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Background: Many investigations have explored the relationship between dietary intake and obesity risk/incidence, but they have only assessed obesity-related dietary patterns and/or single nutrients, not taking into account the diversity of dietary variables or multicollinearity among multiple nutrients. Therefore, this study aimed to use logistic LASSO regression combined with logistic regression to overcome multicollinearity, and overall investigate the possible association between dietary factors and obesity by the National Health and Nutrition Examination Survey (NHANES) (2007-2016). Method: Logistic LASSO regression was performed to examine the relationship between 59 dietary variables, and subsequently identify the most relevant variables associated with obesity. Then we used logistic regression to test the relevant variables, and finally used the receiver operating characteristic curve (ROC) to test the effect of logistic regression. Using the methods described above, we explored the relationship between dietary intake and obesity in 12135 NHANES participants (2007-2016). Result: The set of factors screened by LASSO regression, obesity risk factors including cholesterol and PFUA 20:4 (β>0); protective factors including vitamin E, caffeine, folate, vitamin C and copper (β

The onset of complex diseases at a later stage of life has been linked with maternal folic acid (FA) ingestion. However, little is known regarding the underlying molecular fingerprints of the offspring. We integrated proteomics-metabolomics profiles and analyzed the influence of maternal FA supplementation on the metabolism of adult offspring rats. Twenty pregnant female rats were randomly assigned to a FA supplementation (FolS group, 10 mg/kg FA) or control group (2 mg/kg FA respectively). Such an omics approach revealed that the dopaminergic synapse pathway, tricarboxylic acid cycle and neural development-related metabolites such as glutamic acid and γ-aminobutyric acid were significantly up-regulated in the FolS group, whereas pyruvic acid, oxalic acid and adipic acid were reduced. Maternal FA supplementation can cause alterations of metabolites and protein in the offspring rats.

The process of aging and metabolism is intimately intertwined; thus, developing biomarkers related to metabolism is critical for delaying aging. However, few studies have identified reliable markers that reflect aging trajectories based on machine learning. We generated metabolomic profiles from rat urine using ultra-performance liquid chromatography/mass spectrometry. This was dynamically collected at four stages of the rat’s age (20, 50, 75, and 100 weeks) for both the training and test groups. Partial least squares-discriminant analysis score plots revealed a perfect separation trajectory in one direction with increasing age in the training and test groups. We further screened 25 aging-related biomarkers through the combination of four algorithms (VIP, time-series, LASSO, and SVM-RFE) in the training group. They were validated in the test group with an area under the curve of 1. Finally, six metabolites, known or novel aging-related markers, were identified, including epinephrine, glutarylcarnitine, L-kynurenine, taurine, 3-hydroxydodecanedioic acid, and N-acetylcitrulline. We also found that, except for N-acetylcitrulline (p < 0.05), the identified aging-related metabolites did not differ between tumor-free and tumor-bearing rats at 100 weeks (p > 0.05). Our findings reveal the metabolic trajectories of aging and provide novel biomarkers as potential therapeutic antiaging targets.

Cong Zhang,1,2,&ast; Qingna Yan,1,&ast; Qiushuang Zhu,1,&ast; Jinxiao Liu,1,&ast; Yuanjie Dong,1 Yuqiao Li,1 Ruohua Wang,1 Xuanfeng Tang,1 Xinyi Lv,1 Xiaoqing Li,1 Yunjiang Cai,3 Yucun Niu1 1Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, 150086, People’s Republic of China; 2Center of Disease Control and Prevention of Xishan District, Wuxi, 214000, People’s Republic of China; 3Nursing College of Daqing Campus of Harbin Medical University, Daqing, 163319, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yucun NiuDepartment of Nutrition and Food Hygiene, College of Public Health, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, 150081, People’s Republic of ChinaTel +86-451-8750-2730Fax +86-451-8750-2885Email niuyucun@163.comPurpose: How to prolong life by diet has been widely concerned. There are many reports about the effects of different dietary patterns on life span, but the results are not consistent. The main reason may be that total energy intake has not been considered. This study aims to explore the effects of isocaloric different dietary patterns on population life span.Materials and Methods: From the data of the follow-up population, eligible participators were divided into normal control (NC) group (28.31% fat, 12.37% protein, 62.30% carbohydrate), isocaloric high-fat (IHF) group (38.39% fat, 12.21% protein, 51.32% carbohydrate), isocaloric high-protein (IHP) group (33.41% fat, 17.10% protein, 52.67% carbohydrate) and isocaloric high-carbohydrate (IHC) group (22.23% fat, 10.52% protein, 70.13% carbohydrate) according to the dietary structure and the age stratification. Global serum metabolic profiling analysis by UPLC−Q-TOF-MS/MS technology, fatty acid and amino acid profiles in serum were determined by GC-MS and UPLC-TQ-MS technology. One-way ANOVA followed by Dunnett post hoc test and receiver operating characteristic (ROC) curve analysis were used to statistical analysis.Results: Non-targeted metabolomics was to identify 18 potential metabolites related to longevity. ROC curve analysis to identify biomarkers indicated that the areas under the ROC (AUC) of the 12 of 18 biomarkers are above 0.9. The 12 biomarkers were mainly enriched in three metabolic pathways: lipid metabolism, amino acid metabolism and tricarboxylic acid cycle. Compared to control, 11 and 10 of 12 biomarkers showed the same trend with aging in IHP and IHC groups, respectively. Conversely, no differences were observed between IHF group and NC group.Conclusion: Without consideration of the nature of carbohydrates, fats and proteins, IHP and IHC diets might shorten life span by influencing amino acid metabolism, lipid metabolism and tricarboxylic acid cycle metabolism, while the isocaloric IHF diet has no effects on longevity.Keywords: amino acid, fatty acid, biomarkers, metabolomics

