthAge), INSERM, Toulouse University Hospital, Toulouse, France.

3Lifesearch SAS, Toulouse, France.

4MetaDiab, I2MC, University of Toulouse, INSERM, UPS, UMR1297, Toulouse, France.

5Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

6Biochemistry Laboratory, Toulouse University Hospital, Toulouse, France.

7Institut Universitaire de France (IUF), Paris, France.

Address correspondence to: Laurent Martinez, INSERM, UMR 1297, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. Phone: 33.5.62.74.86.70; Email: Laurent.Martinez@inserm.fr.

Authorship note: CC and SN contributed equally to this work.

Find articles by Velazquez, A. in: JCI | PubMed | Google Scholar

1LiMitAging, Institute of Metabolic and Cardiovascular Diseases (I2MC), University of Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.

2Institut Hospitalo-Universitaire HealthAge, (IHU HealthAge), INSERM, Toulouse University Hospital, Toulouse, France.

3Lifesearch SAS, Toulouse, France.

4MetaDiab, I2MC, University of Toulouse, INSERM, UPS, UMR1297, Toulouse, France.

5Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

6Biochemistry Laboratory, Toulouse University Hospital, Toulouse, France.

7Institut Universitaire de France (IUF), Paris, France.

Address correspondence to: Laurent Martinez, INSERM, UMR 1297, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. Phone: 33.5.62.74.86.70; Email: Laurent.Martinez@inserm.fr.

Authorship note: CC and SN contributed equally to this work.

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

1LiMitAging, Institute of Metabolic and Cardiovascular Diseases (I2MC), University of Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.

2Institut Hospitalo-Universitaire HealthAge, (IHU HealthAge), INSERM, Toulouse University Hospital, Toulouse, France.

3Lifesearch SAS, Toulouse, France.

4MetaDiab, I2MC, University of Toulouse, INSERM, UPS, UMR1297, Toulouse, France.

5Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

6Biochemistry Laboratory, Toulouse University Hospital, Toulouse, France.

7Institut Universitaire de France (IUF), Paris, France.

Address correspondence to: Laurent Martinez, INSERM, UMR 1297, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. Phone: 33.5.62.74.86.70; Email: Laurent.Martinez@inserm.fr.

Authorship note: CC and SN contributed equally to this work.

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

1LiMitAging, Institute of Metabolic and Cardiovascular Diseases (I2MC), University of Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.

2Institut Hospitalo-Universitaire HealthAge, (IHU HealthAge), INSERM, Toulouse University Hospital, Toulouse, France.

3Lifesearch SAS, Toulouse, France.

4MetaDiab, I2MC, University of Toulouse, INSERM, UPS, UMR1297, Toulouse, France.

5Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

6Biochemistry Laboratory, Toulouse University Hospital, Toulouse, France.

7Institut Universitaire de France (IUF), Paris, France.

Address correspondence to: Laurent Martinez, INSERM, UMR 1297, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. Phone: 33.5.62.74.86.70; Email: Laurent.Martinez@inserm.fr.

Authorship note: CC and SN contributed equally to this work.

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

1LiMitAging, Institute of Metabolic and Cardiovascular Diseases (I2MC), University of Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.

2Institut Hospitalo-Universitaire HealthAge, (IHU HealthAge), INSERM, Toulouse University Hospital, Toulouse, France.

3Lifesearch SAS, Toulouse, France.

4MetaDiab, I2MC, University of Toulouse, INSERM, UPS, UMR1297, Toulouse, France.

5Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

6Biochemistry Laboratory, Toulouse University Hospital, Toulouse, France.

7Institut Universitaire de France (IUF), Paris, France.

Address correspondence to: Laurent Martinez, INSERM, UMR 1297, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. Phone: 33.5.62.74.86.70; Email: Laurent.Martinez@inserm.fr.

Authorship note: CC and SN contributed equally to this work.

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

1LiMitAging, Institute of Metabolic and Cardiovascular Diseases (I2MC), University of Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.

2Institut Hospitalo-Universitaire HealthAge, (IHU HealthAge), INSERM, Toulouse University Hospital, Toulouse, France.

3Lifesearch SAS, Toulouse, France.

4MetaDiab, I2MC, University of Toulouse, INSERM, UPS, UMR1297, Toulouse, France.

5Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

6Biochemistry Laboratory, Toulouse University Hospital, Toulouse, France.

7Institut Universitaire de France (IUF), Paris, France.

Address correspondence to: Laurent Martinez, INSERM, UMR 1297, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. Phone: 33.5.62.74.86.70; Email: Laurent.Martinez@inserm.fr.

