npj Metabolic Health and Disease最新文献

Intestine-exclusive metabolic processes involve the degradation of dietary components and xenobiotics through intricate and dynamic interactions between the host epithelial cells and gut microbiota. Disruptions in this fragile equilibrium lead to metabolic and gastrointestinal diseases, highlighting the profound impact of the gut microbiota on the host intestinal metabolic processes. Gut microbes play a crucial role in influencing intestinal metabolic homeostasis by affecting nutrient sensing, gut hormones, neurotransmitters, and redox balance, collectively modulating mucosal gene expression and metabolic signaling pathways. These intestinal-level host-microbe metabolic interactions profoundly impact extra-intestinal tissues and organs. This comprehensive review provides mechanistic insights on the crucial role of gut microbiota in sustaining metabolic health by narrowing down to the gut-level metabolic interactions.

Fibroblast growth factor 21 (FGF21) analogues are in clinical development as treatments for metabolic and alcohol-associated liver disease. The aim of this study was to characterize the first FGF21 knockout (KO) rat line to validate its utility as a translational animal model that recapitulates human disease. We generated an FGF21 KO rat model and exposed 6-month-old WT and KO rats to either chow (n = 8 per genotype) or the obesogenic GAN (Gubra Amylin NASH) diet (n = 16 per genotype) for 12 weeks. Lack of endogenous FGF21 increased plasma transaminases, liver weight, and total levels of liver TG in GAN-fed FGF21 KO rats. FGF21 KO had no impact on body weight, glycaemic traits, or MASH histological endpoints, including hepatic steatosis, NAS score, lobular inflammation, ballooning degeneration, fibrosis stage, or the liver transcriptome. Finally, we demonstrate that endogenous FGF21 does not regulate drinking behaviour in rats.

Dietary composition can significantly influence health and lifespan, however, robust knowledge on which food components, at what concentration exert which long-term health effects is still incomplete. Here, we explored the effects of dietary protein intake on Ercc1 ^Δ/- DNA-repair-deficient mice, which are an excellent model for accelerated ageing and are hyperresponsive to the anti-ageing effect of dietary restriction. Restricting dietary protein by 50% extended lifespan in male mice, but not in females. Restricting protein levels beyond 80% improved various neurological health parameters, while a further reduction to 95% affected appetite and became distinctly detrimental. Conversely, a near doubling of protein intake and isocaloric compensatory lowering with carbohydrates significantly shortened lifespan in both sexes. Gene expression analysis of liver from mice on a high-protein, low-carbohydrate diet to those on high-carbohydrate, low-protein revealed increased expression of oxidative phosphorylation, enrichment of processes associated with tissue injury, inflammation, and gene-length-dependent transcriptional decline (GLTD), recently shown to reflect DNA damage accumulation causing transcription stress, and cellular ageing. Finally, GLTD was also identified by reanalysis of publicly available data of wild-type mice, rats and humans on high-protein diets, suggesting that increased dietary protein enhances GLTD and accelerates systemic ageing. Together, our findings have implications for nutritional guidelines for progeroid DNA-repair-deficient human syndromes, warrant the use of excessive protein intake for sustaining health, and suggests GLTD as a sensitive read-out of overall health and predictor of biological ageing.

Accumulating evidence has linked gut microbiota to bone health. However, investigations into the impacts of aging, gut microbiota, and their interactions in the development of osteoporosis remain inconclusive. We employed quantitative computed tomography to measure lumbar bone mass density (BMD) and analyzed shotgun metagenomic data in 684 Chinese adults. Our analyses revealed significant positive associations between BMD and abundances of multiple Lachnospiraceae species, including Lachnospira eligens, Blautia wexlerae, and Roseburia hominis, as well as pathways involved in L-arginine biosynthesis and butyrate production-independent of age, diet habits, and lifestyles. Moreover, we demonstrated that individuals with enterotype Bacteroides exhibited a more pronounced age-related decline in BMD compared to those with enterotype Prevotella, a pattern we validated in an independent cohort. Our findings offer valuable insights into BMD-related gut microbial features and interactions between aging, gut microbiota, and bone loss, opening potential avenues for microbiota-based prevention and treatment strategies for osteoporosis.

