SIRT1 overexpression attenuates offspring metabolic and liver disorders as a result of maternal high‐fat feeding

Abstract

Key points Maternal high‐fat diet (MHF) consumption led to metabolic and liver disorders in male offspring, which are associated with reduced sirtuin (SIRT)1 expression and activity in the offspring liver SIRT1 overexpression in MHF offspring reduced their body weight and adiposity and normalized lipid metabolic markers in epididymal and retroperitoneal adipose tissues SIRT1 overexpression in MHF offspring improved glucose tolerance, as well as systemic and hepatic insulin sensitivity SIRT1 overexpression ameliorated MHF‐induced lipogenesis, oxidative stress and fibrogenesis in the liver of offspring. Abstract Maternal obesity can increase the risk of metabolic disorders in the offspring. However, the underlying mechanism responsible for this is not clearly understood. Previous evidence implied that sirtuin (SIRT)1, a potent regulator of energy metabolism and stress responses, may play an important role. In the present study, we have shown, in C57BL/6 mice, that maternal high‐fat diet (HFD) consumption can induce a pre‐diabetic and non‐alcoholic fatty liver disease phenotype in the offspring, associated with reduced SIRT1 expression in the hypothalamus, white adipose tissues (WAT) and liver. Importantly, the overexpression of SIRT1 in these offspring significantly attenuated the excessive accumulation of epididymal (Epi) white adipose tissue (WAT) and retroperitoneal (Rp)WAT (P < 0.001), glucose intolerance and insulin resistance (both P < 0.05) at weaning age. These changes were associated with the suppression of peroxisome proliferator‐activated receptor gamma (PPAR)γ (P < 0.01), PPARγ‐coactivator 1‐alpha (P < 0.05) and sterol regulatory element‐binding protein‐1c in EpiWAT (P < 0.01), whereas there was increased expression of PPARγ in RpWAT (P < 0.05). In the liver, PPARγ mRNA expression, as well as Akt protein expression and activity, were increased (P < 0.05), whereas fatty acid synthase and carbohydrate response element binding protein were downregulated (P < 0.05), supporting increased insulin sensitivity and reduced lipogenesis in the liver. In addition, hepatic expression of endogenous anti‐oxidants, including glutathione peroxidase 1 and catalase, was increased (P < 0.01 and P < 0.05 respectively), whereas collagen and fibronectin deposition was suppressed (P < 0.01). Collectively, the present study provides direct evidence of the mechanistic significance of SIRT1 in maternal HFD‐induced metabolic dysfunction in offspring and suggests that SIRT1 is a promising target for fetal reprogramming.

In Utero One‐Carbon Metabolism Interplay and Metabolic Syndrome in Cardiovascular Disease Risk Reduction

“…First, histone deacetylase (HDAC) Sirtuin 1 (SIRT1) was recently shown to inhibit adipose tissue differentiation via deactivation of PPAR‐γ, and this was postulated to lead to a lack of adaptation to a chronic high‐fat diet (HFD), thereby leading to insulin resistance . In contrast, SIRT1 overexpression was shown to attenuate maternal HFD induced metabolic and liver disorders, in part, via suppression of PPAR‐γ . Thus, it is clear that while PPAR‐γ may be essential in fetal adipose tissue differentiation and insulin sensitivity, in the liver, its high expression may be detrimental and could trigger lipid accumulation, a hallmark of NAFLD (Figure ).…”

Breaking the intergenerational cycle of obesity with SIRT1

“…Recent research has also shown that maternal diet can impact on offspring SIRT1 expression where maternal high-fat diet reduces SIRT1 expression in the offspring's kidney after birth (Nguyen et al 2017). Given that maternal high-fat diet programmes offspring obesity, this prompts two questions: (1) does maternal high-fat diet reduce SIRT1 expression in the offspring, resulting in long term metabolic disorders, or (2) is offspring SIRT1 reduced as a result of offspring obesity following maternal high-fat feeding?In this issue of The Journal of Physiology, Nguyen et al asked whether SIRT1 is causal to the development of metabolic disorders in offspring of high fat-fed dams (Nguyen et al 2019). To test this, they genetically overexpressed SIRT1 in offspring of high fat-fed dams such that the increase in SIRT1 precedes any metabolic changes as a result of maternal high-fat feeding.To generate this mouse model, Nguyen et al crossed SIRT1-overexpressing transgenic sires with high fat-fed or chow-fed dams and examined metabolic outcomes of the male offspring, which either overexpress SIRT1 or not.…”

“…This yielded four groups: (1) wild-type offspring of chow-fed dams, (2) wild-type offspring of high fat-fed dams, (3) SIRT1-overexpressing offspring of chow-fed dams, and (4) SIRT1-overexpressing offspring of high fat-fed dams. If SIRT1 is causal to metabolic disorders in offspring of high fat-fed dams, then SIRT1 overexpression would ameliorate the negative metabolic outcomes in these offspring.Indeed, Nguyen et al showed that overexpression of SIRT1 in male offspring of high fat-fed dams protected the offspring against negative metabolic consequences of maternal high-fat feeding (Nguyen et al 2019). Specifically, they found that SIRT1 overexpression corrected maternal high fat diet-induced hyperleptinaemia, glucose intolerance, liver lipogenesis, inflammation and adiposity when compared to wild-type offspring of high fat-fed dams.…”

“…In this issue of The Journal of Physiology, Nguyen et al asked whether SIRT1 is causal to the development of metabolic disorders in offspring of high fat-fed dams (Nguyen et al 2019). To test this, they genetically overexpressed SIRT1 in offspring of high fat-fed dams such that the increase in SIRT1 precedes any metabolic changes as a result of maternal high-fat feeding.…”

“…Indeed, Nguyen et al showed that overexpression of SIRT1 in male offspring of high fat-fed dams protected the offspring against negative metabolic consequences of maternal high-fat feeding (Nguyen et al 2019). Specifically, they found that SIRT1 overexpression corrected maternal high fat diet-induced hyperleptinaemia, glucose intolerance, liver lipogenesis, inflammation and adiposity when compared to wild-type offspring of high fat-fed dams.…”