Resveratrol protects against ethanol-induced impairment of insulin secretion in INS-1 cells through SIRT1-UCP2 axis.
白藜芦醇通过 SIRT1-UCP2 轴保护乙醇诱导的 INS-1 细胞胰岛素分泌受损。
- 作者列表："Luo G","Xiao L","Wang D","Wang N","Luo C","Yang X","Hao L
:SIRT1 has been proposed to enhance insulin secretion in β-cell through repressing the expression of uncoupling protein2 (UCP2), but whether ethanol-induced β-cell dysfunction is mediated by the disrupted SIRT1-UCP2 axis remains unknown. This study was conducted to explore the underlying mechanisms by which ethanol resulted in β-cell dysfunction and the potential protective effects of resveratrol in this process. INS-1 cells (rat pancreatic β-cell line) were cultured with ethanol in the presence or absence of resveratrol (2.5, 12.5 μmol/L). The results showed that ethanol exposure reduced glucose-stimulated insulin secretion, ATP production and SIRT1 expression but increased UCP2 expression, while supplementation with resveratrol restored the function of INS-1 cell by upregulating SIRT1 and inhibiting UCP2. Moreover, the critical role of SIRT1-UCP2 axis was further supported by the results that SIRT1 activator SRT1720 reversed ethanol-induced impairment of glucose-stimulated insulin secretion by decreasing UCP2, while SIRT1 inhibitor Ex527 abolished the beneficial effects of resveratrol. Meanwhile, NAD+ booster nicotinamide mononucleotide also counteracted the deleterious effects of ethanol by increasing SIRT1, suggesting the regulation of SIRT1-UCP2 axis may be associated with cellular NAD+/NADH ratio. In conclusion, our observations imply that ethanol induces impaired insulin secretion from INS-1 cell through disrupting SIRT1-UCP2 axis, while resveratrol may reverse this process by augmenting SIRT1 and inhibiting UCP2.
: SIRT1 被认为通过抑制解偶联蛋白 2 (UCP2) 的表达来增强 β 细胞中的胰岛素分泌, 但乙醇诱导的 β 细胞功能障碍是否由破坏的 SIRT1-UCP2 轴介导仍然未知。本研究旨在探讨乙醇导致 β 细胞功能障碍的潜在机制以及白藜芦醇在此过程中的潜在保护作用。INS-1 细胞 (大鼠胰腺 β 细胞系) 用乙醇在有或无白藜芦醇 (2.5，12.5 μ mol/L) 的条件下培养。结果表明，乙醇暴露降低了葡萄糖刺激的胰岛素分泌、 ATP 产生和 SIRT1 表达，但增加了 UCP2 表达, 而补充白藜芦醇通过上调 SIRT1 和抑制 ucp2 来恢复 INS-1 细胞的功能。此外，SIRT1 激活剂 SRT1720 通过降低 UCP2 逆转乙醇诱导的葡萄糖刺激的胰岛素分泌损伤的结果进一步支持了 SIRT1-UCP2 轴的关键作用, 而 SIRT1 抑制剂 Ex527 消除了白藜芦醇的有益作用。同时，NAD + 升压烟酰胺单核苷酸也通过增加 SIRT1 来抵消乙醇的有害作用，提示 SIRT1-UCP2 轴的调节可能与细胞 NAD +/NADH 比值有关。总之，我们的观察结果意味着乙醇通过破坏 INS-1 细胞轴诱导 SIRT1-UCP2 分泌受损，而白藜芦醇可能通过增强 SIRT1 和抑制 ucp2 来逆转这一过程。
METHODS:BACKGROUND:Given the importance of habitual dietary protein intake, distribution patterns and dietary sources in the aetiology of age-related declines of muscle mass and function, the present study examined these factors as a function of sex and age in Irish adults aged 18-90 years comprising The National Adult Nutrition Survey (NANS). METHODS:In total, 1051 (males, n = 523; females, n = 528) undertook a 4-day semi-weighed food diary. Total, body mass relative intake and percentage contribution to total energy intake of dietary protein were determined in addition to protein distribution scores (PDS), as well as the contribution of food groups, animal- and plant-based foods to total protein intake. RESULTS:Total and relative protein intake [mean (SD)] were highest in those aged 18-35 years [96 (3) g day , 1.32 (0.40) g kg day ], with lower protein intakes with increasing age (i.e. in adults aged ≥65 years [82 (22) g, 1.15 (0.34) g kg day , P < 0.001 for both]. Differences in protein intake between age groups were more pronounced in males compared to females. Protein distribution followed a skewed pattern for all age groups [breakfast, 15 (10) g; lunch, 30 (15) g; dinner, 44 (17) g]. Animal-based foods were the dominant protein source within the diet [63% (11%) versus 37% (11%) plant protein, P < 0.001]. CONCLUSIONS:Protein intake and the number of meals reaching the purported threshold for maximising post-prandial anabolism were highest in young adults, and lower with increasing age. For main meals, breakfast provided the lowest quantity of protein across all age categories and may represent an opportunity for improving protein distribution, whereas, in older adults, increasing the number of meals reaching the anabolic threshold regardless of distribution pattern may be more appropriate.
