npj Metabolic Health and Disease最新文献

Alcoholic beverages have been concerned not only for gastronomic delight but also for certain impacts on health, such as obesity, diabetes, and cardiovascular diseases. In this study, we assessed the bioactive functions of 1,1-Diethoxyethane (1,1-DEE), a flavoring compound formed during the aging process of wine by flor yeast, using both cultured cell lines and a high-fat diet (HFD) mouse model. 1,1-DEE was identified in the batches of ethanol that induced oxidation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) using gel mobility shift assay and gas chromatography-mass spectrometry. PTEN was reversibly oxidized when exposed to 1,1-DEE, but 1,2-DEE did not induce PTEN oxidation. Mechanistically, 1,1-DEE treatment enhanced the production of mitochondrial reactive oxygen species, accompanying by oxidation of PTEN and subsequent activation of Akt signaling. 1,1-DEE treatment elevated Akt activation when combined with insulin, compared with insulin alone, and alleviated palmitate-induced insulin resistance in C2C12 myoblasts. Moreover, the oral administration of 1,1-DEE alleviated glucose intolerance and insulin resistance in HFD-fed mice. 1,1-DEE also mitigated HFD-induced body weight gain and hepatic dyslipidemia without reduction of food intake. Transcriptome analysis revealed significant genes involved in the improvement of insulin sensitivity and dyslipidemia. Thus, 1,1-DEE may serve as a promising therapeutic agent for the intervention of obesity, diabetes, and dyslipidemia.

Ferroptosis, iron-dependent regulated cell death, drives age-related cardiac dysfunction. This review examines aerobic exercise modulation of ferroptosis in aging cardiomyocytes via Parkin-ACSL4 axis. Parkin promotes ACSL4 ubiquitination/degradation, reducing lipid peroxidation and ROS. Exercise activates PINK1/Parkin mitophagy and hepcidin, enhancing mitochondrial resilience and iron homeostasis. Despite promising preclinical evidence, molecular mechanisms remain unclear. Aerobic exercise offers non-pharmacological cardiac protection against ferroptosis in aging.

Prediabetes can progress to type 2 diabetes (T2D), but individual risk varies widely. Few studies have rigorously characterized subgroups at the point of prediabetes (PD) onset. Using electronic health records (EHRs), we developed a machine learning approach to stratify PD and analyze T2D progression risk. We defined PD onset based on strict HbA1c criteria and excluded patients with missing follow-ups or atypical clinical events, yielding a high-fidelity cohort of 14,436 patients from an initial pool of 74,054 (2017-2023, MedStar Health). An XGBoost model using routine features, including HbA1c, BMI, blood pressure, lipids, ALT, medication history, and lifestyle factors, was trained on 2018-2020 data and tested on 2021-2022 patients, achieving an AUC of 81.6%. Risk scores enabled subtyping into high-, medium-, and low-risk groups with distinct progression trajectories. Stratification patterns remained consistent in future cohorts. This approach supports earlier, personalized intervention and diabetes risk prediction using real-world EHR data.

Type 2 diabetes is a global health burden driven by genetic and environmental factors. Continuous glucose monitoring (CGM) can effectively guide lifestyle interventions in non-diabetic. However, predefined CGM metrics fail to fully capture the dysglycemic information contained in the high-dimensional time-series CGM data. This study employed deep learning to learn dysglycemia features from CGM data associated with diabetes and derived a digital biomarker of dysglycemia, validated against traditional dysglycemic biomarkers and diabetes polygenic risk score (PRS). Output of the deep learning model, called the deep learning-score, was significantly associated with multiple existing dysglycemic biomarkers and PRS of diabetes (P = 0.007). Moreover, existing CGM metrics were not associated with prevalent diabetes after adjusting for the deep learning-score, while the deep learning-score remained significantly associated with prevalent diabetes (P < 0.001) in a regression analysis. This digital biomarker demonstrated potential for providing dynamic feedback on dysglycemia and improving long-term intervention adherence.

The neurovascular unit includes multiple cell types that communicate with each other on a second-by-second basis using traditional neurotransmitters and other signaling molecules, however the function of each cell or the mechanisms by which homeostasis is maintained are still unclear. Here, we review the important elements of the astro- and neurovascular unit and the modulators that contribute to the orchestration of functional hyperemia in health and disease.

Low birthweight is a risk factor for hypertension and chronic kidney disease. Kidneys of low birthweight babies typically have a low nephron endowment, which is permanent. Therefore, strategies to boost or rescue nephron endowment in low birthweight offspring might be expected to decrease the prevalence of these chronic conditions. We previously reported that a high-fat diet (17% protein, 43% carbohydrate, 40% fat) fed to mice before mating and until weaning boosted nephron endowment in mice by 20%. Here, we show that offspring from dams fed a normal diet during pregnancy and switched to a high-fat diet at birth had a 14% augmented nephron endowment. Additionally, transition to a high-fat diet at birth completely rescued a 20% nephron deficit induced by feeding dams a low-protein diet (8% protein, 76% carbohydrate, 16% fat) during gestation. The augmentation and rescue of nephron endowment were associated with increased maternal caloric intake on day 1, as well as increased maternal fat and reduced carbohydrate intake during the postnatal period of rapid nephrogenesis. These findings indicate that the balance between the three macronutrients in the maternal diet, both pre- and postnatally, is crucial for nephron endowment.