Background: Whether beverage consumption pattern is associated with risk of metanolic syndrome (MetS) and stroke is of public health interest. Methods: We examined the associations between the healthy beverage index (HBI) scores with prevalence of MetS and stroke among 4162 participants aged 20-80 years from the National Health and Nutrition Examination Survey (2013-2014) in U.S. Binary logistic regression was used to estimate odd ratios (OR) and 95% confidence intervals (95% CI), while adjusting for potential confounders and stratifying by gender. Results: For the prevalence of stroke, there was an inverse association between HBI scores and stroke (adj. OR for Q4 versus Q1: 0.47; 95% CI: 0.27–0.81), and gender stratified models were similar. However, there was a positive association between HBI scores and MetS (adj. OR for Q4 versus Q1: 1.38; 95% CI: 1.46–1.79) in the total participants, and gender stratified models were different. Higher HBI scores was associated with lower prevalence of MetS in females (adj. OR for Q4 versus Q1: 0.95; 95% CI: 0.65–1.38), but with higher prevalence of MetS in males (adj. OR for Q4 versus Q1: 2.02; 95% CI: 1.37–2.99). Further analyses demonstrated differences in the association of SSBs, coffee and tea, alcohol, diet drinks and full-fat milk consumption with MetS and stroke in the total subjects, males and females. Conclusions: Our findings suggested that the HBI scores was a negative association with stroke in a representative U.S. population, and the higher HBI scores was associated with increased prevalence of MetS in males but decreased in females, which may be caused by the same beverage may play a different role in the prevalence of MetS and stroke in the total participants,males and females.

Previous studies have indicated high-protein diet (HPD) promotes weight loss and improves metabolic parameters, but most of these studies have focused on the impact of short-term, long-term effects remain unclear. In this study, male Wistar rats were fed two diets for 88 weeks: normal control diet (NCD, 20.5% of energy as protein) or HPD (30.5% of energy as protein). At 88 weeks intervention, compared to NCD rats, HPD rats had lower fat tissue and higher skeletal muscle to body weight ratio, but there were no significantly differences in body weight and food intake. To explore the mechanism underlying metabolism and diet, we further collected rat urine samples at 16, 40, 64 and 88 weeks diet treatment and analyzed metabolomics profiles using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). Partial least squares-discriminant analysis (PLS-DA) scores plots from ESI- or ESI+ model revealed a perfect separation between two diets at four time points. We identified 11 dramatically different metabolites (with VIP cut-off value 1) in HPD, including 3 up-regulated and 8 down-regulated. And these 11 metabolites were identified as effective biomarkers, which were significantly related to HPD-induced metabolism related outcomes (fat tissue and skeletal muscle to body weight ratio). Our results provided vital information regarding metabolism in long-term HPD and more importantly, a few potentially promising metabolites were firstly identified which may related to metabolic responses.