METHODS:BACKGROUND:Low cardiorespiratory fitness (CRF) increases risk of all-cause mortality and cardiovascular events. Periodic CRF assessment can have an important preventive function. OBJECTIVE:To develop a protocol-free method to estimate CRF in daily life based on heart rate (HR) and body acceleration measurements. METHODS:Acceleration and HR data were collected from 37 subjects (M=49%) while performing a standardized laboratory activity protocol (sitting, walking, running, cycling) and during a 5-days free-living monitoring period. CRF was determined by oxygen uptake (VO2max) during maximal exercise testing. A doubly-labeled water validated equation was used to predict total energy expenditure (TEE) from acceleration data. A fitness index was defined as the ratio between TEE and HR (TEE-pulse). Activity recognition techniques were used to process acceleration features and classify sedentary, ambulatory and other activity types. Regression equations based on TEE-pulse data from each activity type were developed to predict VO2max. RESULTS:TEE-pulse measured within each activity type of the laboratory protocol was highly correlated to VO2max (r from 0.74 to 0.91). Averaging the outcome of each activity-type specific equation based on TEE-pulse from the laboratory data led to accurate estimates of VO2max (RMSE: 300.0 mlO2/min or 10%). The difference between laboratory and free-living determined TEE-pulse was 3.7 ± 11% (r =0.85). The prediction method preserved the prediction accuracy when applied to free-living data (RMSE: 367 mlO2/min or 12%). CONCLUSIONS:Measurements of body acceleration and HR can be used to predict VO2max in daily life. Activity-specific prediction equations are needed to achieve highly accurate estimates of CRF.
METHODS:OBJECTIVE:Postprandial dyslipidemia is a common feature of insulin resistant states and contributes to increased cardiovascular disease risk. Recently, bile acids have been recognized beyond their emulsification properties as important signaling molecules that promote energy expenditure, improve insulin sensitivity, and lower fasting lipemia. While bile acid receptors have become novel pharmaceutical targets, their effects on postprandial lipid metabolism remain unclear. Here we investigated the potential role of bile acids in regulation of postprandial chylomicron production and triglyceride excursion. Approach and Results: Healthy C57BL/6 mice were given an intraduodenal infusion of taurocholic acid (TA) under fat-loaded conditions and circulating lipids were measured. Targeting of bile acid receptors was achieved with GW4064, a synthetic agonist to the farnesoid X receptor (FXR), and with deoxycholic acid (DCA), an activator of the Takeda G-protein-coupled receptor 5. TA, GW4064, and DCA treatments all lowered postprandial lipemia. FXR agonism also reduced intestinal triglyceride content and activity of microsomal triglyceride transfer protein, involved in chylomicron assembly. Importantly, TA effects (but not DCA) were largely lost in FXR knockout mice. These bile acid effects are reminiscent of the anti-diabetic hormone glucagon-like peptide-1 (GLP-1). While the GLP-1 receptor agonist exendin-4 retained its ability to acutely lower postprandial lipemia during bile acid sequestration and FXR deficiency, it did raise hepatic expression of the rate limiting enzyme for bile acid synthesis. CONCLUSIONS:Bile acid signaling may be an important mechanism of controlling dietary lipid absorption and bile acid receptors may constitute novel targets for the treatment of postprandial dyslipidemia.