The intestine is a major contributor to circulating succinate in mice.

The tricarboxylic acid (TCA) cycle is the epicenter of cellular aerobic metabolism. TCA cycle intermediates facilitate energy production and provide anabolic precursors, but also function as intra- and extracellular metabolic signals regulating pleiotropic biological processes. Despite the importance of circulating TCA cycle metabolites as signaling molecules, the source of circulating TCA cycle intermediates remains uncertain. We observe that in mice, the concentration of TCA cycle intermediates in the portal blood exceeds that in tail blood indicating that the gut is a major contributor to circulating TCA cycle metabolites. With a focus on succinate as a representative of a TCA cycle intermediate with signaling activities and using a combination of gut microbiota depletion mouse models and isotopomer tracing, we demonstrate that intestinal microbiota is not a major contributor to circulating succinate. Moreover, we demonstrate that endogenous succinate production is markedly higher than intestinal succinate absorption in normal physiological conditions. Altogether, these results indicate that endogenous succinate production within the intestinal tissue is a major physiological source of circulating succinate. These results provide a foundation for an investigation into the role of the intestine in regulating circulating TCA cycle metabolites and their potential signaling effects on health and disease.

Liraglutide ameliorates non-alcoholic fatty liver disease by enhancing mitochondrial architecture and promoting autophagy through the SIRT1/SIRT3-FOXO3a pathway.

AIM: Overwhelming oxidative stress is implicated as crucial in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Liraglutide, a well-established antidiabetes drug, was recently reported to ameliorate NAFLD with an elusive mechanism. We used a mouse model to examine whether liraglutide could ameliorate NAFLD and explored the possible mechanisms. METHODS: Twenty C57BL/6J mice were randomly treated with a normal-fat diet or high-fat diet for 16 weeks, then further distributed into four groups and subjected to s.c. injection of liraglutide or saline for 4 weeks. The growth/metabolism, oxidative stress, mitochondrial architecture and autophagy were assessed prospectively at the 20th week. RESULTS: High-fat diet inducement resulted in severe NAFLD while liraglutide treatment significantly reversed the trend, marked by reduced bodyweight, improved glucose tolerance and liver triglyceride composition. Reduced hepatic malondialdehyde level, increased mRNA and protein levels of CATALASE and MNSOD indicated liraglutide affected both the oxidative and antioxidative process to ameliorate oxidative stress. After liraglutide administration, the upregulated mRNA and protein levels of mitochondrial fission and fusion-related DRP1, OPA1 and respiratory chain-related COMPLEX1, UCP2 demonstrated the enhancement of mitochondrial architecture which may attenuate the generation of reactive oxygen species (ROS), while the diminished mRNA and protein level of P62 and increased levels of Beclin1 and LC3II/I ratio indicated the promoting autophagy, which probably contribute to the ROS elimination. Further, restored protein levels of Sirtuin1/Sirtuin3 and the downstream p-FOXO3a reveal the probable pathways of liraglutide acting on autophagy. CONCLUSION: Liraglutide diminishes oxidative stress by enhancing mitochondrial architecture and promoting autophagy through the SIRT1/SIRT3-FOXO3a-LC3 pathway to ameliorate diet-induced NAFLD.

Endurance exercise ameliorates low birthweight developed catch-up growth related metabolic dysfunctions in a mouse model.

Low birthweight is known to predict high risk of metabolic diseases in adulthood, while regular endurance exercises are believed sufficient to improve metabolic dysfunction. In this study, we established a mouse model to determine whether long-term exercise training could ameliorate catch-up growth, and we explored the possible underlying mechanisms. By restricting maternal food intake during the last week of gestation, we successfully produced low birthweight pups. Further, normal birthweight mice and low birthweight mice were randomly distributed into one of three groups receiving either a normal fat diet, high fat diet, or high fat diet with exercise training. The growth/metabolism, mitochondrial content and functions were assessed at 6 months of age. Through group comparisons and correlation analyses, the 4th week was demonstrated to be the period of crucial growth and chosen to be the precise point of intervention, as the growth rate at this point is significantly correlated with body weight, intraperitoneal glucose tolerance test (IPGTT), Lee's index and fat mass in adulthood. In addition, regular endurance exercises when started from 4 weeks remarkably ameliorated low birthweight outcomes and induced catch-up growth and glucose intolerance in the 25th week. Furthermore, real-time PCR and western blot results indicated that the effect of long-term exercise on mitochondrial functions alleviated catch-up related metabolic dysfunction. To conclude, long-term exercise training from the 4th week is sufficient to ameliorate catch-up growth and related metabolic disturbances in adulthood by promoting mitochondrial functions in skeletal muscle.

