Danfeng Yang

Constant light (LL) exposure is an established environmental risk factor for metabolic diseases, in which the whitening of brown adipose tissue (BAT) plays a critical role. This study aimed to elucidate the molecular mechanisms through which cordycepin counteracts LL-induced BAT whitening and improves metabolic function. We established an LL-exposed mouse model and employed an integrative approach combining pharmacological, metabolic, molecular, and computational (docking) assays to define cordycepin’s effects and targets. Cordycepin treatment significantly improved cold tolerance and attenuated BAT whitening in LL mice. Mechanistically, cordycepin directly bound to and enhanced the activity of the NAD⁺-dependent deacetylase SIRT1. This activation mitigated LL-induced impairments in mitochondrial biogenesis, dynamics, and autophagy. Furthermore, SIRT1 activation rebalanced fatty acid metabolism by downregulating CD36 and upregulating CPT1, thereby restoring the coupling of fatty acid uptake to oxidation. All beneficial effects of cordycepin were abolished by the selective SIRT1 inhibitor EX-527. In summary, our work provides strong evidence that cordycepin directly interacts with SIRT1 and enhances its deacetylase activity, thereby restoring mitochondrial function and fatty acid oxidative homeostasis in BAT to counteract constant LL-induced metabolic dysfunction. These findings position cordycepin as a promising natural compound targeting the SIRT1 pathway for metabolic disorders.

Background: Chronic cold stress is a significant risk factor for skeletal deterioration; however, effective therapeutic strategies targeting the underlying environmental-metabolic interactions remain unclear. This study investigated the osteoprotective potential of Mixed Polysaccharides (MPs) and elucidated the mediating role of the gut microbiome. Methods: Cold exposure-induced bone loss was established in rats. Fecal microbiota transplantation (FMT), 16S rRNA gene sequencing, and untargeted metabolomics was employed to illustrate the positive effect of MPs on the improvement of cold-exposed bone loss. Results: MPs treatment effectively reversed cold-induced trabecular microarchitecture deterioration and bone mass loss. In femoral tissue, MPs rebalanced skeletal turnover by upregulating osteogenic markers (Runx2, Osterix) and suppressing osteoclastogenic factors (TRAP, c-fos), concurrent with a marked reduction in the levels of pro-inflammatory cytokines TNF-α and IL-1β in femur. Furthermore, MPs restored intestinal barrier integrity by upregulating tight junction proteins (ZO-1, Occludin), thereby mitigating the intestinal barrier impairment driven by cold stress. FMT experiments demonstrated that the osteoprotective effects of MPs are microbiota-dependent, as the transplantation of MPs-modulated microbiota recapitulated the bone-preserving and barrier-restoring phenotypes in recipient mice. Multi-omics integration identified that MPs selectively promoted the expansion of Lactobacillus intestinalis and the accumulation of cholylhistidine. Correlation analysis further revealed a strong link between the enrichment of these microbial and metabolic signatures, reduced pro-inflammatory cytokine levels, and improved bone formation. Conclusion: Our findings indicate that MPs alleviate cold-stress-induced bone loss by remodeling the gut microbiota and metabolic profile, fortifying the intestinal barrier and decreasing pro-inflammatory cytokine.

Cold exposure, a prototypical environmental stressor, activates the metabolic plasticity of adipose tissue (AT) by inducing extensive AT remodeling. This adaptive process not only enhances cold tolerance but also critically improves glucose and lipid (glucolipid) metabolic homeostasis through systemic metabolic reprogramming. This review synthesizes recent high-resolution sequencing studies to comprehensively examine three core dimensions of cold exposure-induced AT remodeling: tissue phenotype, cellular architecture, and metabolic function. In addition, it elucidates intercellular communication and inter-organ interactions within the multiscale regulatory networks that govern AT remodeling, thereby providing a theoretical framework for the development of intervention strategies for metabolic diseases based on mechanisms of cold-induced AT remodeling.

Introduction: Short-term continuous light exposure disrupts circadian rhythms and impairs cognitive function, yet its specific effects on dynamic metabolic oscillations within the hippocampus remain unclear. Methods: This study investigated the impacts of short-term (7-day) continuous light exposure (LL) on hippocampal circadian rhythms, metabolome, and cognition in mice. We established an LL model and utilized behavioral assays, histopathology, qPCR for clock genes, and targeted time-series metabolomics (at ZT0, 6, 12, 18). Results: Our results showed that LL significantly disrupted the circadian oscillations of core clock genes, induced memory decline, and caused hippocampal neuronal abnormalities and neuroinflammation. Metabolomic analysis uncovered extensive remodeling of circadian metabolite rhythms, with a 56.9% reduction in rhythmic metabolites. We identified eight core rhythm-disrupted metabolites, among which the key inhibitory neurotransmitter GABA exhibited a pronounced phase delay (∼6.4 h) and reduced amplitude. Pathway analysis highlighted vitamin B6 metabolism as a central disrupted pathway. Discussion: These results illustrate that short-term continuous light exposure induces multi-level perturbations in the hippocampal circadian-metabolic network, with GABA and vitamin B6 metabolism as potential critical nodes linking circadian disruption to cognitive impairment. This study provides novel metabolomic insights and a descriptive foundation for understanding the mechanisms underlying light pollution-associated cognitive deficits.

