Nutrition & Metabolism

High fat diet (HFD) increases the likelihood of dyslipidemia, which can be a serious risk factor for atherosclerosis, diabetes or hepatosteatosis. Although changes in different blood lipid levels were broadly investigated, such alterations in the liver tissue have not been studied before. The aim of the current study was to investigate the effect of HFD on hepatic triglyceride (TG), diglyceride (DG) and ceramide (CER) levels and on the expression of four key genes involved in lipid homeostasis (Pcsk9, Ldlr, Cd36 and Anxa2) in the liver. In addition, the potential role of PCSK9 in the observed changes was further investigated by using PCSK9 deficient mice. We used two in vivo models: mice kept on HFD for 20 weeks and PCSK9−/− mice. The amount of the major TGs, DGs and CERs was measured by using HPLC–MS/MS analysis. The expression profiles of four lipid related genes, namely Pcsk9, Ldlr, Cd36 and Anxa2 were assessed. Co-localization studies were performed by confocal microscopy. In HFD mice, hepatic PCSK9 expression was decreased and ANXA2 expression was increased both on mRNA and protein levels, and the amount of LDLR and CD36 receptor proteins was increased. While LDLR protein level was also elevated in the livers of PCSK9−/− mice, there was no significant change in the expression of ANXA2 and CD36 in these animals. HFD induced a significant elevation in the hepatic levels of all measured TG and DG but not of CER types, and increased the proportion of monounsaturated vs. saturated TGs and DGs. Similar changes were detected in the hepatic lipid profiles of HFD and PCSK9−/− mice. Co-localization of PCSK9 with LDLR, CD36 and ANXA2 was verified in HepG2 cells. Our results show that obesogenic HFD downregulates PCSK9 expression in the liver and causes alterations in the hepatic lipid accumulation, which resemble those observed in PCSK9 deficiency. These findings suggest that PCSK9-mediated modulation of LDLR and CD36 expression might contribute to the HFD-induced changes in lipid homeostasis.

Gut bacteria Akkermansia has been shown an anti-obesity protective effect in previous studies and may be used as promising probiotics. However, the above effect may be confounded by common factors, such as sex, age and diets, which should be verified in a generalized population. We used datasets from the American Gut Project to strictly reassess the association and further examined the effect of aging on it. A total of 10,534 participants aged 20 to 99 years from the United States and the United Kingdom were included. The relative abundance of Akkermansia was assessed based on 16S rRNA sequencing data. Obesity (body mass index, BMI ≥ 30 kg/m2) risks were compared across Akkermansia quintiles in logistic models with adjustment for common confounders. Restricted cubic splines were used to examine dose response effects between Akkermansia, obesity and age. A sliding-windows-based algorithm was used to investigate the effect of aging on Akkermansia-obesity associations. The median abundance of Akkermansia was 0.08% (interquartile range: 0.006–0.93%), and the prevalence of obesity was 11.03%. Nonlinear association was detected between Akkermansia and obesity risk (P = 0.01). The odds ratios (95% confidence interval) for obesity across the increasing Akkermansia quintiles (referencing to the first quintile) were 1.14 (0.94–1.39), 0.94 (0.77–1.15), 0.70 (0.56–0.85) and 0.79 (0.64–0.96) after adjusting for age and sex (P for trend < 0.001). This association remained unchanged after further controlling for smoking, alcohol drinking, diet, and country. The odds ratios (95% CI) of Akkermansia were 0.19 (0.03–0.62) and 0.77 (0.64–0.91) before and over 40 years, respectively, indicating that the protective effect of Akkermansia against obesity was not stable with aging. High relative abundance of Akkermansia is associated with low risk of obesity and the association declines with aging.

Limited population-based studies have investigated the secular trend of prevalence of gestational diabetes mellitus (GDM) in mainland China. Therefore, this study aimed to estimate the prevalence of GDM and time trends in Chinese female population. Based on Diabetes Surveillance System of Zhejiang Province, 97,063 diagnosed GDM cases aged 20–50 years were identified from January 1, 2016 to December 31, 2018. Annual prevalence, prevalence rate ratios (PRRs) and average annual percentage change with their 95% confidence intervals (CIs) were reported. The age-standardized overall prevalence of GDM was reported to be 7.30% (95% CI 7.27–7.33%); 9.13% (95% CI 9.07–9.19%) in urban areas and 6.24% (95% CI 6.21–6.27%) in rural areas. Compared with 20–24 years age group, women in advanced age groups (25–50 years) were at higher risk for GDM (PRRs ranged from 1.37 to 8.95 and the 95% CIs did not include the null). Compared with rural areas, the risk for GDM was higher in urban areas (PRR: 1.69, 95% CI 1.67–1.72). The standardized annual prevalence increased from 6.02% in 2016 to 7.94% in 2018, with an average annual increase of 5.48%, and grew more rapidly in rural than urban areas (11.28% vs. 0.00%). This study suggested a significant increase in the prevalence of GDM among Chinese female population in Zhejiang province during 2016–2018, especially in women characterized by advanced age and rural areas.