Increased levels of oxidative stress and inflammation are the underlying mechanisms behind the aging process and age-related diseases. The purpose of our research is to explore whether epigallocatechin gallate (EGCG) can extend replicative life span by preventing the oxidative stress and inflammatory effects of WI-38 fibroblasts and the involved mechanisms in vitro. WI-38 cells were treated with different concentrations of EGCG (0, 25, 50 and 100 μM) at population doubling (PD) 25. At late-stage cells, we determined the age-associated genes with signaling through transcriptome sequencing. The expression profile of the targets in WI-38 fibroblasts was confirmed by bioinformatics analysis, qPCR and western blot. We found that EGCG markedly decreased reactive oxygen species (ROS), and inflammation factors, tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and significantly increased cell proliferation at PD 35 and 45. EGCG treatments significantly decreased p53 and retinoblastoma (Rb) expressions, markedly increased p-Rb and E2F2 expressions as well as antioxidant enzymes and superoxide dismutase (SOD) 1 and SOD2 content, and obviously decreased the expressions of inflammation factors IL-32, TNF-α expressions at PD 45 WI-38 cells. Moreover, the effects were changed by EGCG treatment by p53 siRNA or overexpression. These findings in our studies reveal that EGCG treatments improved senescence and enhanced the replicative life span through alleviating oxidative stress and inflammation in WI-38 fibroblasts.

We have recently reported that epigallocatechin gallate (EGCG) could extend lifespan in healthy rats. This study aimed to investigate the effects and mechanisms of a high dose of EGCG in extending the lifespan of obese rats. Ninety adult male Wistar rats were randomly divided into the control (NC), high‐fat (HF) and EGCG groups. Serum glucose and lipids, inflammation and oxidative stress were dynamically determined from adulthood to death, and the transcriptome and proteome of the liver were also examined. The median lifespans of the NC, HF and EGCG groups were 693, 599 and 683 days, respectively, and EGCG delayed death by 84 days in obese rats. EGCG improved serum glucose and lipids and reduced inflammation and oxidative stress associated with aging in obese rats induced by a high‐fat diet. EGCG also significantly decreased the levels of total free fatty acids (FFAs), SFAs and the n‐6/n‐3 ratio but significantly increased the n‐3 FFAs related to longevity. The joint study of the transcriptome and proteome in liver found that EGCG exerted its effects mainly by regulating the suppression of hydrogen peroxide and oxygen species metabolism, suppression of oxidative stress, activation of fatty acid transport and oxidation and cholesterol metabolism. EGCG significantly increased the protein expression of FOXO1, Sirt1, CAT, FABP1, GSTA2, ACSL1 and CPT2 but significantly decreased NF‐κB, ACC1 and FAS protein levels in the livers of rats. All the results indicate that EGCG extends lifespan by improving FFA metabolism and reducing the levels of inflammatory and oxidative stress in obese rats., This study investigates the effects and mechanisms of a high dose of epigallocatechin gallate (EGCG) in extending the lifespan of obese rats. We find that EGCG improved serum glucose, lipids, inflammation, oxidative stress associated with ageing in obese rats induced by a high‐fat diet, total free fatty acids (FFAs), transcriptome, and proteome. The results indicate that EGCG extends lifespan by improving FFA metabolism and reducing the levels of inflammatory and oxidative stress in obese rats.

Summary The health effect of dietary fat has been one of the most vexing issues in the field of nutrition. Few animal studies have examined the impact of high-fat diets on lifespan by controlling energy intake. In this study, we found that compared to a normal diet, an isocaloric moderately high-fat diet (IHF) significantly prolonged lifespan by decreasing the profiles of free fatty acids (FFAs) in serum and multiple tissues via downregulating FFA anabolism and upregulating catabolism pathways in rats and flies. Proteomics analysis in rats identified PPRC1 as a key protein that was significantly upregulated by nearly 2-fold by IHF, and among the FFAs, only palmitic acid (PA) was robustly and negatively associated with the expression of PPRC1. Using PPRC1 transgenic RNAi/overexpression flies and in vitro experiments, we demonstrated that IHF significantly reduced PA, which could upregulate PPRC1 through PPARG, resulting in improvements in oxidative stress and inflammation and prolonging the lifespan.

