Mother with Obesity Induced by High‐Fat Diet Impaired Autophagic Process and Induced Renal Lipid Accumulation in the Offspring

Abstract

IntroductionThe prevalence of obesity has increased worldwide, and more women are entering obese pregnancy. The offspring born to maternal obesity have an increased risk of obesity and insulin resistance in later life and could affect offspring’s kidney injury. The abnormal renal lipid metabolism leads to renal lipid accumulation and these suggested to be the importance mechanism to develop and progress of chronic kidney disease (CKD). Lipophagy is the autophagic process to hydrolyze lipid droplet into free fatty acid for preserve energy and prevent an excess of lipid accumulation. The defect in lipophagy regulation is associated with renal lipid accumulation and contribute to kidney injury. Therefore, we hypothesized that maternal obesity induced by high‐fat diet programmed to increase offspring renal lipid accumulation via dysregulation of autophagic process and abnormal renal lipid metabolism leading to offspring’s kidney injury.MethodsFemale C57BL/6 mice were divided into two groups, control lean mother and maternal obesity groups, fed with standard and high‐fat diet, respectively, for 8 weeks. After that, female mice were mated with normal male mice and were housed and maintain each diet throughout gestation and lactation periods. After weaning, male offspring from each mother were sacrificed and blood samples and kidney were collected to evaluate autophagic and lipid metabolism.ResultsMaternal obesity was significantly increased body weight, fat weight, blood glucose and HOMA‐IR in the offspring. The increasing in renal cholesterol and triglyceride together with upregulated FAS, Srebp1, ADFP and CD36 protein expression indicating increased renal lipid synthesis and renal lipid uptake were observed in the offspring born to maternal obesity. Meanwhile, maternal obesity affected to downregulated PPARα and CPT1A demonstrating decreased renal lipolysis leading to exacerbated renal lipid accumulation in the offspring born to maternal obesity. The significant increase in mTOR, decrease in AMPK, Beclin‐1, LC3B and LAMP2 protein expression were shown in offspring’s kidney born to maternal obesity. These represented the inhibition of autophagic process, impaired autophagosome formation along with aberrant lysosome formation.ConclusionMaternal obesity affected to program offspring obese‐insulin resistance and increased the risk of kidney injury. The stimulation of renal lipogenesis and the suppression of renal lipolysis led to increased renal lipid accumulation. Moreover, maternal obesity induced impaired autophagic process by decreasing autophagosome formation and impaired lysosome formation. These alterations reduced the hydrolyzation of lipid droplet in the offspring’s kidney leading to more severity of renal lipid accumulation and resulting in offspring’s kidney injury.