Vertical sleeve gastrectomy-derived gut metabolite licoricidin activates beige fat thermogenesis to combat obesity.

Obesity is a chronic metabolic disease, affecting individuals throughout the world. Bariatric surgery such as vertical sleeve gastrectomy (VSG) provides sustained weight loss and improves glucose homeostasis in obese mice and humans. However, the precise underlying mechanisms remain elusive. In this study, we investigated the potential roles and the mechanisms of action of gut metabolites in VSG-induced anti-obesity effect and metabolic improvement. Methods: High-fat diet (HFD)-fed C57BL/6J mice were subjected to VSG. Energy dissipation in mice was monitored using metabolic cage experiments. The effects of VSG on gut microbiota and metabolites were determined by 16S rRNA sequencing and metabolomics, respectively. The metabolic beneficial effects of the identified gut metabolites were examined in mice by both oral administration and fat pad injection of the metabolites. Results: VSG in mice greatly increased thermogenic gene expression in beige fat, which was correlated with increased energy expenditure. VSG reshaped gut microbiota composition, resulting in elevated levels of gut metabolites including licoricidin. Licoricidin treatment promoted thermogenic gene expression in beige fat by activating the Adrb3-cAMP-PKA signaling pathway, leading to reduced body weight gain in HFD-fed mice. Conclusions: We identify licoricidin, which mediates the crosstalk between gut and adipose tissue in mice, as a VSG-provoked anti-obesity metabolite. Identification of anti-obesity small molecules should provide new insights into treatment options for obesity and its associated metabolic diseases.

The Effect of Early Time-Restricted Eating vs Later Time-Restricted Eating on Weight Loss and Metabolic Health.

CONTEXT: It remains controversial whether the choice of the daily eating window early or later in time-restricted eating (TRE) intervention (early or later TRE) has different effects on weight loss and metabolic health. OBJECTIVE: A network meta-analysis was performed to evaluate the efficacy between early and later TRE in adults with obesity or overweight. METHODS: We searched PubMed, Embase, Web of Science, and Cochrane Library for randomized controlled trials (RCTs) published until October 16, 2022. We conducted a network meta-analysis to evaluate the efficacy of early and later TRE on body weight and metabolic parameters, including glycemic metabolism, blood pressure, and lipid profiles. RESULTS: Twelve RCTs with 730 obese or overweight adults were included in this meta-analysis. Early TRE and later TRE both elicited moderate reductions in body weight and insulin resistance (IR) (homeostasis model assessment of IR) when compared to non-TRE. Interestingly, early TRE showed more effectiveness than later TRE in improving IR (early vs later TRE: -0.44; 95% CI, -0.86 to -0.02; P < .05), whereas no statistically significant difference was detected in weight loss (early vs later TRE: -0.31 kg; 95% CI, -1.15 to 0.53 kg; P >.05). In addition, early TRE rather than later TRE showed significant benefits in glycemic metabolism and blood pressure when compared to non-TRE. No significant differences between early and later TRE were observed for fasting blood glucose, blood pressure, and lipid profiles. CONCLUSION: This meta-analysis suggests that people may choose early TRE for more effective weight management and metabolic benefits. Nevertheless, further large-scale RCTs are warranted to verify our findings.

Study on Multi-Layer Filling Treatment of Extra-Large Goaf and Its Underground Application.

At present, the many domestic, large mined-out areas caused by single filling ability of the slurry flow state, thin layer flow and hardening after filling in multilayer structure generally need to finish filling for many times, because after a filling experience shows that filling body in the last solidification of flow, this leads to a lower one side of the roof, and far distance part of the filling body cannot pick up top. The determination of backfill strength is the key problem of the cemented backfill method, and it is affected by many factors. Therefore, through theoretical calculation, laboratory testing and numerical simulation methods, combined with the field filling process, this paper has verified the flow accumulation and stratification characteristics of stope layered filling slurry. When the slurry concentration is 60−73%, the slope increases exponentially from 2.5° to 8°. It is revealed that the delamination and meshing state are the key factors to determine the overall strength of large-scale stope filling through the testing of particle size distribution in interlayer and flow direction. The reduction effect of the number and Angle of structural weak surface formed by layering and filling on strength is revealed: cement−sand ratio 1:12, concentration 68%, standard curing R28 > 1.81 MPa. The strength reduction coefficient is 61.31% and 92.96% when the number of layers is 1−4. The higher the number of layers, the greater is the reduction coefficient, and when the stratification angle increases by 2, the strength of backfill decreases by 20−30%. The verification of stope filling coring shows that the in situ strength reaches 2.42 MPa, which is 0.61 MPa higher than the standard curing strength, with an increase of 33.7%. When the depth is from 1 m to 5 m, the strength increases from 2.26 MPa to 2.69 MPa, with an increase rate of 18.2%. Finally, through the research and application of the comprehensive technology of mining and filling coordination under the complex goaf group, the residual ore resources of Xianglushan tungsten mine are effectively recovered, the volume of goaf is significantly reduced, and the safety of goaf is improved.

