The anti-hyperglycemic effect of metformin is believed to be caused by its direct action on signaling processes in hepatocytes, leading to lower hepatic gluconeogenesis. Recently, metformin was reported to alter the gut microbiota community in humans, suggesting that the hyperglycemia-lowering action of the drug could be the result of modulating the population of gut microbiota. However, the critical microbial signaling metabolites and the host targets associated with the metabolic benefits of metformin remained elusive. Here, we performed metagenomic and metabolomic analysis of samples from individuals with newly diagnosed type 2 diabetes (T2D) naively treated with metformin for 3 d, which revealed that Bacteroides fragilis was decreased and the bile acid glycoursodeoxycholic acid (GUDCA) was increased in the gut. These changes were accompanied by inhibition of intestinal farnesoid X receptor (FXR) signaling. We further found that high-fat-diet (HFD)-fed mice colonized with B. fragilis were predisposed to more severe glucose intolerance, and the metabolic benefits of metformin treatment on glucose intolerance were abrogated. GUDCA was further identified as an intestinal FXR antagonist that improved various metabolic endpoints in mice with established obesity. Thus, we conclude that metformin acts in part through a B. fragilis–GUDCA–intestinal FXR axis to improve metabolic dysfunction, including hyperglycemia.
Nonalcoholic fatty liver disease is becoming the most common chronic liver disease in Western countries, and limited therapeutic options are available. Here we uncovered a role for intestinal hypoxia-inducible factor (HIF) in hepatic steatosis. Human-intestine biopsies from individuals with or without obesity revealed that intestinal HIF-2α signaling was positively correlated with body-mass index and hepatic toxicity. The causality of this correlation was verified in mice with an intestine-specific disruption of Hif2a, in which high-fat-diet-induced hepatic steatosis and obesity were substantially lower as compared to control mice. PT2385, a HIF-2α-specific inhibitor, had preventive and therapeutic effects on metabolic disorders that were dependent on intestine HIF-2α. Intestine HIF-2α inhibition markedly reduced intestine and serum ceramide levels. Mechanistically, intestine HIF-2α regulates ceramide metabolism mainly from the salvage pathway, by positively regulating the expression of Neu3, the gene encoding neuraminidase 3. These results suggest that intestinal HIF-2α could be a viable target for hepatic steatosis therapy.
A prolonged or excessive adrenergic activation leads to myocyte loss and heart dysfunction; however, how it contributes to heart failure remains poorly defined. Here we show that isoproterenol (ISO) induced aberrant endoplasmic reticulum (ER) stress and apoptotic cell death, which was inhibited by activating the AMP-activated protein kinase (AMPK) in vitro and in vivo. Persistent ISO stimulation suppressed the AMPK phosphorylation and function, resulting in enhanced ER stress and the subsequent cell apoptosis in cardiomyocytes in vitro and in vivo. AMPK activation decreased the aberrant ER stress, apoptosis, and brain natriuretic peptide (BNP) release in ISO-treated cardiomyocytes, which was blocked by AMPK inhibitor Compound C. Importantly, increased ER stress and apoptosis were observed in ISO-treated cardiomyocytes isolated from AMPKα2(-/-) mice. Inhibition of ER stress attenuated the apoptosis but failed to reverse AMPK inhibition in ISO-treated cardiomyocytes. Moreover, metformin administration activated AMPK and reduced both ER stress and apoptosis in ISO-induced rat heart failure in vivo. We conclude that ISO, via AMPK inactivation, causes aberrant ER stress, cardiomyocyte injury, BNP release, apoptosis, and hence heart failure in vivo, all of which are inhibited by AMPK activation.