Authorship note: CC and SN contributed equally to this work.

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

1LiMitAging, Institute of Metabolic and Cardiovascular Diseases (I2MC), University of Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.

2Institut Hospitalo-Universitaire HealthAge, (IHU HealthAge), INSERM, Toulouse University Hospital, Toulouse, France.

3Lifesearch SAS, Toulouse, France.

4MetaDiab, I2MC, University of Toulouse, INSERM, UPS, UMR1297, Toulouse, France.

5Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

6Biochemistry Laboratory, Toulouse University Hospital, Toulouse, France.

7Institut Universitaire de France (IUF), Paris, France.

Address correspondence to: Laurent Martinez, INSERM, UMR 1297, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. Phone: 33.5.62.74.86.70; Email: Laurent.Martinez@inserm.fr.

Authorship note: CC and SN contributed equally to this work.

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

1LiMitAging, Institute of Metabolic and Cardiovascular Diseases (I2MC), University of Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.

2Institut Hospitalo-Universitaire HealthAge, (IHU HealthAge), INSERM, Toulouse University Hospital, Toulouse, France.

3Lifesearch SAS, Toulouse, France.

4MetaDiab, I2MC, University of Toulouse, INSERM, UPS, UMR1297, Toulouse, France.

5Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

6Biochemistry Laboratory, Toulouse University Hospital, Toulouse, France.

7Institut Universitaire de France (IUF), Paris, France.

Address correspondence to: Laurent Martinez, INSERM, UMR 1297, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. Phone: 33.5.62.74.86.70; Email: Laurent.Martinez@inserm.fr.

Authorship note: CC and SN contributed equally to this work.

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

1LiMitAging, Institute of Metabolic and Cardiovascular Diseases (I2MC), University of Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.

2Institut Hospitalo-Universitaire HealthAge, (IHU HealthAge), INSERM, Toulouse University Hospital, Toulouse, France.

3Lifesearch SAS, Toulouse, France.

4MetaDiab, I2MC, University of Toulouse, INSERM, UPS, UMR1297, Toulouse, France.

5Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

6Biochemistry Laboratory, Toulouse University Hospital, Toulouse, France.

7Institut Universitaire de France (IUF), Paris, France.

Address correspondence to: Laurent Martinez, INSERM, UMR 1297, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. Phone: 33.5.62.74.86.70; Email: Laurent.Martinez@inserm.fr.

Authorship note: CC and SN contributed equally to this work.

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

1LiMitAging, Institute of Metabolic and Cardiovascular Diseases (I2MC), University of Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.

2Institut Hospitalo-Universitaire HealthAge, (IHU HealthAge), INSERM, Toulouse University Hospital, Toulouse, France.

3Lifesearch SAS, Toulouse, France.

4MetaDiab, I2MC, University of Toulouse, INSERM, UPS, UMR1297, Toulouse, France.

5Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

6Biochemistry Laboratory, Toulouse University Hospital, Toulouse, France.

7Institut Universitaire de France (IUF), Paris, France.

Address correspondence to: Laurent Martinez, INSERM, UMR 1297, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. Phone: 33.5.62.74.86.70; Email: Laurent.Martinez@inserm.fr.

Authorship note: CC and SN contributed equally to this work.

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

1LiMitAging, Institute of Metabolic and Cardiovascular Diseases (I2MC), University of Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.

2Institut Hospitalo-Universitaire HealthAge, (IHU HealthAge), INSERM, Toulouse University Hospital, Toulouse, France.

3Lifesearch SAS, Toulouse, France.

4MetaDiab, I2MC, University of Toulouse, INSERM, UPS, UMR1297, Toulouse, France.

5Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

6Biochemistry Laboratory, Toulouse University Hospital, Toulouse, France.

7Institut Universitaire de France (IUF), Paris, France.

Address correspondence to: Laurent Martinez, INSERM, UMR 1297, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. Phone: 33.5.62.74.86.70; Email: Laurent.Martinez@inserm.fr.

Authorship note: CC and SN contributed equally to this work.

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

Authorship note: CC and SN contributed equally to this work.

