bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–12–07
ten papers selected by
Xiong Weng, University of Edinburgh
  1. Ei24 deficiency in brown adipocytes induces severe hypothermia under cold stress independent of UCP1 activity.
  2. Purmorphamine exerts anti-obesity effects by enhancing secretin-activated brown fat thermogenesis.
  3. Epigenome-wide association study of nuclear DNA methylation in relation to mitochondrial heteroplasmy.
  4. Toward the next 20 years of Cell Metabolism.
  5. Metformin Impairs Breast Cancer Growth through the Inhibition of PRMT6.
  6. Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy.
  7. Adipocytes orchestrate obesity-related chronic inflammation through β2-microglobulin.
  8. Excessive vigorous exercise impairs cognitive function through a muscle-derived mitochondrial pretender.
  9. Peritumoral colonic epithelial cell-derived GDF15 sustains colorectal cancer via regulation of glycolysis and histone lactylation.
  10. Improving polygenic risk prediction performance by integrating electronic health records through phenotype embedding.
  1. Nat Commun. 2025 Dec 01. 16(1): 10426
    Ei24 deficiency in brown adipocytes induces severe hypothermia under cold stress independent of UCP1 activity.
    Su Bin Lee, Bui Thanh Thu, Tae Wook Nam, Yaechan Song, Jae Hoon Lee, Yangsik Jeong, Han-Woong Lee.
      Brown adipocytes facilitate non-shivering thermogenesis, which is critical for maintaining energy balance and heat production in response to environmental stimuli. Here, we delineate the physiological and biochemical role of etoposide-induced 2.4 (Ei24) in adenosine triphosphate (ATP) production and thermogenesis in brown adipocytes. We generated Ei24 adipocyte-specific knockout (EiaKO) mice that exhibited brown adipose tissue hypertrophy, lipid accumulation, and various mitochondrial abnormalities. Despite mitochondrial defects, uncoupling protein 1 (UCP1) expression and activity remained unchanged. However, those impairments caused lethal hypothermia in mice subjected to cold challenge, underscoring the key role of Ei24 in mitochondrial functions. Mechanistically, Ei24 deficiency disrupted cristae structure, dissipated mitochondrial membrane potential, and reduced matrix pH, leading to severe ATP depletion. We further identify the C-terminal region of Ei24 as essential for supporting ATP synthase function. Those bioenergetic defects not only destabilized the mitochondrial environment necessary for efficient UCP1-mediated thermogenesis, but also impaired ATP-dependent futile cycles such as SERCA-mediated calcium cycling and creatine substrate cycling. Together, our findings indicate that Ei24 functions as a thermogenic regulator that ensures mitochondrial ATP synthesis and structural integrity, enabling both coupled and uncoupled respiration in brown adipose tissue.
    DOI:  https://doi.org/10.1038/s41467-025-66460-x
  2. Cell Rep. 2025 Dec 04. pii: S2211-1247(25)01400-7. [Epub ahead of print]44(12): 116628
    Purmorphamine exerts anti-obesity effects by enhancing secretin-activated brown fat thermogenesis.
    Fengwei Zhang, Zhengyi Tao, Shaik Abdullah Nawabjan, Minqi Xiang, Xiao Deng, Yan Li, Li Zhang, Billy Kwok Chong Chow.
      Obesity necessitates effective therapeutics targeting energy-regulating pathways. Secretin (SCT) shows therapeutic promise but is limited by its short half-life and lack of potent agonists. We investigated purmorphamine, a small-molecule modulator of the SCT receptor (SCTR), for its ability to enhance the metabolic functions of SCT and promote weight loss. Chronic oral administration of purmorphamine reduced weight gain, improved glucose/lipid homeostasis, and increased energy expenditure in diet-induced obese mice of both sexes without suppressing daily food intake. Mechanistically, purmorphamine acts synergistically with SCT to amplify SCTR-cAMP-protein kinase A (PKA) signaling, stimulate lipolysis, and enhance mitochondrial respiration in mature brown adipocytes. Moreover, lentiviral SCTR knockdown eliminated the effect of purmorphamine in enhancing SCT-stimulated mitochondrial respiration and thermogenic gene expression. These findings demonstrate that purmorphamine promotes negative energy balance by potentiating SCT-activated brown adipose thermogenesis, establishing it as a promising therapeutic strategy against obesity.
