Renal tubule-specific Atgl deletion links kidney lipid metabolism to glucagon-like peptide 1 and insulin secretion independent of renal inflammation or lipotoxicity

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 lipa...

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Published in:	Molecular metabolism (Germany) Vol. 81; p. 101887
Main Authors:	Fernandes, Maria F., Aristizabal-Henao, Juan J., Marvyn, Phillip M., M'Hiri, Iman, Wiens, Meghan A., Hoang, Monica, Sebastian, Manuel, Nachbar, Renato, St-Pierre, Philippe, Diaguarachchige De Silva, Kalsha, Wood, Geoffrey A., Joseph, Jamie W., Doucette, Christine A., Marette, André, Stark, Ken D., Duncan, Robin E.
Format:	Journal Article
Language:	English
Published:	Germany Elsevier GmbH 01-03-2024 Elsevier
Subjects:	Adipose triglyceride lipase (ATGL) Animals Diabetes Diabetes Mellitus, Type 2 - metabolism Female Glucagon-like peptide 1 Glucagon-Like Peptide 1 - metabolism Glucose - metabolism Glucose-stimulated insulin secretion Inflammation - metabolism Insulin - metabolism Insulin Secretion Kidney - metabolism Lipid Metabolism Lipids Lysophosphatidic acid Male Mice Obesity - metabolism Original Renal tubule cells Glucose-stimulated insulin secretion Diabetes Renal tubule cells Lysophosphatidic acid Glucagon-like peptide 1 Adipose triglyceride lipase (ATGL)
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Summary:	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. 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. 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. 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. •Renal-tubule cell triacylglycerol accumulation does not alone cause lipotoxicity.•Renal adipose triglyceride lipase (ATGL) loss increases diacylglycerol kinase-ε.•Renal ATGL loss increases kidney and blood lysophosphatidic acid levels.•Endogenous lysophosphatidic acid (LPA) impairs GLP-1 secretion.•LPA can mediate kidney-gut-pancreas cross-talk to impair glucose homeostasis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2212-8778 2212-8778
DOI:	10.1016/j.molmet.2024.101887