Published March 12, 2024 - More info

Published in Volume 9, Issue 8 on April 22, 2024
JCI Insight. 2024;9(8):e175623. https://doi.org/10.1172/jci.insight.175623.
© 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
Received: September 14, 2023; Accepted: March 5, 2024 View PDF Abstract

Excessive lipolysis in white adipose tissue (WAT) leads to insulin resistance (IR) and ectopic fat accumulation in insulin-sensitive tissues. However, the impact of Gi-coupled receptors in restraining adipocyte lipolysis through inhibition of cAMP production remained poorly elucidated. Given that the Gi-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 humans, mRNA expression of P2Y13-R in WAT was negatively correlated to adipocyte lipolysis. In mice, adipocytes lacking P2Y13-R displayed higher intracellular cAMP levels, indicating impaired Gi signaling. Consistently, the absence of P2Y13-R was linked to increased lipolysis in adipocytes and WAT explants via hormone-sensitive lipase activation. Metabolic studies indicated that mice lacking P2Y13-R showed a greater susceptibility to diet-induced IR, systemic inflammation, and MASLD compared with 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.

Graphical Abstract Introduction

White adipose tissue (WAT) functions as a metabolic and endocrine organ and is composed of a specialist cell type known as adipocytes. The primary role of adipocytes is to store excess nutrient energy as triglycerides (TGs). During fasting or physical exercise, lipolysis in adipocytes breaks down TGs into free fatty acids (FFAs) and glycerol, providing energy substrates to other tissues. Lipolysis involves 2 major lipases: adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (1). ATGL hydrolyzes TGs to diglycerides (DGs), while hormone-sensitive lipase converts DGs to monoglycerides (MGs), releasing FFAs at each step. The non-rate-limiting mono-acylglycerol lipase completes MG hydrolysis, releasing FFA and glycerol.

The major pathway leading to lipolysis is the activation of adenylate cyclase (AC) and subsequent cAMP production. The resulting increase in intracellular cAMP leads to protein kinase A–mediated (PKA-mediated) activation of hormone-sensitive lipase and subsequent release of FFA and glycerol. Lipolysis is mainly stimulated by catecholamines, which bind to G protein–coupled receptors (GPCRs) coupled to a Gαs protein, thereby increasing cAMP production. Conversely, insulin is the most potent antilipolytic molecule, acting by reducing cAMP levels through phosphodiesterase activation (1). Additionally, compounds such as short-chain fatty acids, β-hydroxybutyrate, and lactate negatively regulate AC activity and inhibit lipolysis through Gi-coupled receptors.

Dysfunctional white adipocyte lipolysis links to insulin resistance, obesity, and related disorders such as type 2 diabetes (T2D), dyslipidemia, and metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD) (2–4). Elevated unstimulated lipolysis during obesity leads to increased FFA levels (2, 3), peripheral insulin resistance, lipotoxicity, and ectopic fat accumulation, particularly in the liver (5–7). Therefore, identifying drug targets to improve adipocyte metabolic function is crucial for preventing obesity-related metabolic disorders.

Purinergic receptors (P2Y-Rs) are GPCRs that are activated by nucleotides (8). Recent studies have suggested a link between purinergic signaling in adipocytes and the regulation of lipolysis (9–11). Eight P2Y-Rs exist in mammals, coupled with different Gα proteins (8, 12). Among them, P2Y13-R (also named GPR-86) is activated by ADP and primarily coupled to Gαi protein (13). In humans, P2RY13 mRNA is detected in various tissues and cell types, with the highest expression found in the spleen, placenta, different brain regions, hepatocytes, bone marrow, lung, and subcutaneous adipocytes (14–17). In mice, P2Y13-R activity has been linked to neuronal protection against oxidative stress and microglial function (18–21), mesenchymal stem cells’ differentiation into osteoblasts (22, 23), alarmins’ release from airway epithelial cells in response to aeroallergens or respiratory viruses (24), and high-density lipoprotein (HDL) endocytosis by hepatocytes (25, 26). However, the contribution of P2Y13-R in adipocyte lipolysis and obesity-related metabolic disorders remains underresearched.

To address this issue, we determined the impact of P2Y13-R deficiency in mice on adipose tissue lipolysis and whole-body lipid and glucose homeostasis. We show that the absence of P2Y13-R results in enhanced adipocyte lipolysis and aggravates diet-induced insulin resistance and hepatic steatosis and fibrosis. We also examined whether P2Y13-R’s antilipolytic function affects ectopic fat accumulation in the liver. Our findings suggest that targeting P2Y13-R could be a potentially effective approach in treating metabolic dysfunction associated with obesity.

Results

The activity of P2Y13-R in white adipocytes has a negative regulatory effect on lipolysis. In humans, linear regression analysis showed a negative correlation between subcutaneous adipose tissue P2RY13 mRNA expression and lipolytic activity in adipocytes from the same fat sample (r = –0.36, P = 0.007, Figure 1). This suggests that human P2Y13-R might play a role in regulating adipocyte lipolysis.

