Metformin alleviates sphingolipids dysregulation and improves obesity-related kidney disease in high-fat diet rats.

Obesity-related kidney disease (ORKD) has recently become a global health issue. Metformin is widely used in patients with type 2 diabetes with concomitant obesity, but its effects on ORKD are insufficiently understood. Accumulation of lipid species including sphingolipids has been reported to disrupt glomerular functions and drive progression of chronic kidney disease. The present study aimed to test the hypothesis that metformin could exert beneficial effects on ORKD, which may be associated with changes in renal lipidomics. Male Sprague-Dawley rats were divided into normal chow diet (ND) group or high-fat diet (HFD)-fed group. After 8 weeks, HFD-fed group was subdivided into metformin treatment (HFD-Met) group and control (HFD-C) group for an additional 8 weeks. Sphingolipids and phospholipids in renal cortex were measured by targeted lipidomics. Compared with ND group, HFD-C group developed histopathological features of ORKD. Metformin alleviated dyslipidemia, renal dysfunction, proteinuria, glomerular hypertrophy, podocyte damage, and renal fibrosis in HFD-fed rats. Renal sphingolipid analysis showed elevations of total ceramide, sphingosine, glucosylceramide, and galactosylceramide levels in HFD-C versus ND group. Specific species, such as ceramide d18:1/22:0, glucosylceramide d18:1/20:0, and galactosylceramide d18:1/16:0, which were positively associated with oxidative stress and insulin resistance, were reduced in HFD-Met versus HFD-C group. Renal phospholipid analysis showed increased levels of total phosphatidylcholine and lysophosphatidylcholine (LPC) in HFD-C rats versus ND rats. The ratio of saturated and monounsaturated LPCs to polyunsaturated LPCs was significantly reduced in HFD-Met rats. These results suggest that metformin alleviates sphingolipids dysregulation and improves ORKD in HFD-fed rats. SIGNIFICANCE STATEMENT: To date, this is the first report to explore effects of metformin on renal lipidomics. These findings reveal specific changes of renal lipid species, which are crucial for deeper understanding the underlying mechanisms of obesity-related kidney disease and effects of metformin on it. The associated signature sphingolipids and phospholipids in the study may have significant implications for developing targeted therapeutic strategies for obesity-related kidney disease.