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 injuries from kidney fat accumulation in weight problems and diabetes type 2 (T2D) is implicated in connected kidney damage. However, models analyzing results of kidney ectopic fat accumulation separate from weight problems or T2D are missing. We generated kidney tubule-specific adipose triglyceride lipase knockout (RT-SAKO) rodents to find out if the targeted triacylglycerol (TAG) over-storage affects glycemic control and kidney health.
Methods: Men and women RT-SAKO rodents as well as their control littermates were tested for alterations in glycemic control at 10-12 and 16-18 days old. Markers of kidney health insurance and bloodstream fat and hormone concentrations were examined. Kidney and bloodstream lysophosphatidic acidity (LPA) levels were measured, along with a role for Ki16425 LPA in mediating impaired glycemic control was evaluated while using LPA receptor 1/3 inhibitor Ki-16425.
Results: All groups continued to be insulin sensitive, but 16- to 18-week-old male RT-SAKO rodents grew to become glucose intolerant, without developing kidney inflammation or fibrosis. Rather, these rodents 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 bloodstream LPA levels were elevated in older male although not female RT-SAKO rodents, connected with elevated 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 inadequate to result in kidney tubule lipotoxicity. The work is the first one to reveal that endogenously derived LPA modulates GLP-1 levels in vivo, demonstrating a brand new mechanism of kidney-gut-pancreas crosstalk to manage insulin secretion and glucose homeostasis.