Renal tubule-specific Atgl deletion links kidney lipid metabolism to glucagon-like peptide 1 and insulin secretion independent of renal inflammation or lipotoxicity
Objective: Lipotoxic injury from renal lipid accumulation in obesity and type 2 diabetes (T2D) is implicated in associated kidney damage. However, models examining effects of renal ectopic lipid accumulation independent of obesity or T2D are lacking. We generated renal tubule-specific adipose trigly...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-03-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877824000188 |
| _version_ | 1827325503472664576 |
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| author | Maria F. Fernandes Juan J. Aristizabal-Henao Phillip M. Marvyn Iman M'Hiri Meghan A. Wiens Monica Hoang Manuel Sebastian Renato Nachbar Philippe St-Pierre Kalsha Diaguarachchige De Silva Geoffrey A. Wood Jamie W. Joseph Christine A. Doucette André Marette Ken D. Stark Robin E. Duncan |
| author_facet | Maria F. Fernandes Juan J. Aristizabal-Henao Phillip M. Marvyn Iman M'Hiri Meghan A. Wiens Monica Hoang Manuel Sebastian Renato Nachbar Philippe St-Pierre Kalsha Diaguarachchige De Silva Geoffrey A. Wood Jamie W. Joseph Christine A. Doucette André Marette Ken D. Stark Robin E. Duncan |
| author_sort | Maria F. Fernandes |
| collection | DOAJ |
| description | Objective: Lipotoxic injury from renal lipid accumulation in obesity and type 2 diabetes (T2D) is implicated in associated kidney damage. However, models examining effects of renal ectopic lipid accumulation independent of obesity or T2D are lacking. We generated renal tubule-specific adipose triglyceride lipase knockout (RT-SAKO) mice to determine if this targeted triacylglycerol (TAG) over-storage affects glycemic control and kidney health. Methods: Male and female RT-SAKO mice and their control littermates were tested for changes in glycemic control at 10–12 and 16–18 weeks of age. Markers of kidney health and blood lipid and hormone concentrations were analyzed. Kidney and blood lysophosphatidic acid (LPA) levels were measured, and a role for LPA in mediating impaired glycemic control was evaluated using the LPA receptor 1/3 inhibitor Ki-16425. Results: All groups remained insulin sensitive, but 16- to 18-week-old male RT-SAKO mice became glucose intolerant, without developing kidney inflammation or fibrosis. Rather, these mice displayed lower circulating insulin and glucagon-like peptide 1 (GLP-1) levels. Impaired first-phase glucose-stimulated insulin secretion was detected and restored by Exendin-4. Kidney and blood LPA levels were elevated in older male but not female RT-SAKO mice, associated with increased kidney diacylglycerol kinase epsilon. Inhibition of LPA-mediated signaling restored serum GLP-1 levels, first-phase insulin secretion, and glucose tolerance. Conclusions: TAG over-storage alone is insufficient to cause renal tubule lipotoxicity. This work is the first to show that endogenously derived LPA modulates GLP-1 levels in vivo, demonstrating a new mechanism of kidney-gut-pancreas crosstalk to regulate insulin secretion and glucose homeostasis. |
| first_indexed | 2024-03-07T14:29:12Z |
| format | Article |
| id | doaj.art-8c9b9df421da488caebe865e8aca19a9 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-03-07T14:29:12Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-8c9b9df421da488caebe865e8aca19a92024-03-06T05:26:39ZengElsevierMolecular Metabolism2212-87782024-03-0181101887Renal tubule-specific Atgl deletion links kidney lipid metabolism to glucagon-like peptide 1 and insulin secretion independent of renal inflammation or lipotoxicityMaria F. Fernandes0Juan J. Aristizabal-Henao1Phillip M. Marvyn2Iman M'Hiri3Meghan A. Wiens4Monica Hoang5Manuel Sebastian6Renato Nachbar7Philippe St-Pierre8Kalsha Diaguarachchige De Silva9Geoffrey A. Wood10Jamie W. Joseph11Christine A. Doucette12André Marette13Ken D. Stark14Robin E. Duncan15Department of Kinesiology and Health Sciences, University of Waterloo, Ontario, CanadaDepartment of Kinesiology and Health Sciences, University of Waterloo, Ontario, CanadaDepartment of Kinesiology and Health Sciences, University of Waterloo, Ontario, CanadaDepartment of Kinesiology and Health Sciences, University of Waterloo, Ontario, CanadaDepartment of Kinesiology and Health Sciences, University of Waterloo, Ontario, CanadaSchool of Pharmacy, University of Waterloo, Ontario, CanadaMax Rady College of Medicine, University of Manitoba, Manitoba, CanadaQuébec Heart and Lung Institute, Department of Medicine, Laval University, Québec, CanadaQuébec Heart and Lung Institute, Department of Medicine, Laval University, Québec, CanadaDepartment of