Dual Modification of P3-Type Layered Cathodes to Achieve High Capacity and Long Cyclability for Sodium-Ion Batteries.

Sodium-ion batteries (SIBs) have garnered extensive attentions in recent years as a low-cost alternative to lithium-ion batteries. However, achieving both high capacity and long cyclability in cathode materials remains a challenge for SIB commercialization. P3-type Na0.67Ni0.33Mn0.67O2 cathodes exhibit high capacity and prominent Na+ diffusion kinetics but suffer from serious capacity decay and structural deterioration due to stress accumulation and phase transformations upon cycling. In this work, a dual modification strategy with both morphology control and element doping is applied to modify the structure and optimize the properties of the P3-type Na0.67Ni0.33Mn0.67O2 cathode. The modified Na0.67Ni0.26Cu0.07Mn0.67O2 layered cathode with hollow porous microrod structure exhibits an excellent reversible capacity of 167.5 mAh g-1 at 150 mA g-1 and maintains a capacity above 95 mAh g-1 after 300 cycles at 750 mA g-1. For one thing, the specific morphology shortens the Na+ diffusion pathway and releases stress during cycling, leading to excellent rate performance and high cyclability. For another, Cu doping at the Ni site reduces the Na+ diffusion energy barrier and mitigates unfavorable phase transitions. This work demonstrates that the electrochemical performance of P3-type cathodes can be significantly improved by applying a dual modification strategy, resulting in reduced stress accumulation and optimized Na+ migration behavior for high-performance SIBs.

"Metformin Impairs Intestinal Fructose Metabolism".

Objective: To investigate the effects of metformin on intestinal carbohydrate metabolism in vivo. Method: Male mice preconditioned with a high-fat, high-sucrose diet were treated orally with metformin or a control solution for two weeks. Fructose metabolism, glucose production from fructose, and production of other fructose-derived metabolites were assessed using stably labeled fructose as a tracer. Results: Metformin treatment decreased intestinal glucose levels and reduced incorporation of fructose-derived metabolites into glucose. This was associated with decreased intestinal fructose metabolism as indicated by decreased enterocyte F1P levels and diminished labeling of fructose-derived metabolites. Metformin also reduced fructose delivery to the liver. Proteomic analysis revealed that metformin coordinately down-regulated proteins involved carbohydrate metabolism including those involved in fructolysis and glucose production within intestinal tissue. Conclusion: Metformin reduces intestinal fructose metabolism, and this is associated with broad-based changes in intestinal enzyme and protein levels involved in sugar metabolism indicating that metformin's effects on sugar metabolism are pleiotropic.

A serum metabolomics study of vascular cognitive impairment patients based on Traditional Chinese medicine syndrome differentiation.