The aquaporin-7 (AQP7) channel mediates glycerol release from adipocytes. Genetic variants decreasing AQP7 expression are associated with adiposity and metabolic complications in humans. Using human data, mouse models, and cellular systems, we investigated how AQP7 influences adipose tissue maturation and homeostasis. Negative correlations between methylation on the AQP7 locus, expression of AQP7 in the adipose tissue and BMI were observed in humans. Mice lacking Aqp7 had increased body weight and visceral fat accumulation, due to adipocyte hypertrophy and chronic inflammation, impairing transport across the peritoneal membrane. These changes were further intensified by a high-glucose diet. Mechanistically, AQP7 deficiency disrupted the expression of genes related to adipogenesis and adipocyte function, resulting in a shift toward fibrosis and inflammation, while secreted factors from AQP7-null adipocytes promoted fibroblast activation. These findings establish AQP7 as a key regulator of adipose tissue homeostasis, metabolic dysregulation, and inflammation/fibrosis, exacerbated by glucose-induced obesity.

Protein acetylation is a fundamental regulatory mechanism occurring primarily on lysine amino acids. Here we report systematic in vivo characterization of cysteine S-acetylation as a widespread post-translational modification in mammalian tissues. By developing specialized sample preparation methods that preserve the labile thioester bond, we identified over 400 sites of cysteine acetylation in mouse liver, mirroring the abundance of lysine acetylation. Proteomic surveys across nine murine tissues revealed tissue-specific acetylation patterns that are enriched on metabolic enzymes in the cytoplasm. Cold exposure in mice triggers coordinated remodeling of the brown adipose tissue cysteine acetylome. Functional studies demonstrate that the acetylation of GAPDH Cys150 abolishes catalytic activity and correlates with nuclear enrichment, paralleling the known effects of S-nitrosylation on this enzyme. These findings establish cysteine acetylation as a widespread modification of metabolic proteins that responds to changes in cellular acetyl-CoA availability, fundamentally expanding the landscape of protein acetylation beyond lysine.

Left ventricular hypertrophy (LVH) is associated with increased cardiac expression of fibroblast growth factor-23 (FGF23) in mice and men. To further elucidate the role of cardiac FGF23 in LVH, we specifically ablated Fgf23 in cardiomyocytes, and employed transverse aortic constriction (TAC) to induce LVH by pressure overload. LVH developed independently of cardiac FGF23, but cardiomyocyte-specific Fgf23 knock-out (Fgf23^CKO) TAC mice were characterized by ameliorated hypertension and a distinct reduction of cardiac fibrosis, relative to Fgf23^fl/fl TAC controls. Spatial metabolomics revealed reduced intracellular glucose abundance and lowered cardiac energy charge in Fgf23^CKO TAC mice, whereas treatment of cultured cardiomyocytes with FGF23 increased intracellular glucose abundance. Spatial transcriptomics showed a downregulation of glucose transporters and glycolytic enzymes, but an upregulation of enzymes involved in fatty acid oxidation in Fgf23^CKO TAC mice. These findings suggest that reduced cardiac FGF23 signaling promotes cardiac metabolic health by downregulating glucose consumption and favoring fatty acid oxidation. Created in https://BioRender.com.

Profound social and economic changes in recent generations have led to reduced physical activity and increased calorie intake, leading to a higher incidence of metabolic disease. These effects may propagate across generations, amplifying the impact on descendants. Here we found that limited physical activity of dams brought about increased liver weight and lipid accumulation in the male offspring on a moderate fat calorie western-like diet from weaning to adulthood, while maternal voluntary exercise on running wheels during the postpartum period was sufficient to prevent the development of the phenotype in the otherwise sedentary offspring. Elevated fatty acid (FA) and reduced acylcarnitine levels in the liver of offspring of exercising mothers suggested increased FA flux for oxidation that, with elevated mitochondrial β-oxidation, indicated a maternally programmed mechanism to cope with increased fat calories. Finally, single-nucleus transcriptional profiling indicated dysregulated lipid metabolism in hepatocytes and upregulation of phagocytosis-related genes in Kupffer cells/macrophages and minimal response in stellate cells, indicating a moderate liver damage in the offspring of sedentary but not exercising mothers. A similar combination of maternal sedentary lifestyle and increased fat calorie intake from childhood could contribute to the increased incidence of obesity and NAFLD in recent generations.