Polygenic risk scores (PRS) are useful for assessing disease risk; however, knowledge about their effectiveness among Asian and other populations is limited. This study aimed to compare the classification accuracy of PRSs for type 2 diabetes (T2D-PRS) developed from different ancestry groups using genotype data from 14,083 Japanese participants. Participants' scores were calculated using T2D-PRS models, and logistic regression analysis and receiver operating characteristic curves were assessed. The odds ratio of diabetes per 1 standard deviation increase in PRS was 2.18 and 1.55 for the Japanese and European T2D-PRSs, respectively. The area under the curve (AUC) for the Japanese T2D-PRS was 0.781, whereas that for the European T2D-PRS was 0.738 (P < 0.001). Additionally, age-stratified analysis showed higher AUCs in younger than older age groups. The PRS developed from matched ancestry populations has high classification accuracy for diabetes and is particularly useful for the early detection of high-risk individuals with diabetes.

Low carbohydrate diets (LCD) have shown efficacy in managing clinical outcomes in type 2 diabetes (T2D). Incorporating digital tools into health care provides an adjunct treatment modality, to educate patients and provide clinical support. This study examines the effect of a mobile health (mHealth) LCD application (app) on glycaemic profile, blood pressure and weight status, in people with T2D. The study is an online single-arm, pre-post study that recruited people with T2D from around Australia, referred via registered supporting general practitioners (GPs). The intervention (Defeat Diabetes app) provides education and resources on the use of a LCD for ongoing management of T2D. After 3 months, our cohort of 99 participants (mean age 59 ± 11 years, 55 females) showed reduced dietary carbohydrate intake as a proportion of overall energy (-14%kJ/day, 95% CI: -17 to -11). Improvement in the primary outcome HbA1c (-1.0%, 95% CI: -1.3 to -0.7), was associated with reduction in dietary carbohydrate intake. Systolic blood pressure (SBP) improved (-6 mmHg, 95% CI: -10 to -1), while 21 participants reduced their diabetes medication dose with two participants discontinuing all diabetes medication. These findings demonstrate that people with T2D receiving LCD education and resources through the Defeat Diabetes app for 3 months improved their glycaemic profile and SBP despite decreased overall medication usage in almost one third of the study sample prescribed medication at baseline.

This study examined the longitudinal association of metabolic dysfunction-associated fatty liver disease (MAFLD) with distinct cognitive function trajectories, and determine whether and to what extent this association was mediated by MAFLD-related metabolites among 845 participants. Two cognitive function trajectories were identified as normal (n = 714, 84.50%) or large decrease (n = 131, 15.50%) pattern over 7 years. Participants with MAFLD (N = 277, 32.78%) had an 81% higher risk of developing a large decrease in cognitive function (odds ratio, 1.81; 95% confidence interval, 1.16-2.94) than non-MAFLD. Three MAFLD-related metabolites were identified as lysoPC(20:3(5z,8z,11z)), lysoPE(18:1(9z)/0:0), and valine, of which lysoPE(18:1(9z)/0:0) and valine played a partially mediated role in the association of MAFLD with a large decrease in cognitive function (mediation proportion = 9.93% and 11.04%, respectively). The results indicated that MAFLD was associated with a higher risk of developing a large decrease in cognitive function, which was partially mediated by lipid and amino acid metabolism.

Pathological retinal neovascularization (RNV) is a major cause of vision loss and blindness during ischemic retinopathies. Our investigations in the mouse model of oxygen-induced retinopathy (OIR) demonstrate a novel mechanism of pathological RNV and neurovascular injury. We show that OIR-induced activation of macrophage/microglial cells, retinal inflammation, and pathological RNV are mediated by increases in cholesterol ester (CE) formation due to activation of the acyl-CoA: Cholesterol Acyltransferase 1/Sterol O-Acyltransferase 1 (ACAT1/SOAT1) enzyme.

Metabolic shifts are a hallmark of numerous biological processes, including the differentiation of stem cells along a specific lineage and the activation of diverse cell types, such as immune cells. This review examines the intricate energy metabolic alterations that occur in diverse biological settings, from embryonic development to adult tissue homoeostasis and disease states. In particular, we emphasise the regulatory function of RNA-binding proteins (RBPs) in coordinating these metabolic shifts and examine how they modulate key pathways, such as glycolysis and oxidative phosphorylation, to meet the dynamic cellular energy demands. This review highlights the various mechanisms by which RBPs regulate these changes, ranging from active involvement in the post-transcriptional regulation of metabolically relevant genes to alteration of an RBP's function by specific RNAs, metabolites or growth factors. Finally, we consider how ageing and disease affect the function of RBPs and how RBPs can disrupt the delicate balance of metabolic regulation. Taken together, this review provides a comprehensive overview of the critical interplay between RBPs and metabolism and offers insights into potential therapeutic targets for regenerative medicine and age-related diseases.