To prospectively examine the associations of baseline serum uric acid (SUA) and SUA changes with incident metabolic syndrome (MetS) and update the evidence through a meta-analysis. Our analyses were based on the China Health and Retirement Longitudinal Study from 2011–2012 to 2015–2016. The exposures were baseline SUA and SUA changes, and the outcome was incident MetS assessed in 2015–2016. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). A meta-analysis was conducted to synthesize evidence from all cohort studies on the same topic. Of 3779 participants (47.2% men; mean age: 59.5 years) without MetS, 452 participants developed MetS after a follow-up of 4 years. Compared to the lowest quartiles, the adjusted ORs (95% CIs) for MetS were 1.08 (0.77–1.50), 1.32 (0.95–1.82), and 1.55 (1.12–2.16) for three higher quartiles of baseline SUA, and 1.23 (0.89–1.71), 1.39 (1.00–1.93), and 1.89 (1.38–2.58) for three higher quartiles of SUA changes. Each increment of 1 mg/dL of baseline SUA level was associated with 19% higher odds of MetS (adjusted OR 1.19; 95% CI 1.07–1.33). In the meta-analysis of 24 cohort studies among 140,913 participants, the pooled relative risk (95% CI) was 1.32 (1.25–1.40) for the highest versus lowest SUA category, and 1.15 (1.09–1.21) for each 1 mg/dL increase in the SUA level. Both baseline SUA and longitudinal SUA changes were positively associated with risk of MetS among middle-aged and elderly Chinese, which was supported by findings from a comprehensive meta-analysis across multiple populations. SUA levels might need to be monitored closely for subsequent risk of MetS in clinical practice.

Coffee consumption is associated with a lower risk of type 2 diabetes. We tested the hypothesis that this is mediated by incretin hormones by measuring the acute effects of decaffeinated coffee and coffee components on GLP-1 and GIP concentrations. A randomized cross-over trial of the effects of 12 g decaffeinated coffee, 1 g chlorogenic acid, 500 mg trigonelline, and placebo on total and intact GLP-1 and GIP concentrations during an oral glucose tolerance test took place in fifteen overweight men. No treatment significantly affected the overall GLP-1 or GIP secretion pattern following an OGTT relative to placebo. Decaffeinated coffee slightly increased total GLP-1 concentration 30 minutes after ingestion (before the OGTT) relative to placebo (2.7 pmol/L, p = 0.03), but this change did not correspond with changes in glucose or insulin secretion. These findings do not support the hypothesis that coffee acutely improves glucose tolerance through effects on the secretion of incretin hormones. Chronic effects of coffee and its major components still need to be investigated.

The beneficial actions of exercise training on lipid, glucose and energy metabolism and insulin sensitivity appear to be in part mediated by PGC-1α. Previous studies have shown that spontaneously exercised rats show at rest enhanced responsiveness to exogenous insulin, lower plasma insulin levels and increased skeletal muscle insulin sensitivity. This study was initiated to examine the functional interaction between exercise-induced modulation of skeletal muscle and liver PGC-1α protein expression, whole body insulin sensitivity, and circulating FFA levels as a measure of whole body fatty acid (lipid) metabolism. Two groups of male Wistar rats (2 Mo of age, 188.82 ± 2.77 g BW) were used in this study. One group consisted of control rats placed in standard laboratory cages. Exercising rats were housed individually in cages equipped with running wheels and allowed to run at their own pace for 5 weeks. At the end of exercise training, insulin sensitivity was evaluated by comparing steady-state plasma glucose (SSPG) concentrations at constant plasma insulin levels attained during the continuous infusion of glucose and insulin to each experimental group. Subsequently, soleus and plantaris muscle and liver samples were collected and quantified for PGC-1α protein expression by Western blotting. Collected blood samples were analyzed for glucose, insulin and FFA concentrations. Rats housed in the exercise wheel cages demonstrated almost linear increases in running activity with advancing time reaching to maximum value around 4 weeks. On an average, the rats ran a mean (Mean ± SE) of 4.102 ± 0.747 km/day and consumed significantly more food as compared to sedentary controls (P < 0.001) in order to meet their increased caloric requirement. Mean plasma insulin (P < 0.001) and FFA (P < 0.006) concentrations were lower in the exercise-trained rats as compared to sedentary controls. Mean steady state plasma insulin (SSPI) and glucose (SSPG) concentrations were not significantly different in sedentary control rats as compared to exercise-trained animals. Plantaris PGC-1α protein expression increased significantly from a 1.11 ± 0.12 in the sedentary rats to 1.74 ± 0.09 in exercising rats (P < 0.001). However, exercise had no effect on PGC-1α protein content in either soleus muscle or liver tissue. These results indicate that exercise training selectively up regulates the PGC-1α protein expression in high-oxidative fast skeletal muscle type such as plantaris muscle. These data suggest that PGC-1α most likely plays a restricted role in exercise-mediated improvements in insulin resistance (sensitivity) and lowering of circulating FFA levels.