Objective: Vascular cognitive impairment (VCI) accounts for approximately 50%-70% of all dementia cases and poses a significant burden on existing medical systems. Identifying an optimal strategy for preventing VCI and developing efficient symptomatic treatments remains a significant challenge. Syndrome differentiation represents a fundamental approach for personalized diagnosis and treatment in Traditional Chinese Medicine (TCM) and aligns with the principles of precision medicine. The objective of this study was to elucidate the metabolic characteristics of VCI based on TCM syndrome differentiation, thus providing novel insights into the diagnosis and treatment of VCI. Methods: A 2-year cross-sectional cognitive survey was conducted in four communities in Beijing between September 2020 and November 2022. The syndrome differentiation of participants was based on the Kidney-Yang Deficiency Syndrome Scale (KYDSS), which was originally developed by Delphi expert consultation. The identification of serum metabolites was performed by Ultra performance liquid chromatography (UPLC) analysis coupled with an electrospray ionization quadruple time-of-flight mass spectrometer (ESI-QTOF MS). Multivariate, univariate, and pathway analyses were used to investigate metabolic changes. Logistic regression models were also used to construct metabolite panels that were capable of discerning distinct groups. Phospholipase A2 (PLA2) levels were measured by a commercial ELISA kit. Results: A total of 2,337 residents completed the survey, and the prevalence of VCI was 9.84%. Of the patients with VCI, those with Kidney-Yang deficiency syndrome (VCIS) accounted for 70.87% of cases and exhibited more severe cognitive impairments. A total of 80 participants were included in metabolomics study, including 30 with VCIS, 20 without Kidney-Yang deficiency syndrome (VCINS), and 30 healthy control participants (C). Ultimately, 45 differential metabolites were identified when comparing the VCIS group with group C, 65 differential metabolites between the VCINS group and group C, and 27 differential metabolites between the VCIS group and the VCINS group. The downregulation of phosphatidylethanolamine (PE), and phosphatidylcholine (PC) along with the upregulation of lysophosphatidylethanolamine (LPE), lysophosphatidylcholine (LPC), phosphatidic acid (PA) and phospholipase A2 (PLA2) can be considered as the general metabolic characteristics associated with VCI. Dysfunction of glycerophospholipids, particularly LPEs and PCs, was identified as a key metabolic characteristic of VCIS. In particular Glycerophospho-N-Arachidonoyl Ethanolamine (GP-NArE) was discovered for the first time in VCI patients and is considered to represent a potential biomarker for VCIS. The upregulation of PLA2 expression was implicated in the induction of alterations in glycerophospholipid metabolism in both VCIS and VCINS. Moreover, robust diagnostic models were established based on these metabolites, achieving high AUC values of 0.9322, 0.9550, and 0.9450, respectively. Conclusion: These findings contribute valuable information relating to the intricate relationship between metabolic disorders in VCI, neurodegeneration and vascular/neuroinflammation. Our findings also provide a TCM perspective for the precise diagnosis and treatment of VCI in the context of precision medicine.

HGFAC is a ChREBP-regulated hepatokine that enhances glucose and lipid homeostasis.

Carbohydrate response element-binding protein (ChREBP) is a carbohydrate-sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-Seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified hepatocyte growth factor activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone hepatocyte growth factor. We demonstrate that HGFAC-KO mice had phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain- and loss-of-function genetic mouse models, we demonstrate that HGFAC enhanced lipid and glucose homeostasis, which may be mediated in part through actions to activate hepatic PPARγ activity. Together, our studies show that ChREBP mediated an adaptive response to overnutrition via activation of HGFAC in the liver to preserve glucose and lipid homeostasis.

[The efficiency and safety of laparoscopic surgery for colorectal carcinoma: a systematic review].

OBJECTIVE: To evaluate and compare the efficiency and safety of laparoscopic surgery (LS) and open surgery (OS) in the treatment of colorectal carcinoma. METHODS: Randomized controlled trials on laparoscopic surgery and open surgery for colorectal carcinoma from January 2000 to October 2010 were searched in the databases of EMbase, PubMed, Cochrane Library, Sciencedirect, Springer, VIP, CNKI, CBMdisc. The methodological quality was assessed according to the standard of Cochrane systematic review. For homogeneous studies, RevMan5.0 software was used for meta-analysis. RESULTS: A total of 13 RCTs involving 4603 patients were included in this study, and among those 6 were multi-center randomized controlled trials. The meta-analysis showed that: the operation time of the LS group was longer than that of the OS group (WMD = 38.91, 95%CI: 33.89 - 43.93, P < 0.001), the blood loss (WMD = -138.14, 95%CI: -195.79 - -80.50, P < 0.001) and the length of hospital stay (WMD = 2.91, 95%CI: -4.65 - -1.17, P = 0.001) of the LS group was less than those in OS group. There was no significant differences between the two groups in the number of dissected lymph nodes (WMD = -0.62, 95%CI: -1.47 - 0.23, P = 0.150). There was no significant differences between the two groups in terms of the postoperative complications (30 days) (RR = 0.78, 95%CI: 0.59 - 1.01, P = 0.06). There was no significant differences between the two groups in 3-year overall survival (RR = 1.00, 95%CI: 0.96 - 1.04, P = 0.970). There was no significant differences between the two groups in 5-year overall survival (RR = 1.03, 95%CI: 0.99 - 1.08, P = 0.140). There was no significant differences between the two groups in 5-year overall recurrence (RR = 0.89, 95%CI: 0.74 - 1.07, P = 0.200). CONCLUSIONS: Laparoscopic surgery for colorectal carcinoma is a safe and effective therapy as open surgery in the short term or long term outcomes. It could be an acceptable alternative to open surgery for colorectal carcinoma.