Background: A High-fat diet has been reported to produce excess lipid accumulation and increase inflammatory factors and oxidative stress in various metabolic diseases. Caloric restriction (CR) is one of the most valuable tools in reducing inflammation, enhancing anti-oxidative activity and ameliorating various metabolic diseases. However, excess CR may restrain growth, development and normal physiological processes. Our study was conducted to investigate the effects of a high-fat diet containing the same number of calories as a basic diet on the health and gene expression patterns of rats.Methods: 30 Wistar male rats were randomly devided into a normal control (NC) group, an equicaloric high-fat (EHF) group as the NC group, and a high-fat (HF) ad libitum group. Food consumption and body weight were recorded once a week. Blood biochemistical and genomic assessments of the liver were carried out after intervention for 20 weeks. Results: Compared with the NC group, serum triglycerides (TG), total cholesterol (TCHO), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST) and andalanine aminotransferase (ALT) levels were significantly increased in the HF group, and the serum levels of interleukin- 6 (IL-6), reactive oxygen species (ROS) and glutathione (GSH) were significantly decreased in the HF group. Compared with the HF group, serum TG,TCHO,LDL-C, AST, ALT, IL-6, ROS levels were significantly decreased in the EHF group, and the serum levels of GSH and superoxide dismutase (SOD) were also significantly increased. Histological studies showed decreased macrovesicular steatosis, inflammatory cell infiltration and structural damagein EHF group compared to the HF group. In addition, transcription analysis revealed that an EHF led tochanges in gene expression, including a reduction inToll-like receptor 4 (TRL4),which inhibited NF-kappa B signaling pathway and upregulatedglutathione S-transterases (GSTs) to increase antiocidative activity.Conclusions: an EHF restored deleterious changes in the health and gene expression patterns induced by a high-fat diet ad libitum in rats via reduced inflammation and increased antioxidative activity.

Background There has been increased recognition that prenatal or perinatal nutrition has an effect on the development of type 2 diabetes (T2D) in adulthood, although studies that have directly examined whether the effect could be transmitted to the next generation remain sparse. Objective We investigated the role of prenatal exposure to the Chinese famine in affecting future T2D risk in adulthood in 2 consecutive generations. Design A total of 1034 families, including 2068 parents [parental generation (F1)] and 1183 offspring [offspring generation (F2)], were recruited from the Suihua rural area that was affected by the Chinese Famine of 1959-1961. Participants born between 1 October 1959 and 30 September 1961 were defined as famine exposed, and those born between 1 October 1962 and 30 September 1964 were defined as nonexposed. The F2 were classified as having 1) no parent exposed to famine, 2) only a mother exposed to famine, 3) only a father exposed to famine, or 4) both parents exposed to famine. Classical risk factors for T2D as well as fasting-glucose- and oral-glucose-tolerance tests were measured in both the F1 and F2. Results Prenatal exposure to famine was associated with elevated risks of hyperglycemia (multivariable-adjusted OR: 1.93; 95% CI: 1.51, 2.48) and T2D (OR: 1.75; 95% CI: 1.20, 2.54) in adulthood in F1. Furthermore, compared with the offspring of nonexposed parents, the F2 with exposed parents- especially both exposed parents-had increased hyperglycemia risk (OR: 2.02; 95% CI: 1.12, 3.66) in adulthood. Conclusion Prenatal exposure to famine remarkably increases hyperglycemia risk in 2 consecutive generations of Chinese adults independent of known T2D risk factors, which supports the notion that prenatal nutrition plays an important role in the development of T2D across consecutive generations of Chinese adults. This trial was registered at www.chictr.org.cn as ChiCTR-ECH-13003644.

Background The temporal sequence between serum calcium and insulin resistance (IR) and their effects on hypertension are unclear. We studied the association between serum calcium and IR, with risk of hypertension events in a longitudinal cohort conducted in China. Methods and Results Data from 8653 subjects aged 20 to 74 years with an average follow‐up of 5.3 years were analyzed. Serum calcium, and fasting and 2‐hour serum glucose and insulin were measured at baseline and follow‐up. Cross‐lagged panel and mediation analysis were used to examine the temporal relationship between serum calcium and IR and its impact on hypertension incidence. The conjoint effects of serum calcium and IR at baseline on hypertension at follow‐up were observed ( P =0.029 for HOMA_IR [hepatic IR] and P =0.009 for Gutt index [peripheral IR]). The cross‐lagged path coefficient (β 2 ) from baseline serum calcium to follow‐up peripheral IR were significantly greater than path coefficient (β 1 ) from baseline peripheral insulin resistance to follow‐up serum calcium (β 2 =−0.354 versus β 1 =−0.005; P =0.027). However, no directional relationships were observed in the serum calcium↔hepatic IR analysis. The mediation effect of peripheral IR on the association of serum calcium at baseline with hypertension at follow‐up was estimated at 16.4% ( P Conclusions Our findings demonstrate that higher serum calcium levels probably precede peripheral IR, and this 1‐directional relation plays a role in the development of hypertension.