    Keywords:  CP: Metabolism; brown adipose tissue; obesity; purmorphamine; secretin; thermogenesis
    DOI:  https://doi.org/10.1016/j.celrep.2025.116628
  3. Nat Commun. 2025 Dec 02.
    Epigenome-wide association study of nuclear DNA methylation in relation to mitochondrial heteroplasmy.
    NHLBI Trans-Omics for Precision Medicine (TOPMed) mtDNA Working Group
      We analyze 10,986 participants (mean age 77; 63% women; 54% non-White) across seven U.S. cohorts to study the relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA methylation. We identify 597 CpGs associated with heteroplasmy burden, generally showing lower methylation. These CpGs are enriched in dynamically regulated island shores and depleted in CpG islands, indicating involvement in context-specific rather than constitutive gene regulation. In HEK293T cells, we introduce a truncating mtDNA mutation (MT-COX3, mt.9979) and observe a positive correlation between variant allele fraction and methylation at cg04569152, supporting a direct mtDNA-nDNA epigenetic link. Many heteroplasmy-associated CpGs overlap with known methylation-trait associations for metabolic and behavioral traits. Composite CpG scores predict all-cause mortality and incident CVD, with one-unit increases associated with 1.27-fold and 1.12-fold higher hazards, respectively. These findings suggest an mtDNA-nDNA epigenetic connection in aging and disease, though its direction and mechanisms remain to be studied.
    DOI:  https://doi.org/10.1038/s41467-025-65845-2
  4. Cell Metab. 2025 Dec 02. pii: S1550-4131(25)00488-7. [Epub ahead of print]37(12): 2295
    Toward the next 20 years of Cell Metabolism.
    Salvatore Fabbiano, Mari-Carmen Fernández-Agüera, Beste Mutlu, Patrick Schaefer, Yongmei Sun.
      
    DOI:  https://doi.org/10.1016/j.cmet.2025.11.004
  5. Adv Sci (Weinh). 2025 Dec 01. e08525
    Metformin Impairs Breast Cancer Growth through the Inhibition of PRMT6.
    Yinsheng Wu, Xinlin Xu, Yue Tong, Min Wang, Feng Ge, Min Wu, Yunlong Wang, Gang Chen, Xilan Yu, Shanshan Li.
      Metformin is the world's widely prescribed oral medication for the treatment of type 2 diabetes mellitus, which is also shown to repress tumorigenesis without a complete understanding of its therapeutic targets. Here, it is shown that metformin impairs the growth of breast cancer cells by inhibiting PRMT6, a protein arginine methyltransferase primarily responsible for asymmetric dimethylation of histone H3 arginine 2 (H3R2me2a). Mechanistically, metformin directly binds PRMT6 and inhibits its activity to methylate H3R2, leading to PRMT6 transcriptional repression and further reduces H3R2me2a. By decreasing PRMT6-catalyzed H3R2me2a, metformin enhances the chromatin association of UHRF1, an accessory factor of DNMT1 to promote DNA methylation and repress the transcription of DNA replication-associated genes, resulting in retarded DNA replication and cell cycle arrest. Metformin and a DNA replication inhibitor synergistically inhibit tumor growth. Furthermore, genetic disruption of the interaction between metformin and PRMT6 attenuates the inhibitory effect of metformin on breast cancer growth. Together, this work identifies a previously unrecognized mechanism for metformin to inhibit breast cancer growth.
    Keywords:  DNA methylation; DNA replication; H3R2me2a; Metformin; PRMT6; breast cancer
    DOI:  https://doi.org/10.1002/advs.202508525
  6. Nat Metab. 2025 Dec 03.
    Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy.
    Olaya Santiago-Fernández, Luisa Coletto, Inmaculada Tasset, Susmita Kaushik, Axel R Concepcion, Rizwan Qaisar, Adrián Macho-González, Kristen Lindenau, Antonio Diaz, Rabia R Khawaja, Stefano Donega, Nirad Banskota, Ceereena Ubaida-Mohien, Gavin Pharaoh, Bumsoo Ahn, Lisa M Hartnell, Ignacio Ramírez-Pardo, Bhakti Chavda, Aiara Gazteluiturri, Michael Kinter, Luigi Ferrucci, Julie A Reisz, Angelo D'Alessandro, Holly Van Remmen, Pura Muñoz-Cánoves, Stefan Feske, Ana Maria Cuervo.
