SIRT1 overexpression attenuates offspring metabolic and liver disorders as a result of maternal high-fat feeding
- Publication Type:
- Journal Article
- Journal of Physiology, 2019, 597 (2), pp. 467 - 480
- Issue Date:
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© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society 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.
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