A Systems Approach Dissociates Fructose-Induced Liver Triglyceride from Hypertriglyceridemia and Hyperinsulinemia in Male Mice.

The metabolic syndrome (MetS), defined as the co-occurrence of disorders including obesity, dyslipidemia, insulin resistance, and hepatic steatosis, has become increasingly prevalent in the world over recent decades. Dietary and other environmental factors interacting with genetic predisposition are likely contributors to this epidemic. Among the involved dietary factors, excessive fructose consumption may be a key contributor. When fructose is consumed in large amounts, it can quickly produce many of the features of MetS both in humans and mice. The mechanisms by which fructose contributes to metabolic disease and its potential interactions with genetic factors in these processes remain uncertain. Here, we generated a small F2 genetic cohort of male mice derived from crossing fructose-sensitive and -resistant mouse strains to investigate the interrelationships between fructose-induced metabolic phenotypes and to identify hepatic transcriptional pathways that associate with these phenotypes. Our analysis indicates that the hepatic transcriptional pathways associated with fructose-induced hypertriglyceridemia and hyperinsulinemia are distinct from those that associate with fructose-mediated changes in body weight and liver triglyceride. These results suggest that multiple independent mechanisms and pathways may contribute to different aspects of fructose-induced metabolic disease.

Protective effects of Xiongshao Capsule () on anti-inflammatory function of high-density lipoprotein in an atherosclerosis rabbit model.

OBJECTIVE: To observe the effects of Xiongshao Capsule (, XSC) on anti-inflflammatory properties of high-density lipoprotein (HDL), myeloperoxidase (MPO) and paraoxonase 1 (PON1) in serum of atherosclerosis (AS) rabbit model and explore the anti-inflflammatory protective effects of XSC on HDL. METHODS: Sixty rabbits were randomized into the control, the model, XSC low-, medium- and high-dose (Rhizoma Chuanxiong + Radix Paeoniae rubra: 0.6+0.3, 1.2+0.6, 2.4+1.2g·kg-1·day-1, respectively), and simvastatin (1g·kg-1·day-1) groups. The model rabbits were fed with high-fat diet and drugs for 15 weeks. The blood and thoracic aortas samples were collected at the end of 15 weeks. The levels of serum MPO and PON1 as well as total cholesterol (TC) and free cholesterol (FC) in aorta wall cells were tested by enzyme linked immunosorbent assay. RESULTS: TC and FC in the model group were significantly higher than those in the control group (P<0.01). Compared with the model group, TC and FC in the XSC groups were signifificantly lower (P<0.05 or P<0.01), so was simvastatin group (P<0.01). There was no signifificant difference in PON1 level between groups (P>0.05), even between model and control groups (P>0.05). The serum MPO level in the model group was signifificantly higher than that in the control group (P<0.05), which was signifificantly lower in XSC groups as well as simvastatin group (P<0.05 or P<0.01), and no difference was found between XSC groups and simvastatin group (P>0.05). CONCLUSIONS: XSC can reduce the serum MPO level in AS rabbits to protect the anti-inflammatory function of HDL, maintaining the normal lipid transport function. TC and FC levels in aorta cells decline, and this process initiated by XSC plays an anti-AS role.

Antioxidant MMCC ameliorates catch-up growth related metabolic dysfunction.

