SIRT1 reduction is associated with sex-specific dysregulation of renal lipid metabolism and stress responses in offspring by maternal high-fat diet

Long The Nguyen,Carol Pollock,Sonia Saad,Hui Chen

doi:10.1038/s41598-017-08694-4

Long The Nguyen, Carol Pollock + Show 2 more

Open Access

https://doi.org/10.1038/s41598-017-08694-4

Copy DOI

Abstract

Rodent models of maternal obesity have been associated with kidney damage and dysfunction in offspring. However, the underlying mechanisms are yet to be elucidated. In this study, female rats were fed a high-fat diet (HFD) for 6 weeks prior to mating, throughout gestation and lactation; both male and female offspring were examined at weaning. Our results demonstrate that renal lipid deposition was increased in male offspring only, which is associated with reduced protein expression of Sirtuin (SIRT) 1, an essential regulator of lipid metabolism and stress response. Other components in its signalling network including phosphorylated 5′-AMP-activated protein kinase (pAMPKα), Forkhead box FOXO3a and Peroxisome proliferator-activated receptor (PPAR)γ coactivator 1-alpha (PGC-1α) were also downregulated. By contrast, in female offspring, renal fat/lipid distribution was unchanged in coupling with normal SIRT1 regulation. Specific autophagy and antioxidant markers were suppressed in both sexes. On the other hand, fibronectin and Collagen type IV protein expression was significantly higher in the offspring born HFD-fed dams, particularly in the males. Collectively, these findings suggest that maternal HFD consumption can induce sex-specific changes in offspring kidney lipid metabolism and stress responses at early ages, which may underpin the risk of kidney diseases later in life.

Highlights

Chronic kidney disease (CKD) is a global health crisis, characterised by a gradual loss of kidney function and requiring renal replacement therapy
Lipid metabolism and autophagy are among the earliest possible mechanisms that can be affected by maternal obesity considering their direct relevance to energy intake and dietary composition
We examine the hypothesis that maternal obesity induces renal lipid metabolic disorders and autophagy deficiency in the offspring and SIRT1 signalling plays a central role in this mechanism

Summary

Introduction

Chronic kidney disease (CKD) is a global health crisis, characterised by a gradual loss of kidney function and requiring renal replacement therapy. There is increasing recognition that a predisposition to CKD is evident in children and young adults, overt renal failure may not manifest till older age is reached[2]. Such phenomenon has been attributed in part to “fetal programming”, a term for fetal metabolic and epigenetic alterations induced by an abnormal intrauterine environment[3,4,5]. We examine the hypothesis that maternal obesity induces renal lipid metabolic disorders and autophagy deficiency in the offspring and SIRT1 signalling plays a central role in this mechanism. As the risk of CKD differs between sexes[23] and so does the fetal programming of kidney disorders[24,25,26,27], we examined whether these mechanisms are regulated in a sex-specific manner

Methods

Results

Conclusion