Figure 1

Relationships between P2RY13 gene expression and lipolysis measures in human subcutaneous WAT samples. The scatterplot represents simple linear regression analysis, and the results are expressed as r (correlation coefficient) tested by Pearson correlation coefficient analysis (n = 56). WAT, white adipose tissue.

In mice, quantitative analysis of gene expression in major metabolically active tissues and organs revealed high relative mRNA expression of P2ry13 in the cortex, followed by epididymal WAT (eWAT) and liver, and equally in inguinal WAT (iWAT; equivalent to subcutaneous WAT), jejunum, and heart, while being barely detectable in the quadriceps and kidney (Figure 2A). Similar results were obtained when considering the cycle threshold (Ct) values, except in the jejunum, where the expression of P2ry13 was as low as in the quadriceps and the kidney (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.175623DS1). P2ry13 expression was more than double in inguinal and epididymal adipocytes compared with the stromal vascular fraction (SVF), and the adipocyte expression of the 2 other genes coding for ADP receptors, P2ry1 and P2ry12, was much lower than that of P2ry13 (Figure 2B).

Figure 2

P2ry13 gene expression and P2Y13-R activity in mouse primary adipocytes. (A) Relative mRNA expression levels of P2ry13 in mouse tissue (n = 5 mice). (B) Relative mRNA expression levels of ADP purinergic receptors (P2ry1, P2ry12, and P2ry13) in primary adipocytes and SVF from iWAT and eWAT (n = 3 mice). (C) cAMP level in primary inguinal or epididymal adipocytes isolated from WT (control) and P2Y13-R–KO mice (n = 3 mice per group). Open blue and red circles represent WT and P2Y13-R–KO mice, respectively. mRNA expression data were normalized relative to the expression of Rps29. All data are expressed as mean ± SEM. *P < 0.05, **P < 0.01 (C, 2-tailed unpaired Student’s t test was used for genotype comparison). All results were obtained from 24-month-old mice fed a chow diet. eWAT, epididymal white adipose tissue; iWAT, inguinal white adipose tissue; KO, knockout; Rps29, ribosomal protein S29; SVF, stromal vascular fraction; WT, wild-type.

We next examined P2Y13-R activity in mouse primary adipocytes by measuring the level of intracellular cAMP. We found that cAMP production triggered by forskolin (FK), a direct AC activator, was significantly higher in both inguinal and epididymal adipocytes isolated from P2Y13-R–KO mice compared with those isolated from WT littermates (Figure 2C). This finding verifies that signaling through P2Y13-R in adipocytes involves coupling to Gi protein to inhibit AC.

In adipocytes, β-adrenergic receptors (β-ARs) trigger a lipolytic response mediated by the GαS protein, which leads to AC activation, cAMP production, and subsequent activation of hormone-sensitive lipase through PKA (2). To investigate whether P2Y13-R signaling affects lipolytic activity in primary adipocytes, we measured the extracellular release of lipolysis by-products, glycerol and FFA (Figure 3). The dose-dependent increase in lipolytic activity stimulated by CL316,243, a β3-AR agonist, was significantly higher in inguinal and epididymal adipocytes lacking P2Y13-R compared with those expressing the receptor (Figure 3, A and B, and Figure 3, E and F, respectively), consistent with the cAMP data. Similar results were observed when using FSK or isoprenaline, a nonselective β-AR agonist, to activate lipolysis (Figure 3, C and D, and Figure 3, G and H, respectively). Regardless of P2Y13-R expression, pharmacological inhibition of hormone-sensitive lipase with BAY suppressed isoprenaline-induced lipolysis. Collectively, the data indicate that P2Y13-R signaling in adipocytes inhibits cAMP production by AC. This tonic inhibition mediated by P2Y13-R results in reduced stimulation of lipolysis induced by β-ARs.

