bims-mimead 2025-12-28 papers

Issue of 2025–12–28
four papers selected by
Rachel M. Handy, University of Guelph

J Transl Med. 2025 Dec 22.

Single-nucleus RNA sequencing resolves microenvironmental dynamics in brown/beige adipose tissue after bariatric surgery.

Wei Wang, Yangxingyun Wang, Zhonghao Guo, Yao Lu, Wei Xie, Ruibin Li.

BACKGROUND: Obesity is a chronic condition characterized by excessive adipose tissue accumulation, which significantly contributes to a range of systemic comorbidities, including type 2 diabetes, cardiovascular diseases, and various forms of cancer. These associated health issues severely compromise individuals' quality of life and pose substantial challenges for public health. Despite the known benefits of bariatric surgery as the most effective intervention for achieving sustained weight loss and improving metabolic profiles, the underlying biological mechanisms that facilitate adipose tissue remodeling following surgical intervention remain inadequately understood.
METHODS: In this study, we employed single-nucleus RNA sequencing to construct high-resolution transcriptional maps of murine brown adipose tissue (BAT) and beige adipose tissue both before and after bariatric surgery. This comprehensive analysis allowed us to explore dynamic changes in the adipose tissue microenvironment post-surgery.
RESULTS: Our findings revealed a significant post-surgical expansion of fibroblastoid (FBO) populations in both BAT and beige adipose tissues. This expansion was accompanied by a marked reduction in adipocytes (AP). To further understand the cellular interactions underlying these changes, cell communication analysis was conducted through the CellChat platform. This analysis indicated enhanced crosstalk between adipocytes and fibroblastoid cells, predominantly mediated by IGF1 signaling activation. In contrast, interactions involving the VEGF pathway between adipocytes and endothelial cells (EC) were suppressed. Moreover, pseudotemporal trajectory analysis identified a distinct subpopulation of adipocytes, termed AP6, that was enriched for fibrosis-associated genes and showed progressive upregulation of 11 genes along differentiation toward fibroblastoid states.
CONCLUSION: We delineate post-bariatric microenvironmental reprogramming in thermogenic adipose depots and highlight a candidate pathway in which 11 putative transition regulators cooperate with IGF1 signaling to promote AP6-cell transdifferentiation toward fibroblastoid lineages. These data nominate testable targets for therapeutic modulation of obesity and its complications. Given the limited sample size, findings are descriptive and hypothesis-generating; definitive lineage inference awaits validation by fate mapping or RNA-velocity in larger cohorts.

Keywords: Adipocytes; Bariatric surgery; Fibroblastoid; Obesity; Single-nucleus RNA sequencing

DOI: https://doi.org/10.1186/s12967-025-07480-5

NPJ Aging. 2025 Dec 26.

Reversal of proteomic aging with exercise-results from the UK biobank and a 12-week intervention study.

Sindre Lee-Ødegård, M Austin Argentieri, Frode Norheim, Christian Andre Drevon, Kåre Inge Birkeland.

Biological aging varies between individuals and may be influenced by health behaviors. Using data from 45,438 UK Biobank participants, we found that a higher proteomic aging score (ProtAgeGap) was linked to lower physical activity and increased risk of type 2 diabetes. The UK Biobank cohort included both men and women. In a 12-week supervised exercise study (MyoGlu) in 26 men, ProtAgeGap decreased by the equivalent of 10 months. While most of the 204 proteins in the score remained stable, some, like CLEC14A, changed with exercise and were linked to improved insulin sensitivity. Transcriptomic data from muscle and fat tissue supported these protein-level changes, highlighting pathways, such as PI3K-Akt and MAPk signaling, involved in tissue remodeling and metabolism. Our findings suggest that while proteomic aging is mostly stable, it can be modestly reversed by exercise. Specific proteins within the signature may act as sensitive indicators of metabolic adaptation, supporting the idea that proteomic aging is a modifiable marker linked to lifestyle and disease risk. Clinical trial number: clinicaltrials.gov: NCT01803568 registered 2013-02-26.

DOI: https://doi.org/10.1038/s41514-025-00318-w

iScience. 2025 Dec 19. 28(12): 114112

Site-specific ERα phosphorylation determines sex-dependent metabolic, reproductive, and body-compositional phenotypes in mice.

Binghao Zou, Jarvis Williams, Madeleine B Landau, Weiqiang Lin, Sallie Fell, Ziqi Yang, MaryJane Jones, Robert Blair, Chad H Steele, Pratik Khare, Cissy Zhang, Anne Le, Muralidharan Anbalagan, Brian G Rowan.

Estrogen receptor alpha (ERα) phosphorylation regulates receptor activity and tissue-specific gene expression. We generated serine (S) to alanine (A) phosphorylation-deficient knock-in mice targeting two conserved ERα sites, S171 and S216, to examine their physiological roles. ERα S216A females were subfertile, with ∼30% smaller litters and diminished uterine growth in response to estradiol (E2). Single-cell spatial transcriptomics revealed a disrupted E2-regulated transcriptome in the myometrium. Metabolic profiling revealed the suppression of glycolytic and redox pathways in ERα S216A mice, with males exhibiting reduced adiposity and increased lean mass. Skeletal analysis revealed opposing effects: ERα S216A females exhibited reduced femoral bone density, while ERα S171A females showed an increase. These data demonstrate critical roles for site-specific ERα phosphorylation in modulating receptor levels and activity, as well as gene expression, which have a profound impact on murine body composition, fertility, and metabolism.

Keywords: cell biology; metabolomics; transcriptomics

DOI: https://doi.org/10.1016/j.isci.2025.114112

iScience. 2025 Dec 19. 28(12): 114128

A microbial community that alters mitochondrial morphology and age-related motor function in C. elegans.

Nathan Dennis, Mireya Vazquez-Prada, Laura M Freeman, Feng Xue, Lisa-Jane White, Antonis A Karamalegos, William G Sullivan, Brigita Kudzminkaite, Ian Brown, Jennifer R Hiscock, Marina Ezcurra.

Across diverse taxa, the composition of the microbiota is associated with host fitness. A mechanistic understanding of how microbial communities influence host physiology could lead to microbiota-based interventions for lifelong health. Here, we have developed a host-microbiota model system consisting of the model organism C. elegans combined with a defined natural microbiota (DefNatMta) consisting of 11 bacterial strains isolated from wild C. elegans to study natural host-microbiota interactions in the laboratory. We show that DefNatMta persists in the C. elegans gut, forming a stable and distinct gut microbiota. Utilizing this host-microbiota system, we find that DefNatMta affects age-related motility and protects against age-related decline in motor function. DefNatMta acts by altering metabolism and mitochondrial network dynamics in muscle and requires dynamin-related protein 1 (DRP-1), a regulator of mitochondrial fission to protect against age-related motility decline. Our findings are consistent with microbe-mitochondria communication affecting age-related muscle function.

Keywords: Microbiology; Microbiome; Molecular biology

DOI: https://doi.org/10.1016/j.isci.2025.114128