Abstract
Maternal obesity can contribute to the development of obesity and related metabolic disorders in progeny. Sirtuin (SIRT)1, an essential regulator of metabolism and stress responses, has recently emerged as an important modifying factor of developmental programming. In this study, to elucidate the effects of parental SIRT1 overexpression on offspring mechanism, four experimental groups were included: (1) Chow-fed wild-type (WT)-dam × Chow-fed WT-sire; (2) High-fat diet (HFD)-fed WT-dam × Chow-fed WT-sire; (3) HFD-fed hemizygous SIRT1-transgenic (Tg)-dam × Chow-fed WT-sire; and (4) HFD-fed WT dam × Chow-fed Tg-sire. Our results indicate that Tg breeders had lower body weight and fat mass compared to WT counterparts and gave birth to WT offspring with reductions in body weight, adiposity and hyperlipidaemia compared to those born of WT parents. Maternal SIRT1 overexpression also reversed glucose intolerance, and normalised abnormal fat morphology and the expression of dysregulated lipid metabolism markers, including SIRT1. Despite having persistent hepatic steatosis, offspring born to Tg parents showed an improved balance of hepatic glucose/lipid metabolic markers, as well as reduced levels of inflammatory markers and TGF-β/Smad3 fibrotic signalling. Collectively, the data suggest that parental SIRT1 overexpression can ameliorate adverse metabolic programming effects by maternal obesity.
Highlights
Obesity is a global health concern, affecting more than 650 million people worldwide and considered as one of the major risk factors of type 2 diabetes (T2D), hypertension and other metabolism-related chronic diseases [1,2]
Fat mass and plasma non-esterified fatty acid (NEFA) levels were significantly increased (p < 0.001 and p < 0.05 respectively) in High-fat diet (HFD)-fed dams compared to Chow-fed dams, while blood glucose level (BGL) and triglyceride levels were unchanged
SIRT1-Tg sires had lower body weight and fat mass at week 24 (p < 0.05, Figure 1B), but similar BGL, NEFA and triglyceride levels compared to their wild-type (WT) counterparts (Figure 1B)
Summary
Obesity is a global health concern, affecting more than 650 million people worldwide and considered as one of the major risk factors of type 2 diabetes (T2D), hypertension and other metabolism-related chronic diseases [1,2]. Apart from the unarguable roles of socioeconomic and genetic factors that predispose individuals of certain races and countries to the development of obesity, an emerging hypothesis for the pandemic of obesity and related diseases is the process of developmental programming, which is defined as a multigenerational transmission of diseases due to adverse environmental stimuli prior to and during pregnancy. Disease transmission via maternal linage has been demonstrated to be the predominant pathway in foetal programming, an increasing number of reports indicated the potent contributions of paternal factors, such as paternal obesity or stress, to the overall formulation of the offspring’s phenotype [3]. It is imperative to explore alternative treatment approaches to limit the adverse transgenerational impact of maternal obesity
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