A Review of the Effects of Raw Material Compositions and Steam Curing Regimes on the Performance and Microstructure of Precast Concrete.

In this paper, the effects of steam curing conditions on concrete properties and microstructural characteristics are reviewed, and technical approaches such as appropriate raw material compositions and curing regimes are explored. Moreover, the environmental effects of precast concrete are evaluated. The main conclusion is that steam curing can improve the early strength of concrete, but thermal damage, shrinkage cracking, delayed ettringite formation (DEF), and other factors cause the later strength to increase more slowly or even deteriorate. Accordingly, it is necessary to undertake methods for improvement: (1) Adopt a lot of high-activity mineral admixture + a few low-activity mineral admixture combinations to ensure that the early strength of concrete meets the standard while allowing the subsequent development of concrete hydration to ensure durability. (2) Control the precuring time and temperature gradient of the concrete to allow the initial structure of the concrete to form. (3) Use effective secondary curing, such as soaking in an aqueous solution of limestone, in addition to standard curing to further improve the compactness of concrete. Moreover, the replacement of cement with less than 30% mineral admixtures in steam-cured concrete should be promoted to alleviate the environmental hazards caused by excessive CO2 emissions.

LRG1 is an adipokine that mediates obesity-induced hepatosteatosis and insulin resistance.

Dysregulation in adipokine biosynthesis and function contributes to obesity-induced metabolic diseases. However, the identities and functions of many of the obesity-induced secretory molecules remain unknown. Here, we report the identification of leucine-rich alpha-2-glycoprotein 1 (LRG1) as an obesity-associated adipokine that exacerbates high fat diet-induced hepatosteatosis and insulin resistance. Serum levels of LRG1 were markedly elevated in obese humans and mice compared with their respective controls. LRG1 deficiency in mice greatly alleviated diet-induced hepatosteatosis, obesity, and insulin resistance. Mechanistically, LRG1 bound with high selectivity to the liver and promoted hepatosteatosis by increasing de novo lipogenesis and suppressing fatty acid ß-oxidation. LRG1 also inhibited hepatic insulin signaling by downregulating insulin receptor substrates 1 and 2. Our study identified LRG1 as a key molecule that mediates the crosstalk between adipocytes and hepatocytes in diet-induced hepatosteatosis and insulin resistance. Suppressing LRG1 expression and function may be a promising strategy for the treatment of obesity-related metabolic diseases.

The Yin and Yang function of microRNAs in insulin signalling and cancer.

Data accumulated over the past several decades uncover a vital role of microRNAs (miRNAs) in various biological processes. It is well established that, by binding to target mRNAs, miRNAs act as post-transcription suppressors to inhibit mRNA translation and/or to promote mRNA degradation. Very recently, miRNAs have been found to act as positive regulators to promote gene transcription. In this review, we briefly summarize the regulation and functional roles of miRNAs in metabolic diseases and cancer development. We also review recent advances on the mechanisms by which miRNAs regulate gene expression, focusing on their unconventional roles as enhancers to promote gene expression. Given the high potential of miRNAs as biomarkers for risk assessment and as high-value targets for therapy, a better understanding of the Yin-Yang functional feature of miRNAs and their mechanisms of action could have significant clinical implications for the treatment of various diseases such as obesity, type 2 diabetes, and cancer.

TERC promotes cellular inflammatory response independent of telomerase.

TERC is an RNA component of telomerase. However, TERC is also ubiquitously expressed in most human terminally differentiated cells, which don't have telomerase activity. The function of TERC in these cells is largely unknown. Here, we report that TERC enhances the expression and secretion of inflammatory cytokines by stimulating NK-κB pathway in a telomerase-independent manner. The ectopic expression of TERC in telomerase-negative cells alters the expression of 431 genes with high enrichment of those involved in cellular immunity. We perform genome-wide screening using a previously identified 'binding motif' of TERC and identify 14 genes that are transcriptionally regulated by TERC. Among them, four genes (LIN37, TPRG1L, TYROBP and USP16) are demonstrated to stimulate the activation of NK-κB pathway. Mechanistically, TERC associates with the promoter of these genes through forming RNA-DNA triplexes, thereby enhancing their transcription. In vivo, expression levels of TERC and TERC target genes (TYROBP, TPRG1L and USP16) are upregulated in patients with inflammation-related diseases such as type II diabetes and multiple sclerosis. Collectively, these results reveal an unknown function of TERC on stimulating inflammatory response and highlight a new mechanism by which TERC modulates gene transcription. TERC may be a new target for the development of anti-inflammation therapeutics.