Figure 3

Lack of P2Y13-R in mouse primary adipocytes increases lipolysis. (A) Glycerol and (B) FFA release in culture media of adipocytes isolated from iWAT under basal condition or following stimulation with CL316,243 10–10 to 10–6 M (n = 3 mice per group). (C) Glycerol and (D) FFA release in culture me dia of adipocytes isolated from iWAT under basal condition or following stimulation with 10–6 M forskolin or 10–6 M isoprenaline (n = 3 mice per group). (E) Glycerol and (F) FFA release in culture media of adipocytes isolated from eWAT under basal condition or following stimulation with CL316,243 10–10 to 10–6 M (n = 3 mice per group). (G) Glycerol and (H) FFA release in culture media of adipocytes isolated from eWAT under basal condition or following stimulation with 10–6 M forskolin or 10–6 M isoprenaline (n = 3 mice per group). The experiments included a group treated with BAY 59-9435 (BAY), a potent and selective pharmacological inhibitor of hormone-sensitive lipase (n = 3 mice per group). Open blue and red circles represent WT and P2Y13-R–KO mice, respectively. All data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 (A–H, 2-way ANOVA followed by Bonferroni’s post hoc test was used for genotype comparison). All results were obtained from 24-month-old mice fed a chow diet. eWAT, epididymal white adipose tissue; FFA, free fatty acids; FK, forskolin; iWAT, inguinal white adipose tissue; KO, knockout; WT, wild-type.

The absence of P2Y13-R increases lipolysis and inflammation in adipose tissue. To investigate the potential in vivo activity of P2Y13-R signaling in obesity-related metabolic disorders, we fed P2Y13-R–KO and control mice either a standard chow diet (CD) or a high-fat high-sucrose high-cholesterol (HFSC) diet for 16 weeks (27). An additional group was maintained on the HFSC diet for up to 40 weeks (Figure 4, study design).

Figure 4

Experimental study design of metabolic studies in P2Y13-R–KO and WT (control) mice. eWAT, epididymal white adipose tissue; OGTT, oral glucose tolerance test; HFSC, high-fat high-sucrose high-cholesterol; ITT, insulin tolerance test; iWAT, inguinal white adipose tissue; KO, knockout; WT, wild-type.

Compared with the CD group, HFSC feeding resulted in increased total body weight, as well as increased iWAT, eWAT, and liver weight, with no significant differences observed between P2Y13-R–KO and control mice, except for body and liver weights, which were higher in P2Y13-R–KO mice after being on the HFSC diet for up to 40 weeks (Supplemental Figure 2, A–D).

Lipolysis was assessed both in vivo at the 12-week HFSC feeding and ex vivo on adipose tissues explants at the end of the 40-week diet period. Consistent with the antilipolytic role of P2Y13-R signaling, in vivo β-AR–stimulated lipolysis, measured by plasma levels of glycerol and FFA after injection with CL316,243, was significantly increased in HFSC-fed mice lacking P2Y13-R (Figure 5A). Similarly, ex vivo assessment of lipolysis in WAT explants from mice fed HFSC revealed that the absence of P2Y13-R enhanced stimulated lipolytic activity in both iWAT and eWAT (Figure 5, B and C). Mechanistically, the absence of P2Y13-R in WAT resulted in heightened CL316,243-induced activation of hormone-sensitive lipase in WAT explants, evidenced by increased phosphorylation of hormone-sensitive lipase at Ser660 (Figure 5D). This correlated with a higher release of pro-inflammatory cytokines, including interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), but not tumor necrosis factor-α (TNF-α), from WAT explants lacking P2RY13-R (Figure 5E).

Figure 5

In vivo and ex vivo lipolytic activities of adipose tissues are increased in HFSC diet–fed P2Y13-R–KO mice. (A) Glycerol and FFA plasma levels from mice after being stimulated by CL316,243 (1 mg/kg body weight) for 15 minutes (n = 10 mice per group). (B) Glycerol and FFA release in supernatant of iWAT explants after being stimulated by 10–6 M CL316,243 (n = 9 mice per group). (C) Glycerol and FFA release in supernatant of eWAT explants after being stimulated by 10–6 M CL316,243 (n = 9 mice per group). (D) Western blot analysis and quantification of immunoblotting data of hormone-sensitive lipase phosphorylation at Ser660 (P-HSL) in iWAT and eWAT explants isolated from mice and stimulated with 10–6 M CL316,243 (n = 3 mice per group). (E) Concentrations of IL-6, MCP-1, and TNF-α in supernatant of iWAT and eWAT explants from HFSC diet–fed mice (n = 6 or 7 mice per group). Open blue and red circles represent WT and P2Y13-R–KO mice, respectively. All data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 (A–E, 2-tailed unpaired Student’s t test was used for genotype comparison). Results were obtained from mice fed HFSC for 12 weeks (A) or 40 weeks (B–E). eWAT, epididymal white adipose tissue; FFA, free fatty acids; HFSC, high-fat high-sucrose high-cholesterol; IL-6, interleukin-6; iWAT, inguinal white adipose tissue; KO, knockout; MCP-1, monocyte chemoattractant protein-1; TNF-α, tumor necrosis factor-α; WT, w