Hypertension (HTN) is a leading cause of cardiovascular and cerebrovascular diseases. Lifestyle modification may be the preferential approach to prevent and control HTN. The purpose of this study was to evaluate the effects of a community intervention program, which focused on improving the HTN knowledge, diets and lifestyles in a rural Chinese area. The study was carried out in a rural area of the Hubei Province from May 2003 to April 2006. A total of 1632 participants were recruited. Of the participants, 826 from the town of Xiaoxita and 806 from the town of Fenxiang were assigned to the intervention group (group I) and to the control group (group C), respectively. Group I participants underwent an intervention that included HTN education and dietary and lifestyle guidance. Group C participants were not subjected to an intervention. The outcome measures included HTN knowledge, dietary and lifestyle behaviors, and prevalence, awareness, treatment and control rates of HTN. Along with the changes in HTN education (Po0.05), the participants in group I exhibited a significantly greater improvement in dietary habits and lifestyle behaviors, including reducing salty food intake (13.6%), fat intake (22.9%) and alcohol consumption (9.6%), after 3 years in comparison with those in group C (21.7, 31.9 and 18%, respectively). The prevalence of HTN was significantly lower in group I (22.5%) than in group C (36%) after the intervention strategies. The study showed that the implementation of a community intervention program involving HTN education and lifestyle modifications for rural residents is a powerful approach to reduce HTN prevalence and improve long-term health outcomes.
Purpose To compare the efficacy of individualized herbal decoction with standard decoction for patients with stable bronchiectasis through N-of-1 trials. Methods We conducted a single center N-of-1 trials in 17 patients with stable bronchiectasis. Each N-of-1 trial contains three cycles. Each cycle is divided into two 4-week intervention including individualized decoction and fixed decoction (control). The primary outcome was patient self-reported symptoms scores on a 1–7 point Likert scale. Secondary outcomes were 24-hour sputum volume and CAT scores. Results Among 14 completed trials, five showed that the individualized decoction was statistically better than the control decoction on symptom scores (P < 0.05) but was not clinically significant. The group data of all the trials showed that individualized decoction was superior to control decoction on symptom scores (2.13 ± 0.58 versus 2.30 ± 0.65, P = 0.002, mean difference and 95% CI: 0.18 (0.10, 0.25)), 24 h sputum volume (P = 0.009), and CAT scores (9.69 ± 4.89 versus 11.64 ± 5.59, P = 0.013, mean difference and 95% CI: 1.95 (1.04, 2.86)) but not clinically significant. Conclusion Optimizing the combined analysis of individual and group data and the improvement of statistical models may make contribution in establishing a method of evaluating clinical efficacy in line with the characteristics of traditional Chinese medicine individual diagnosis and treatment.
Liver kinase B1 (LKB1), a tumor suppressor, is a central regulator of cell polarity and energy homeostasis. The role of LKB1 in endothelial function in vivo has not been explored.
Methods and Results
Endothelium-specific LKB1 knockout (LKB1endo−/−) mice were generated by crossbreeding LKB1flox/flox mice with VE-Cadherin-Cre mice. LKB1endo−/− mice exhibited hypertension, cardiac hypertrophy, and impaired endothelium-dependent relaxation. LKB1endo−/− endothelial cells exhibited reduced endothelial nitric oxide synthase (eNOS) activity and adenosine monophosphate-activated protein kinase (AMPK; downstream enzyme of LKB1) phosphorylation at Thr172, compared with those of wild-type (WT) cells. In addition, the levels of caveolin-1 were higher in the endothelial cells of LKB1endo−/− mice, and knockdown of caveolin-1 by siRNA normalized eNOS activity. Human antigen R (HuR) bound with the AU-rich elements of caveolin-1 mRNA 3′ UTR, resulting in the increased stability of caveolin-1, and genetic knockdown of HuR decreased the expression of caveolin-1 in LKB1-deficient endothelial cells. Finally, adenoviral overexpression of constitutively active AMPK (CA-AMPK), but not green fluorescent protein (GFP), decreased caveolin-1, lowered blood pressure, and improved endothelial function in LKB1endo−/− mice in vivo.
Our findings indicate that endothelial LKB1 regulates eNOS activity, endothelial function, and blood pressure by modulating AMPK-mediated caveolin-1 expression.
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