Long-term liraglutide ameliorates nigrostriatal impairment via regulating AMPK/PGC-1a signaling in diabetic mice.

Growing evidence indicates links between type 2 diabetes and Parkinson's disease. The glucagon-like peptide 1 analogue, liraglutide, a commonly used anti-diabetic drug, has protective effects on neurons. The goal of this study was to determine whether long-term liraglutide treatment could reduce the risk of adult type 2 diabetic mice developing Parkinson's disease. Male diabetic db/db mice (12 weeks old) were injected daily with liraglutide (n = 8), or saline (n = 8), and non-diabetic m/m littermates (n = 6) were included as controls. Motor function was assessed every 4 weeks and all mice were sacrificed after 8 weeks of drug intervention for further analysis. The results revealed that long-term treatment of liraglutide protected the db/db mice against the motor function decay and the dopaminergic neuron loss. Liraglutide also restored the impaired AMP kinase (AMPK)/peroxisome proliferator-activated receptor-γ coactivator 1a (PGC-1a) signaling in the striatum of db/db mice. Further experiments in SH-SY5Y cells supported that AMPK is involved in the neuroprotective effect of liraglutide. In summary, long-term liraglutide ameliorated motor dysfunction and dopaminergic neuron impairment in type 2 diabetic mice, probably via enhancing AMPK/PGC-1a signaling.

Association between antidiabetic agents use and leukocyte telomere shortening rates in patients with type 2 diabetes.

Telomere length and telomere shortening rate (TSR) are accepted indicators of aging in cross-sectional population studies. This study aimed to investigate the potential influence of common antidiabetic agents on telomere length and TSR in patients with type 2 diabetes mellitus (T2DM). Leukocyte telomere length was measured through terminal restriction fragment analysis, and TSR was calculated in 388 T2DM patients. Depending on whether or not they received antidiabetic medication, patients were first divided into a treatment group and a nontreatment group. Treated patients were further subdivided into an acarbose-free group (patients taking antidiabetic agents without acarbose) and an acarbose group (patients using acarbose for more than 3 months). Results showed that untreated patients had higher TSRs than patients on antidiabetic drugs. Interestingly, patients in the acarbose group had significantly higher TSRs than patients in the acarbose-free group. Compared to the nontreatment group, the acarbose group showed better glycemic control of HbA1c, but the TSR was also higher. Our results suggest that antidiabetic treatments without acarbose can slow aging. By contrast, acarbose may accelerate biological aging in patients with T2DM, independently of glycemic control.

Capsaicin reduces Alzheimer-associated tau changes in the hippocampus of type 2 diabetes rats.

Type 2 diabetes (T2D) is a high-risk factor for Alzheimer's disease (AD) due to impaired insulin signaling pathway in brain. Capsaicin is a specific transient receptor potential vanilloid 1 (TRPV1) agonist which was proved to ameliorate insulin resistance. In this study, we investigated whether dietary capsaicin could reduce the risk of AD in T2D. T2D rats were fed with capsaicin-containing high fat (HF) diet for 10 consecutive days (T2D+CAP). Pair-fed T2D rats (T2D+PF) fed with the HF-diet of average dose of T2D+CAP group were included to control for the effects of reduced food intake and body weight. Capsaicin-containing standard chow was also introduced to non-diabetic rats (NC+CAP). Blood glucose and insulin were monitored. The phosphorylation level of tau at individual sites, the activities of phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) and glycogen synthase kinase-3ß (GSK-3ß) were analyzed by Western blots. The results revealed that the levels of phosphorylated tau protein at sites Ser199, Ser202 and Ser396 in hippocampus of T2D+CAP group were decreased significantly, but these phospho-sites in T2D+PF group didn't show such improvements compared with T2D group. There were almost no changes in non-diabetic rats on capsaicin diet (NC+CAP) compared with the non-diabetic rats with normal chow (NC). Increased activity of PI3K/AKT and decreased activity of GSK-3ß were detected in hippocampus of T2D+CAP group compared with T2D group, and these changes did not show in T2D+PF group either. These results demonstrated that dietary capsaicin appears to prevent the hyperphosphorylation of AD-associated tau protein by increasing the activity of PI3K/AKT and inhibiting GSK-3ß in hippocampus of T2D rats, which supported that dietary capsaicin might have a potential use for the prevention of AD in T2D.