Postnatal catch-up growth may be related to reduce mitochondrial content and oxidation capacity in skeletal muscle. The aim of this study is to explore the effect and mechanism of antioxidant MitoQuinone mesylate beta cyclodextrin complex (MMCC) ameliorates catch-up growth related metabolic disorders. Catch-up growth mice were created by restricting maternal food intake during the last week of gestation and providing high fat diet after weaning. Low birthweight mice and normal birthweight controls were randomly subjected to normal fat diet, high fat diet and high fat diet with MMCC drinking from the 4th week. MMCC treatment for 21 weeks slowed down the catch up growth and ameliorated catch-up growth related obesity, glucose intolerance and insulin resistance. MMCC administration significantly inhibited the peroxidation of the membrane lipid and up-regulated the antioxidant enzymes Catalase and MnSOD. In addition, MMCC treatment effectively enhanced mitochondrial functions in skeletal muscle through the up-regulation of the ATP generation, and the promotion of mitochondrial replication and remodeling. To conclude, this study demonstrates that antioxidant MMCC effectively ameliorates catch-up growth related metabolic dysfunctions by increasing mitochondrial functions in skeletal muscle.

Metabolic Biomarkers for Prognostic Prediction of Pre-diabetes: results from a longitudinal cohort study.

To investigate the metabolic biomarkers of predicting the transition from pre-diabetes (pre-DM) to normal glucose regulation (NGR) and diabetes (DM) in a longitudinal cohort study. 108 participants with pre-DM were followed up for ten years and divided into 3 groups according to different glycemic outcomes. 20 participants progressed to DM, 20 regressed to NGR, and 68 remained at pre-DM. Alterations in plasma metabolites in these groups were evaluated by untargeted ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). Twenty three metabolites related to glycerophospholipid metabolism, oxidation and antioxidation were associated with the process from pre-DM to NGR, while twenty two metabolites related to amino acid metabolism, glycerophospholipid metabolism and mitochondrial ß-oxidation played important roles in the progression to DM. Results from stepwise logistic regression analysis showed that five biomarkers (20-Hydroxy-leukotriene E4, Lysopc(20:4), 5-methoxytryptamine, Endomorphin-1, Lysopc(20:3)) were good prediction for the restoration to NGR, and five biomarkers (Iso-valeraldehyde, linoleic acid, Lysopc(18:1), 2-Pyrroloylglycine, Dityrosine) for the development of DM. The findings suggest that the combination of these potential metabolites may be used for the prognosis of pre-DM. Targeting the pathways that involved in these prognostic biomarkers would be beneficial for the regression to NGR and the early prevention of DM among pre-DM.

Contribution of birth weight and adult waist circumference to cardiovascular disease risk in a longitudinal study.

To determine the association of birth weight (BW) and waist circumference (WC) on cardiovascular disease (CVD). The longitudinal cohort study consisted of 745 participants who were able to provide their birth weight information and were followed from 2002 to 2014. During the follow-up, 83 events of CVD were confirmed. After adjusting for confounding factors, subjects with birth weight <2500 g were at a significantly increased CVD risk when compared to subjects with birth weight between 2500-3999 g (OR 2·47, 95%CI, 1·07-5·71). When high waist circumference (HWC), a measurement of adult obesity, was incorporated into stratifying factors according to presence or absence of low birth weight (LBW, birth weight <2500 g), adjusted CVD risk was significantly elevated in -LBW/+ HWC group (OR 1·94, 95%CI, 1·10-3·43) and marginally significantly increased in +LBW/-HWC group (OR 2·94, 95%CI, 1·00-8·64). CVD risk was highest in subjects with LBW and HWC (+LBW/+HWC), OR 4·74 (95%CI, 1·48-15·21). Higher waist circumference in adulthood is an especially strong risk factor for cardiovascular disease among those small at birth. In this cohort, birth size and adiposity in adulthood interact to predict events of cardiovascular disease.

Author Correction: Metabolic Biomarkers for Prognostic Prediction of Pre-diabetes: results from a longitudinal cohort study.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

Deletion of Macrophage Mineralocorticoid Receptor Protects Hepatic Steatosis and Insulin Resistance Through ERα/HGF/Met Pathway.