Aims High levels of circulating free fatty acids (FFAs), inflammation and oxidative stress are important causes for insulin resistance (IR) and type 2 diabetes mellitus. The aim of this study was to investigate the mechanisms of EGCG in alleviating IR in HepG2 cells. Methods HepG2 cells were treated with 25 mM glucose, 0.25 mM palmitic acid (PA), or 50 μM EGCG for 24 h. Results EGCG increased glucose uptake and decreased glucose content. EGCG markedly decreased the levels of inflammatory and oxidative stress factors including nuclear factor κB (NF-κB), tumor necrosis factor-α, interleukin-6, reactive oxygen species, malondialdehyde and p53 protein, and markedly increased superoxide dismutases (SOD), glutathione peroxidase and SOD2 protein. EGCG significantly downregulated the levels of FFAs, triacylglycerol and cholesterol in HepG2 cells. The glucose transporter 2 (GLUT2) protein and its downstream proteins peroxisome proliferator-activated receptor γ coactivator (PGC)-1β were significantly increased, and sterol regulatory element-binding-1c (SREBP-1c) protein, and fatty acid synthase (FAS) were significantly decreased by EGCG in HepG2. Moreover, the foregoing effects were reversed by siRNA-mediated knockdown of GLUT2. Conclusion Our data demonstrated that EGCG improved IR, possibly through ameliorating glucose (25 mM) and PA (0.25 mM)-induced inflammation, oxidative stress, and FFAs via the GLUT2/PGC-1β/SREBP-1c/FAS pathway in HepG2 cells.

The association between dietary Mn and type 2 diabetes is unclear. We aimed to elucidate whether dietary Mn is associated with type 2 diabetes, to investigate whether this association is independent of dietary total antioxidant capacity (TAC) and to explore the underlying mechanisms in their association. Two prospective cohorts of 3350 and 7133 Chinese adults (20–74 years old) were enrolled including, respectively, 244 and 578 individuals newly diagnosed with type 2 diabetes, with mean values of 4.2 and 5.3 years of follow-up. Cox’s proportional-hazards regression and linear regression were performed to investigate the association between dietary Mn and type 2 diabetes (diagnosed by OGTT) or HbAlc and to analyse the joint association between dietary Mn and TAC. Restricted cubic spline (RCS) regression was applied to the non-linear association between dietary Mn and incidence of type 2 diabetes. Mediation analysis was applied to explore potential mediators in their association in a subgroup of 500 participants. Dietary Mn intakes were 4.58 ± 1.04 and 4.61 ± 1.08 (mean ± SD) mg/day in the two cohorts. Dietary Mn was inversely associated with type 2 diabetes incidence and HbAlc concentration in both cohorts (ptrend 6.01 and 6.10–6.97 mg/day were associated with a significantly lower type 2 diabetes incidence in the two respective cohorts. Mediation analysis showed that high plasma Mn and low oxidative stress (increased Mn superoxide dismutase and decreased 8-hydroxydeoxyguanosine) contributed to the association between dietary Mn and both type 2 diabetes and HbAlc. Dietary Mn was inversely associated with type 2 diabetes independently of TAC. In addition, this association was stronger in a high- rather than low-TAC diet. Plasma Mn and oxidative stress were mediators in the association between dietary Mn and type 2 diabetes. Future studies on absolute Mn intake should be conducted to study the potential non-linearity and optimal levels of dietary Mn and type 2 diabetes.

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Our previous studies have shown that mangiferin decreased serum triglycerides and free fatty acids (FFAs) by increasing FFAs oxidation in both animal and cell experiments. This study sought to evaluate the effects of mangiferin on serum lipid profiles in overweight patients with hyperlipidemia. Overweight patients with hyperlipidemia (serum triglyceride ≥ 1.70 mmol/L and total cholesterol ≥ 5.2 mmol/L) were included in this double-blind randomized controlled trial. Participants were randomly allocated to groups, either receiving mangiferin (150 mg/day) or identical placebo for 12 weeks. The lipid profile and serum levels of mangiferin, glucose, L-carnitine, β-hydroxybutyrate and acetoacetate were determined at baseline and 12 weeks. A total of 97 participants completed the trial. Compared with the placebo control, mangiferin supplementation significantly decreased the serum levels of triglycerides and FFAs and insulin resistance index. Mangiferin supplementation also significantly increased the serum levels of mangiferin, high-density lipoprotein cholesterol, L-carnitine, β-hydroxybutyrate and acetoacetate and increased lipoprotein lipase activity. However, there were no differences in the serum levels of total cholesterol, low-density lipoprotein cholesterol, serum glucose and insulin between groups. Mangiferin supplementation could improve serum lipid profiles by reducing serum triglycerides and FFAs in overweight patients with hyperlipidemia, partly due to the promotion of FFAs oxidation.