      Chaperone-mediated autophagy (CMA) contributes to proteostasis maintenance by selectively degrading a subset of proteins in lysosomes. CMA declines with age in most tissues, including skeletal muscle. However, the role of CMA in skeletal muscle and the consequences of its decline remain poorly understood. Here we demonstrate that CMA regulates skeletal muscle function. We show that CMA is upregulated in skeletal muscle in response to starvation, exercise and tissue repair, but declines in ageing and obesity. Using a muscle-specific CMA-deficient mouse model, we show that CMA loss leads to progressive myopathy, including reduced muscle force and degenerative myofibre features. Comparative proteomic analyses reveal CMA-dependent changes in the mitochondrial proteome and identify the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA) as a CMA substrate. Impaired SERCA turnover in CMA-deficient skeletal muscle is associated with defective calcium (Ca2+) storage and dysregulated Ca2+ dynamics. We confirm that CMA is also downregulated with age in human skeletal muscle. Remarkably, genetic upregulation of CMA activity in old mice partially ameliorates skeletal muscle ageing phenotypes. Together, our work highlights the contribution of CMA to skeletal muscle homoeostasis and myofibre integrity.
    DOI:  https://doi.org/10.1038/s42255-025-01412-9
  7. Signal Transduct Target Ther. 2025 Dec 03. 10(1): 394
    Adipocytes orchestrate obesity-related chronic inflammation through β2-microglobulin.
    Jie Li, Yuhao Li, Xiaoyang Zhou, Shushu Yang, Dong Liu, Hao Wen, Xiaoling Chen, Chengjie Duan, Meiling Yu, Mengjun Zhang, Bo Tang, Yong Wang, Li Wang, Yuzhang Wu.
      Chronic inflammation in adipose tissue is widely recognized as a pivotal link connecting obesity to a spectrum of related chronic diseases, including type 2 diabetes, non-alcoholic fatty liver disease, and cardiovascular disorders. In this pathogenic process, the dysregulated interaction between adipocytes and adipose-resident immune cells plays a critical regulatory role; however, the underlying mechanisms governing this abnormal interaction remain largely unknown. In this study, we showed that upregulated β2-microglobulin expression in hypertrophic adipocytes during obesity not only mediated the activation of adipose-resident CD8+ T cells in a cell contact-dependent manner but also facilitated iron overload and the ferroptosis of adipocytes, thereby promoting the M1 polarization of adipose tissue macrophages. Conversely, specific ablation of β2-microglobulin in adipocytes effectively suppressed the activation and accumulation of adipose-resident CD8+ T cells, as well as adipocyte ferroptosis and M1 polarization, ultimately preventing high-fat diet-induced obesity and its related inflammation and metabolic disorders. Additionally, adeno-associated virus-mediated adipose-targeted knockdown of β2-microglobulin has been demonstrated to therapeutically alleviate high-fat diet-induced obesity, as well as its related chronic inflammation and metabolic disorders. Furthermore, our bioinformatic analysis of human adipose transcriptome data revealed a strong correlation between adipose β2-microglobulin and obesity. More importantly, β2-microglobulin is significantly upregulated in adipocytes isolated from patients with obesity. Thus, our findings highlight the pivotal role of adipocytes in obesity-associated chronic inflammation and metabolic disorders via β2-microglobulin-dependent mechanisms.
    DOI:  https://doi.org/10.1038/s41392-025-02486-3
  8. Cell Metab. 2025 Dec 03. pii: S1550-4131(25)00486-3. [Epub ahead of print]
    Excessive vigorous exercise impairs cognitive function through a muscle-derived mitochondrial pretender.
    Yan Huang, Biao Hu, Ya Liu, Ling-Qi Xie, Yu Dai, Yu-Ze An, Xin-Yi Peng, Ya-Lun Cheng, Yi-Fan Guo, Wei-Hong Kuang, Yao Xiao, Xin Chen, Yong-Jun Zheng, Gen-Qing Xie, Jian-Ping Wang, Hui Peng, Xiang-Hang Luo.
      Excessive exercise impairs cognitive function, but the underlying mechanism remains unclear. Here, we show that excessive vigorous exercise-induced lactate accumulation stimulates muscles to secrete mitochondria-derived vesicles (MDVs), driving cognitive impairment. These MDVs (named otMDVs) are characterized by high mtDNA levels and the surface marker PAF. They tend to migrate into hippocampal neurons, substituting endogenous mitochondria and triggering a synaptic energy crisis. Mechanistically, otMDVs release mtDNA, which activates cGAS-STING-dependent inhibition of kinesin family member 5, preventing hippocampal mitochondria from transporting to synapses. Simultaneously, the otMDV marker PAF cooperates with syntaphilin to occupy mitochondrial anchoring sites, impairing synaptic energy supply. Blocking otMDVs migration into the hippocampus with a PAF-neutralizing antibody alleviates excessive vigorous exercise-induced synapse loss and cognitive dysfunction. Notably, human studies link high circulating otMDV levels to cognitive impairment. Together, our findings reveal that a unique muscle-derived MDV subpopulation, which displaces hippocampal mitochondria and disrupts their function, causes cognitive decline.
