Kidney outcomes are altered by preconception weight modulation in rodent mothers with obesity

Abstract

Abstract Obesity increases the risk of chronic kidney disease in the mother. We have previously demonstrated the benefits of preconception maternal weight loss on fertility and pregnancy outcomes in a mouse model of maternal obesity. In this study, we aimed to determine if preconception weight loss, either by diet modification or the glucose-like peptide 1 agonist liraglutide, improves maternal kidney outcomes in late gestation. C57BL/6 female mice were fed either a high-fat-diet (HFD) or a standard chow (control) diet for 8 weeks. To induce pre-pregnancy weight loss, HFD-fed dams were either switched to a chow diet pre-pregnancy (4 weeks before mating, HFD-C) or administered liraglutide (0.3mg/kg subcutaneous, for 4weeks) whilst continuing on HFD (HFD-L). Liraglutide was discontinued one week prior to mating. HFD-V mice continued on HFD, with saline injections. Finally, a group of HFD-fed dams were ‘diet switched’ to a chow diet after conception (i.e., post-conception, HFD-PC). Maternal body weight and glucose tolerance were measured at two time points: prior to pregnancy and during late gestation followed by blood, urine and kidney collection. Serum creatinine, urinary creatinine and albumin, and kidney tissue gene expression and protein were measured. In the preconception period, the HFD-L and HFD-C mothers had lower urine albumin: creatinine ratios (UACR) and fatty acid synthase (FAS) protein expression (both P < 0.005 vs HFD-V). At late gestation, the kidneys of HFD-V and HFD-PC dams had increased gene expression of insulin receptor and FAS (both P < 0.05) and higher UACR compared to controls (P < 0.01). In the HFD-PC group, the kidneys showed increased mRNA and protein expression of metabolic and oxidative stress markers (FAS, 8-OHdG vs control, P < 0.05, P < 0.0001 respectively). The preconception intervention groups with liraglutide, or diet change showed reduced renal oxidative stress markers (protein expression of 8-OHdG, P < 0.05 vs HFD), mRNA and protein expression of FAS (P < 0.05 vs HFD), protein expression of fibrosis markers (collagen IV, fibronectin vs HFD, P < 0.05), and UACR (P < 0.05 vs HFD). Preconception weight loss benefits maternal kidney health during pregnancy, superior to diet intervention once pregnancy is established. This study suggests that pre-pregnancy weight reduction is necessary to optimise kidney outcomes in maternal obesity.