White adipose tissue can be classified based on its location as subcutaneous and visceral fat, and the latter accumulation is reported to be more detrimental to metabolism. Endoplasmic reticulum (ER) stress has been demonstrated to regulate lipogenesis. The peptide angiotensin(1–7) [Ang(1–7)], which can be produced from angiotensin II (AngII) by angiotensin-converting enzyme 2 (ACE2), plays its role through Mas receptor, also participates in the regulation of lipid metabolism in adipose tissue, however, whether ER stress is involved in the mechanism remains unclear. Therefore, we aimed to explore the role of Ang(1–7) pathway in regulating visceral adipose tissue expansion and ER stress. ACE2 knockout (KO), Mas KO and C57BL/6 J mice were fed with high fat diet. Db/db mice were treated with either normal saline, Ang(1–7) or Ang(1–7) combined with Mas receptor inhibitor A779 using mini osmotic pumps. Fat mass was weighted, fat distribution was evaluated by MRI, and lipid profile and adipokines in epididymal adipose tissue were measured by ELISA kits, and histology of epididymal adipose tissue was also analyzed in multiple animal models. Additionally, differentiated 3T3-L1 cells were pre-loaded with palmitic acid to induce ER stress, then treated with drugs as those administrated to db/db mice. ER stress and lipogenesis related proteins in mice adipose and differentiated 3T3L-1 cells were analyzed by Western blot. ACE2 or Mas KO mice exhibited increased visceral adipose tissue, adipocyte size and protein expression of lipogenesis and ER stress related markers in epididymal adipose tissue compared to wild-type mice. Db/db mice treated with Ang(1–7) displayed decreased visceral fat mass, adipocyte size and protein expression of lipogenesis and ER stress markers in epididymal adipose tissue compared to those treated with normal saline, while A779 partly attenuated these effects. Additionally, Ang(1–7) improved ER stress and lipogenesis markers in differentiated 3T3-L1 cells pre-loaded with palmitic acid. Our findings indicated that Ang(1–7) attenuated visceral adipose tissue expansion and lipogenesis by suppression of ER stress via Mas receptor. The present study provides a potential perspective for Ang(1–7) for the therapeutics of obesity and related disorders.

Serum cholinesterase (ChE) is positively associated with incident diabetes and dyslipidemia. We aimed to investigate the relationship between ChE and the incidence of diabetic retinopathy (DR). Based on a community-based cohort study followed for 4.6 years, 1133 participants aged 55–70 years with diabetes were analyzed. Fundus photographs were taken for each eye at both baseline and follow-up investigations. The presence and severity of DR were categorized into no DR, mild non-proliferative DR (NPDR), and referable DR (moderate NPDR or worse). Binary and multinomial logistic regression models were used to estimate the risk ratio (RR) and 95% confidence interval (CI) between ChE and DR. Among the 1133 participants, 72 (6.4%) cases of DR occurred. The multivariable binary logistic regression showed that the highest tertile of ChE (≥ 422 U/L) was associated with a 2.01-fold higher risk of incident DR (RR 2.01, 95%CI 1.01-4.00; P for trend < 0.05) than the lowest tertile (< 354 U/L). The multivariable binary and multinomial logistic regression showed that the risk of DR increased by 41% (RR 1.41, 95%CI 1.05–1.90), and the risk of incident referable DR was almost 2-fold higher than no DR (RR 1.99, 95%CI 1.24–3.18) with per 1-SD increase of loge-transformed ChE. Furthermore, multiplicative interactions were found between ChE and elderly participants (aged 60 and older; P for interaction = 0.003) and men (P for interaction = 0.044) on the risk of DR. In this study, ChE was associated with the incidence of DR, especially referable DR. ChE was a potential biomarker for predicting the incident DR.