    Keywords:  MDVs; cognitive decline; excessive vigorous exercise
    DOI:  https://doi.org/10.1016/j.cmet.2025.11.002
  9. Nat Aging. 2025 Dec 03.
    Peritumoral colonic epithelial cell-derived GDF15 sustains colorectal cancer via regulation of glycolysis and histone lactylation.
    Bingjie Guan, Mantang Zhou, Weixing Dai, Jing Zhang, Bowen Xie, Yushuai Mi, Xin Zhang, Ping Wei, Youdong Liu, Shanbao Li, Haonan Guan, Xiaoming Zhang, Sanjun Cai, Dawei Li, Dongwang Yan, Senlin Zhao.
      One of the most abundant cellular components of the normal adjacent tissue surrounding colorectal cancer is colonic epithelial cells (CECs); however, little is known about their interactions with tumor cells. Here we found that peritumoral CECs collaborate with cancer cells to orchestrate a pro-carcinogenic niche. In clinical cohort analyses, we show that growth differentiation factor 15 (GDF15) levels increase in normal adjacent tissue, in particular in CECs, at advanced disease and are inversely correlated with survival. Using mouse models, organoids and in vitro approaches, we link GDF15 upregulation to senescence in peritumoral CECs and identify a CEC-derived GDF15-driven metabolic feedback loop fueling tumor survival. We show that GDF15 secretion upregulates the glycolytic enzyme ENO1 in cancer cells, which triggers extracellular lactate release and subsequent lactylation of H4K8 in CECs, augmenting GDF15 transcription. Our findings establish a mode of intercellular crosstalk mediating collaboration between colorectal cancer cells and peritumoral CECs, providing a potential avenue for targeted intervention in colorectal cancer.
    DOI:  https://doi.org/10.1038/s43587-025-01023-9
  10. Am J Hum Genet. 2025 Dec 04. pii: S0002-9297(25)00431-8. [Epub ahead of print]112(12): 3030-3045
    Improving polygenic risk prediction performance by integrating electronic health records through phenotype embedding.
    Leqi Xu, Wangjie Zheng, Jiaqi Hu, Yingxin Lin, Jia Zhao, Gefei Wang, Tianyu Liu, Hongyu Zhao.
      Large-scale biobanks provide comprehensive electronic health records (EHRs) that capture detailed clinical phenotypes, potentially enhancing disease prediction. However, traditional polygenic risk score (PRS) methods rely on simplified phenotype definitions or predefined trait sets, limiting their ability to represent the complex structures embedded within EHRs. To address this gap, we introduce EHR-embedding-enhanced PRS (EEPRS), leveraging phenotype embeddings derived from EHRs to improve PRSs using only genome-wide association study (GWAS) summary statistics. Employing embedding methods such as Word2Vec and GPT, we conducted EHR-embedding-based GWASs and identified a cardiovascular cluster via hierarchical clustering of genetic correlations. Across 41 traits in the UK Biobank, EEPRS consistently outperformed single-trait PRSs, particularly within this cluster. PRS-based phenome-wide association studies further demonstrated robust associations between EHR-embedding-based PRS and circulatory system diseases. We then developed EEPRS_optimal, a data-adaptive method that uses cross-validation to select the best embedding, yielding additional improvements. We also developed MTAG_EEPRS for multi-trait PRSs, which further improved prediction accuracy compared to single-trait PRSs and MTAG_PRS. Finally, we validated the benefits of EEPRS in the All of Us cohort for seven selected diseases. Overall, EEPRS represents a robust and interpretable framework, enhancing single-trait and multi-trait PRSs by integrating EHR embeddings.
    Keywords:  EHRs; GWAS; PRS; PheWAS; electronic health records; genome-wide association study; multi-trait analysis; phenome-wide association study; phenotype embeddings; polygenic risk score
    DOI:  https://doi.org/10.1016/j.ajhg.2025.11.006
This page is being maintained by Thomas Krichel. It was last updated on 2025‒12‒07 at 10:38.