Kinesiology and Health Sciences, University of Waterloo, Ontario, CanadaOntario Veterinary College, University of Guelph, Ontario, CanadaSchool of Pharmacy, University of Waterloo, Ontario, CanadaMax Rady College of Medicine, University of Manitoba, Manitoba, CanadaQuébec Heart and Lung Institute, Department of Medicine, Laval University, Québec, CanadaDepartment of Kinesiology and Health Sciences, University of Waterloo, Ontario, CanadaDepartment of Kinesiology and Health Sciences, University of Waterloo, Ontario, Canada; Corresponding author. Department of Kinesiology and Health Sciences, University of Waterloo, 200 University Ave W, Waterloo, ON, N2L 3G1, Canada.Objective: Lipotoxic injury from renal lipid accumulation in obesity and type 2 diabetes (T2D) is implicated in associated kidney damage. However, models examining effects of renal ectopic lipid accumulation independent of obesity or T2D are lacking. We generated renal tubule-specific adipose triglyceride lipase knockout (RT-SAKO) mice to determine if this targeted triacylglycerol (TAG) over-storage affects glycemic control and kidney health. Methods: Male and female RT-SAKO mice and their control littermates were tested for changes in glycemic control at 10–12 and 16–18 weeks of age. Markers of kidney health and blood lipid and hormone concentrations were analyzed. Kidney and blood lysophosphatidic acid (LPA) levels were measured, and a role for LPA in mediating impaired glycemic control was evaluated using the LPA receptor 1/3 inhibitor Ki-16425. Results: All groups remained insulin sensitive, but 16- to 18-week-old male RT-SAKO mice became glucose intolerant, without developing kidney inflammation or fibrosis. Rather, these mice displayed lower circulating insulin and glucagon-like peptide 1 (GLP-1) levels. Impaired first-phase glucose-stimulated insulin secretion was detected and restored by Exendin-4. Kidney and blood LPA levels were elevated in older male but not female RT-SAKO mice, associated with increased kidney diacylglycerol kinase epsilon. Inhibition of LPA-mediated signaling restored serum GLP-1 levels, first-phase insulin secretion, and glucose tolerance. Conclusions: TAG over-storage alone is insufficient to cause renal tubule lipotoxicity. This work is the first to show that endogenously derived LPA modulates GLP-1 levels in vivo, demonstrating a new mechanism of kidney-gut-pancreas crosstalk to regulate insulin secretion and glucose homeostasis.http://www.sciencedirect.com/science/article/pii/S2212877824000188Adipose triglyceride lipase (ATGL)Renal tubule cellsLysophosphatidic acidGlucagon-like peptide 1Glucose-stimulated insulin secretionDiabetes |
| spellingShingle | Maria F. Fernandes Juan J. Aristizabal-Henao Phillip M. Marvyn Iman M'Hiri Meghan A. Wiens Monica Hoang Manuel Sebastian Renato Nachbar Philippe St-Pierre Kalsha Diaguarachchige De Silva Geoffrey A. Wood Jamie W. Joseph Christine A. Doucette André Marette Ken D. Stark Robin E. Duncan Renal tubule-specific Atgl deletion links kidney lipid metabolism to glucagon-like peptide 1 and insulin secretion independent of renal inflammation or lipotoxicity Molecular Metabolism Adipose triglyceride lipase (ATGL) Renal tubule cells Lysophosphatidic acid Glucagon-like peptide 1 Glucose-stimulated insulin secretion Diabetes |
| title | Renal tubule-specific Atgl deletion links kidney lipid metabolism to glucagon-like peptide 1 and insulin secretion independent of renal inflammation or lipotoxicity |
| title_full | Renal tubule-specific Atgl deletion links kidney lipid metabolism to glucagon-like peptide 1 and insulin secretion independent of renal inflammation or lipotoxicity |
| title_fullStr | Renal tubule-specific Atgl deletion links kidney lipid metabolism to glucagon-like peptide 1 and insulin secretion independent of renal inflammation or lipotoxicity |
| title_full_unstemmed | Renal tubule-specific Atgl deletion links kidney lipid metabolism to glucagon-like peptide 1 and insulin secretion independent of renal inflammation or lipotoxicity |
| title_short | Renal tubule-specific Atgl deletion links kidney lipid metabolism to glucagon-like peptide 1 and insulin secretion independent of renal inflammation or lipotoxicity |
| title_sort | renal tubule specific atgl deletion links kidney lipid metabolism to glucagon like peptide 1 and insulin secretion independent of renal inflammation or lipotoxicity |
| topic | Adipose triglyceride lipase (ATGL) Renal tubule cells Lysophosphatidic acid Glucagon-like peptide 1 Glucose-stimulated insulin secretion Diabetes |
| url | http://www.sciencedirect.com/science/article/pii/S2212877824000188 |
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