npj Metabolic Health and Disease最新文献

Mitochondria play a central role in regulating cellular energy metabolism, redox homeostasis, and biosynthesis. Mitochondrial uncoupling, through the alteration in the permeability of the inner mitochondrial membrane (IMM) to the leak of protons without adenosine triphosphate (ATP) synthesis, regulates thermogenesis, glucose and lipid metabolism, and reactive oxygen species (ROS) generation. In brown adipose tissue (BAT), proton leak via uncoupling protein 1 (UCP1) is essential for thermogenesis and has been shown to improve systemic glucose homeostasis, and recent studies indicate that BAT activation can also suppress tumor growth by competing with cancer cells for glucose. Several small-molecule mitochondrial uncouplers have demonstrated anticancer effects in preclinical models, although endogenous UCPs-particularly UCP2-are often upregulated in tumors, where they may support tumor growth by buffering ROS and increasing metabolic flexibility. These seemingly contradictory observations highlight the context-dependent effects of mitochondrial uncoupling in cancer. Here, we review current understanding of mitochondrial uncoupling mechanisms, the roles of UCP isoforms, and the metabolic interplay between BAT, cancer cells, and the tumor microenvironment, with a focus on therapeutic implications.

Glucagon-like peptide 1 receptor (GLP-1R) agonists are used along with ethanol consumption, but their interactions are not understood. Our aim was to determine the effects of GLP-1R agonism on the liver in mouse models of high ethanol consumption. We identified that GLP-1R agonism reduced ethanol consumption, mitigated ethanol-induced upregulation of several liver metabolizing enzymes, including Cyp2e1 and also reduced Cyp2e1 independent of ethanol intake. As expected from a reduction in Cyp2e1, GLP-1R agonism resulted in increased blood ethanol levels. This occurred after a single dose of ethanol when given by gavage, and by the intraperitoneal route. This suggests that GLP-1R agonism can reduce ethanol-mediated hepatotoxicity despite continued ethanol consumption and elevate blood alcohol levels.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained fatigue, post-exertional malaise (PEM), and cognitive dysfunction. ME/CFS patients often report a prodrome consistent with infection. We present a multi-omics analysis based on plasma metabolomic and proteomic profiling, and immune responses to microbial stimulation, before and after exercise. We report evidence of an exaggerated innate immune response after exposure to microbial antigens; impaired energy production involving the citric acid cycle, beta-oxidation of fatty acids, and urea cycle energy production from amino acids; systemic inflammation linked to lipid abnormalities; disrupted extracellular matrix homeostasis with release of endogenous ligands that promote inflammation; reduced cell-cell adhesion and associated gut dysbiosis; complement activation; redox imbalance reflected by disturbances in copper-dependent antioxidant pathways; and dysregulation of tryptophan-serotonin-kynurenine pathways. Many abnormalities were worse following exercise and correlated with the intensity of symptoms. Our findings may inform development of targeted therapeutic interventions for ME/CFS and PEM.

Molecular aging clocks estimate biological age from molecular biomarkers and often outperform chronological age in predicting health outcomes. Types include epigenetic, transcriptomic, proteomic, and metabolomic clocks. NMR-based metabolomic clocks provide a non-invasive, high-throughput platform to assess metabolic health. We summarize key NMR-based models and present a new approach that combines high predictive accuracy with clinical interpretability, identifying disease-specific metabolic distortions and supporting risk stratification and early detection of accelerated aging.

All animals age, but the rate of aging across species varies widely. The environmental pressures and molecular factors underlying this remarkable diversity in aging across species remains largely enigmatic. The Mexican tetra, Astyanax mexicanus, provides an intriguing new model to study how adaptation to different environments alter aging. This species exists as the river-dwelling surface fish, living in food and light rich environments, and the blind cave-adapted cavefish, thriving in dark, nutrient-limited, caves. How adaption to these extreme environments alter aging in this species remains unknown. Here, we compared aging markers between surface and cavefish populations, focusing on morphological, behavioral changes, and molecular signatures. We found aging markers were more pronounced in surface fish, but less distinct in aged cavefish. We also observed that insulin receptor mutation is limited in its impact to increase lifespan in cavefish. Instead, metabolic shifts, particularly in mitochondrial function, may contribute to cavefish's extended longevity.

Although diversity in clinical trials is important to test the efficacy of a treatment, weight loss trials rarely account for age and sex. To highlight this deficiency, we set out to test whether age and sex affect WAT mobilization after weight loss surgery or intermittent fasting, in an obese mouse model. Here we show that male sex, youth, and WAT transcriptomic plasticity are characteristics associated with improved weight loss outcomes. Conversely, aging impairs WAT mobilization and transcriptomic plasticity. Greater surgical weight loss is associated with changes in the expression of genes relevant to the IL17 inflammatory signaling pathway, angiotensin converting enzyme 2 (ACE2) signaling, lipolysis, carbohydrate metabolism and adipocyte differentiation. In conclusion, female sex and older age appear to hinder molecular processes necessary for the reversal of WAT expansion. Future studies should examine the relevance of these findings to human obesity therapeutics.

Skeletal muscle accounts for 30-40% of body weight and plays an indispensable role in maintaining movement and is also a central regulator of whole-body metabolism. As such, understanding the molecular mechanisms of skeletal muscle health and disease is vital. Proteomics has been revolutionized in recent years and provided new insights into skeletal muscle. In this review, we first highlight important considerations unique to the field which make skeletal muscle one of the most challenging tissues to analyse by mass spectrometry. We then highlight recent advances using the latest case studies and how this has allowed coverage of the skeletal muscle temporal, fibre type and stem cells proteome. We also discuss how exercise and metabolic dysfunction can remodel the muscle proteome. Finally, we discuss the future directions of the field and how they can be best leveraged to increase understanding of human biology.

This prospective cohort study included 408,760 older adults to investigate complex interaction between waist circumference (WC), blood glucose (BG) or blood pressure (BP), and sex in relation to elderly mortality. We used Cox regression models incorporating a tensor product interaction function to model joint impacts of WC and four cardiometabolic markers on mortality, and developed a two-dimensional exposure-response function (ERF) to quantify the population adaptability to cardiometabolic dysfunction across different WC levels. The linear and nonlinear effects of BG and BP on mortality varied by WC, with significant synergistic interactions. The two-dimensional ERF quantified variations in excess mortality risk across different WC and cardiometabolic marker combinations. Individuals with higher WC exhibited a forward shift in risk thresholds, indicating reduced adaptability to elevated BG and BP levels. Our findings highlight the need for targeted cardiometabolic health management strategies to enhance adaptability and reduce the burden of cardiometabolic diseases in aging populations.