Although the importance of macrophages in nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) has been recognized, how macrophages affect hepatocytes remains elusive. Mineralocorticoid receptor (MR) has been implicated to play important roles in NAFLD and T2DM. However, cellular and molecular mechanisms are largely unknown. We report that myeloid MR knockout (MRKO) improves glucose intolerance, insulin resistance, and hepatic steatosis in obese mice. Estrogen signaling is sufficient and necessary for such improvements. Hepatic gene and protein expression suggests that MRKO reduces hepatic lipogenesis and lipid storage. In the presence of estrogen, MRKO in macrophages decreases lipid accumulation and increases insulin sensitivity of hepatocytes through hepatocyte growth factor (HGF)/Met signaling. MR directly regulates estrogen receptor 1 (Esr1 [encoding ERα]) in macrophages. Knockdown of hepatic Met eliminates the beneficial effects of MRKO in female obese mice. These findings identify a novel MR/ERα/HGF/Met pathway that conveys metabolic signaling from macrophages to hepatocytes in hepatic steatosis and insulin resistance and provide potential new therapeutic strategies for NAFLD and T2DM.

Gender-related affecting factors of prediabetes on its 10-year outcome.

OBJECTIVE: To investigate the gender-related affecting factors of prediabetes on its 10-year outcome, in a longitudinal study. METHODS AND RESULTS: This longitudinal population-based study was performed in the Ping Liang community, Yangpu district, Shanghai, between November 2002 and October 2014. There were 334 participants with prediabetes enrolled in the final analysis. While a certain proportion of the prediabetic population progress to diabetes, the majority remain at the same level or even revert to normal glucose regulation. No gender difference was observed in the change of glucose regulation. However, results from an adjusted logistic regression analysis in males showed that physical activity was significantly associated with both elevated odds of reverting to normal glucose regulation (active vs inactive, OR 3.00, 95% CI 1.09 to 8.30) and developing diabetes (OR 0.34, 95% CI 0.13 to 0.92). Age, baseline 2 h glucose, triglycerides and smoking status were also risk factors significantly associated with diabetes development; while for females, waist circumference played a key role in the outcome. Every unit elevation of waist circumference was associated with lower odds of reverting to normal glucose regulation (OR, 0.94; 95% CI 0.89 to 0.98) and higher odds of progressing to diabetes (OR, 1.05; 95% CI 1.01 to 1.10). Baseline hypertension and family history of diabetes carried higher risk for developing diabetes as well. CONCLUSIONS: Physical activity in males and waist circumference in females are important factors predicting both progression to diabetes and regression to normal glucose regulation, indicating that more exercise for males and lower waist circumference for females are beneficial for prediabetes to achieve reversion.

Effects of prediabetes mellitus alone or plus hypertension on subsequent occurrence of cardiovascular disease and diabetes mellitus: longitudinal study.

Whether prediabetes mellitus alone or combined with other disorders means a higher risk for cardiovascular disease (CVD) is still controversial. This study aimed to investigate the association between prediabetes mellitus and CVD and diabetes mellitus and to explore whether prediabetes mellitus alone or combined with other syndromes, such as hypertension, could promote CVD risks significantly. This longitudinal population-based study of 1609 residents from Shanghai in Southern China was conducted between 2002 and 2014. Participants with a history of CVD at baseline were excluded from analysis. Multivariate log-binomial regression models were used to adjust possible coexisting factors. Incidence of CVD during follow-up was 10.1%. After adjusting for age, sex, and other factors, the association between prediabetes mellitus and CVD was not observed. When hypertension was incorporated in stratifying factors, adjusted CVD risk was elevated significantly (odds ratio, 2.41; 95% confidence interval, 1.25-4.64) in prediabetes mellitus and hypertension combined group, and coexistence of diabetes mellitus and hypertension made CVD risk highly significantly increased, reaching 3.43-fold higher than the reference group. Blood glucose level within prediabetic range is significantly associated with elevated risks for diabetes mellitus after multivariable adjustment, but only when it is concurrent with other disorders, such as hypertension, it will significantly increase CVD risk.