Renal Medicine, Kolling Institute, Royal North Shore Hospital, University of Sydney , Sydney, New South Wales , Australia.
School of Life Sciences, Faculty of Science, University of Technology Sydney , Sydney, New South Wales , Australia.
Am J Physiol Endocrinol Metab. 2018 Aug 1;315(2):E196-E203. doi: 10.1152/ajpendo.00472.2017. Epub 2018 Mar 13.
Recent studies indicate that sirtuin-1 (SIRT1), an important metabolic sensor and regulator of life span, plays a mechanistic role in maternal obesity-induced programming of metabolic disorders in the offspring. In this study we investigate whether SIRT1 activation in early childhood can mitigate metabolic disorders due to maternal and postnatal high-fat feeding in mice. Male offspring born to chow-fed (MC) or high fat diet-fed dams (MHF) were weaned onto postnatal chow or high-fat diet and treated with SRT1720 (25 mg/kg ip every 2 days) or vehicle control for 6 wk and examined for metabolic disorders. MHF exacerbated offspring body weight and insulin resistance in the offspring exposed to postnatal HFD (OHF). These metabolic changes were associated with reduced hepatic lipid droplet accumulation but increased plasma levels of alanine aminotransferase (ALT), a marker of liver damage. SRT1720 significantly decreased offspring body weight, adiposity, glucose intolerance, and hyperleptinemia due to OHF and reversed hyperinsulinemia and adipocyte hypertrophy due to the additive effects of MHF. Although SRT1720 suppresses liver lipogenesis, inflammation, and oxidative stress markers, it also reduces antioxidants and increased liver collagen deposition in OHF offspring independent of MHF. Hepatic steatosis was attenuated only in MC/OHF offspring in association with elevated plasma ALT levels. The study suggests that postnatal SRT1720 administration can mitigate obesity and insulin resistance in the offspring due to maternal and postnatal HFD exposure. However, the possibility of liver toxicity needs to be further examined.
最近的研究表明，长寿的重要代谢传感器和调节因子之一——Sirtuin-1（SIRT1），在母源性肥胖引起的后代代谢紊乱的编程中发挥着机制作用。在这项研究中，我们研究了在幼年时激活 SIRT1 是否可以减轻由于母代和子代高脂肪饮食引起的代谢紊乱。用标准饮食喂养的母鼠（MC）或高脂肪饮食喂养的母鼠（MHF）所生的雄性幼鼠在断奶后被喂食标准饮食或高脂肪饮食，并接受 SRT1720（每 2 天腹腔注射 25mg/kg）或载体对照处理 6 周，并检查代谢紊乱情况。暴露于产后高脂肪饮食（OHF）的 MHF 加重了后代的体重和胰岛素抵抗。这些代谢变化与肝脂肪滴积累减少但血浆丙氨酸氨基转移酶（ALT）水平升高有关，ALT 是肝损伤的标志物。SRT1720 显著降低了由于 OHF 引起的后代体重、肥胖、葡萄糖耐量降低和高瘦素血症，并逆转了由于 MHF 的附加作用引起的高胰岛素血症和脂肪细胞肥大。尽管 SRT1720 抑制了肝脂肪生成、炎症和氧化应激标志物，但它也降低了抗氧化剂并增加了 OHF 后代的肝胶原沉积，而与 MHF 无关。MC/OHF 后代的肝脂肪变性仅减轻，与血浆 ALT 水平升高有关。该研究表明，产后 SRT1720 给药可以减轻由于母代和子代高脂肪饮食暴露引起的肥胖和胰岛素抵抗。然而，还需要进一步检查肝毒性的可能性。