Background: Long-term exposure to light has emerged as a novel risk factor for metabolic diseases. The whitening of brown adipose tissue (BAT) may play an important role in metabolic disorders caused by long-term continuous light exposure. This study aimed to investigate the morphological and functional alterations in BAT under continuous light conditions and to identify traditional Chinese medicine compounds capable of reversing these changes. Methods: A metabolic disorder model was established by subjecting mice to continuous light exposure for 5 weeks. During this period, body weight, food intake, and body fat percentage were monitored. Serum levels of triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) were measured to assess lipid metabolism. Histological changes in BAT were examined using H&E staining. The expression of the thermogenic marker uncoupling protein 1 (UCP1) in BAT was determined by RT-qPCR and Western blot to evaluate thermogenic function. RNA sequencing (RNA-seq) was employed to identify differentially expressed genes (DEGs) involved in BAT whitening induced by prolonged continuous light exposure. DEGs were analyzed using the connectivity map (CMap) database to identify potential preventive and therapeutic compounds. The therapeutic efficacy of the selected compounds was subsequently evaluated using the above indicators, and key pathways were validated through western blot analysis. Results: After 5 weeks of continuous light exposure, mice exhibited increased body fat percentage and serum levels of TG, impaired mitochondrial function, reduced thermogenic capacity, and whitening of BAT. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses indicated that BAT whitening was primarily associated with the adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathway, fatty acid metabolism, and circadian rhythm. Ten hub genes identified using Cytoscape were mainly related to AMPK signaling and heat shock proteins. In vivo experiments showed that cordycepin significantly attenuated the increase in body fat percentage caused by prolonged light exposure. This effect was mediated by activation of the AMPK/PGC-1α/UCP1 signaling pathway, which restored the multilocular morphology and thermogenic function of BAT. Conclusion: Cordycepin mitigates continuous light-induced BAT whitening and metabolic disturbances by activating the AMPK signaling pathway.

Introduction: Cold stimulation induces browning of subcutaneous white adipose tissue (sWAT), making it a prime target for treating obesity and metabolic disorders. However, this remodeling is reversible: upon return to thermoneutrality (rewarming), sWAT whitens and loses its enhanced metabolic functions. Given the limited understanding of the microscopic dynamic changes and underlying mechanisms during this process, we established a temporally dynamic mouse model spanning the entire period from cold stimulation to the return to thermoneutrality, with inguinal sWAT (iWAT) selected as the study subject.Methods: Based on preliminary data demonstrating stabilization in iWAT histology, expression levels of key thermogenic proteins, and the bulk transcriptome, we selected the two-week time point after the return to thermoneutrality for detailed analysis. Subsequently, we employed single-nucleus RNA sequencing (snRNA-seq) to comprehensively characterize iWAT cellular dynamics during cold stimulation and the subsequent two-week period after the return to thermoneutrality.Results: Our findings revealed that while iWAT phenotypically reverts to a white state after 2 weeks of rewarming, as evidenced by structural, functional, and bulk transcriptomic characteristics, significant cold-induced molecular and cellular signatures persist. Specifically, we observed altered differentiation trajectories in both adipose stem and progenitor cells (ASPCs) and adipocytes, suggesting dedifferentiation and reprogramming tendencies. Furthermore, the ANGPTL signaling pathway, activated in thermogenic adipocyte subpopulation A3 during cold stimulation, remained active and influenced cell-cell communication even after the loss of thermogenic capacity.Discussion: hese findings provide novel insights into elucidating the complex cellular and molecular mechanisms underlying the temperature-dependent plasticity of iWAT, and suggest that the ANGPTL signaling pathway may play a potential role in maintaining the white phenotype of iWAT after withdrawal from cold stimulation.

Introduction: Visceral adipose tissue (VAT) plays a crucial role in regulating systemic metabolic balance. Excess accumulation of VAT is closely associated with various metabolic disorders, a process that involves the coordinated actions of multiple cell types within the tissue. Cold exposure, as a potential intervention, has been proposed to improve metabolic dysfunction. However, the heterogeneity of VAT and its comprehensive metabolic characteristics under cold exposure remain unclear.Methods: We collected epididymal white adipose tissue (eWAT) of C57BL/6J mice after cold exposure at three different time points for single-nucleus RNA sequencing (snRNA-seq) analysis.Results: We successfully identified ten major cell types in eWAT, enabling understanding of the dynamic changes in the eWAT microenvironment and its metabolic features during cold exposure. This study revealed that cold exposure for 1 day reduced cellular metabolic activity and intercellular communication in eWAT including receptor-ligand-based cell communication and metabolite-mediated interactions. However, after 14 days of cold acclimation, the metabolic activity of adipocytes was significantly enhanced, and intercellular metabolic communication was restored. Additionally, prolonged cold exposure promoted the formation of a distinct adipocyte subpopulation that may be associated with UCP1-independent thermogenesis. These changes may be a new homeostatic state established by VAT to adapt to the cold environment. The study also identified the importance of adipocytes, adipose stem and progenitor cells, myeloid cells, and endothelial cells in the process of cold adaptation.Discussion: This research provides valuable insights into the cellular heterogeneity, adipocyte remodeling, and metabolic reprogramming in eWAT after cold exposure. It highlights the critical role of transcriptional dynamics in eWAT during cold exposure and provides new perspectives on the prevention and treatment of metabolic diseases.

Sciendo provides publishing services and solutions to academic and professional organizations and individual authors. We publish journals, books, conference proceedings and a variety of other publications.

Sciendo provides publishing services and solutions to academic and professional organizations and individual authors. We publish journals, books, conference proceedings and a variety of other publications.