Role of lipotoxicity in insulin resistance in subtotally nephrectomized mouse model

Chronic kidney disease (CKD) is associated with a large range of metabolic alterations among which insulin resistance and dyslipidemia. We hypothesize that a phenomenon of lipotoxicity and ectopic fat redistribution could be responsible for the insulin-resistance associated to CKD.C57BL/6 mice underwent a 5/6 nephrectomy and were compared to pair fed sham-operated mice. Insulin sensitivity was estimated through intra-peritoneal insulin (ipITT) and glucose tolerance (ipGTT) tests. Anthropometric (body weight, lean and fad pad mass) and metabolic parameters (glycemia, insulin, cholesterol, triglycerides) were measured. The phosphorylation of a key protein of insulin signaling pathway (protein kinase B, PKB/Akt) was studied by Western blot. The intra-muscular and intra-hepatic lipids were extracted using Chloroform-Methanol (2:1, v/v).The CKD mice exhibited a marked decrease in insulin sensitivity (−76%, p<0.01) and altered glucose tolerance (+24%, p<0.001). CKD mice exhibited a profile of insulin resistance. CKD mice exhibited a significant decrease in white adipose tissue accretion (−57%, p< 0.001) associated with increased muscle (+138%, p<0.05) and liver (+38%, P<0.05) lipid contents compared to sham-operated mice. The CKD mice presented a blunted insulin-induced Akt phosphorylation (−34%, p