bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–01–19
ten papers selected by
Xiong Weng, University of Edinburgh
  1. Absence of MCJ/DnaJC15 promotes brown adipose tissue thermogenesis.
  2. Systematical identification of regulatory GPCRs by single-cell trajectory inference reveals the role of ADGRD1 and GPR39 in adipogenesis.
  3. Robust single-nucleus RNA sequencing reveals depot-specific cell population dynamics in adipose tissue remodeling during obesity.
  4. Somatic mutation as an explanation for epigenetic aging.
  5. Epigenetic ageing clocks: statistical methods and emerging computational challenges.
  6. Ablation of PI3Kγ in neurons protects mice from diet-induced obesity MASLD and insulin resistance.
  7. Single-cell transcriptome atlas of lamprey exploring Natterin- induced white adipose tissue browning.
  8. Proline exacerbates hepatic gluconeogenesis via paraspeckle-dependent mRNA retention.
  9. Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence.
  10. Recommendations for mitochondria transfer and transplantation nomenclature and characterization.
  1. Nat Commun. 2025 Jan 13. 16(1): 229
    Absence of MCJ/DnaJC15 promotes brown adipose tissue thermogenesis.
    Beatriz Cicuéndez, Alfonso Mora, Juan Antonio López, Andrea Curtabbi, Javier Pérez-García, Begoña Porteiro, Daniel Jimenez-Blasco, Pedro Latorre-Muro, Paula Vo, Madison Jerome, Beatriz Gómez-Santos, Rafael Romero-Becerra, Magdalena Leiva, Elena Rodríguez, Marta León, Luis Leiva-Vega, Noemi Gómez-Lado, Jorge L Torres, Lourdes Hernández-Cosido, Pablo Aguiar, Miguel Marcos, Martin Jastroch, Andreas Daiber, Patricia Aspichueta, Juan Pedro Bolaños, Jessica B Spinelli, Pere Puigserver, José Antonio Enriquez, Jesús Vázquez, Cintia Folgueira, Guadalupe Sabio.
      Obesity poses a global health challenge, demanding a deeper understanding of adipose tissue (AT) and its mitochondria. This study describes the role of the mitochondrial protein Methylation-controlled J protein (MCJ/DnaJC15) in orchestrating brown adipose tissue (BAT) thermogenesis. Here we show how MCJ expression decreases during obesity, as evident in human and mouse adipose tissue samples. MCJKO mice, even without UCP1, a fundamental thermogenic protein, exhibit elevated BAT thermogenesis. Electron microscopy unveils changes in mitochondrial morphology resembling BAT activation. Proteomic analysis confirms these findings and suggests involvement of the eIF2α mediated stress response. The pivotal role of eIF2α is scrutinized by in vivo CRISPR deletion of eIF2α in MCJKO mice, abrogating thermogenesis. These findings uncover the importance of MCJ as a regulator of BAT thermogenesis, presenting it as a promising target for obesity therapy.
    DOI:  https://doi.org/10.1038/s41467-024-54353-4
  2. Sci China Life Sci. 2025 Jan 14.
    Systematical identification of regulatory GPCRs by single-cell trajectory inference reveals the role of ADGRD1 and GPR39 in adipogenesis.
    Chuan Ye, Xuemei Wang, Jun Lin, Chenyang Wu, Yuhua Gao, Chenghao Guo, Yunxi Liao, Ziyan Rao, Shaodong Huang, Weixuan Chen, Ying Huang, Jinpeng Sun, Dongyu Zhao, Changtao Jiang.
      Adipogenesis is the healthy expansion of white adipose tissue (WAT), serving as a compensatory response to maintain metabolic homeostasis in the presence of excess energy in the body. Therefore, the identification of novel regulatory molecules in adipogenesis, specifically membrane receptors such as G protein-coupled receptors (GPCRs), holds significant clinical promise. These receptors can serve as viable targets for pharmaceuticals, offering potential for restoring metabolic homeostasis in individuals with obesity. We utilized trajectory inference methods to analyze three distinct single-nucleus sequencing (sNuc-seq) datasets of adipose tissue and systematically identified GPCRs with the potential to regulate adipogenesis. Through verification in primary adipose progenitor cells (APCs) of mice, we discovered that ADGRD1 promoted the differentiation of APCs, while GPR39 inhibits this process. In the obese mouse model induced by a high-fat diet (HFD), both gain-of-function and loss-of-function studies validated that ADGRD1 promoted adipogenesis, thereby improving metabolic homeostasis, while GPR39 inhibited adipogenesis, leading to metabolic dysfunction. Additionally, through the analysis of 2,400 ChIP-seq data and 1,204 bulk RNA-seq data, we found that the transcription factors (TFs) MEF2D and TCF12 regulated the expression of ADGRD1 and GPR39, respectively. Our study revealed the regulatory role of GPCRs in adipogenesis, providing novel targets for clinical intervention of metabolic dysfunction in obese patients.
    Keywords:  GPCRs; adipogenesis; trajectory inference
    DOI:  https://doi.org/10.1007/s11427-024-2732-8
  3. Elife. 2025 Jan 13. pii: RP97981. [Epub ahead of print]13
    Robust single-nucleus RNA sequencing reveals depot-specific cell population dynamics in adipose tissue remodeling during obesity.
    Jisun So, Olivia Strobel, Jamie Wann, Kyungchan Kim, Avishek Paul, Dominic J Acri, Luke C Dabin, Jungsu Kim, Gang Peng, Hyun Cheol Roh.
      Single-nucleus RNA sequencing (snRNA-seq), an alternative to single-cell RNA sequencing (scRNA-seq), encounters technical challenges in obtaining high-quality nuclei and RNA, persistently hindering its applications. Here, we present a robust technique for isolating nuclei across various tissue types, remarkably enhancing snRNA-seq data quality. Employing this approach, we comprehensively characterize the depot-dependent cellular dynamics of various cell types underlying mouse adipose tissue remodeling during obesity. By integrating bulk nuclear RNA-seq from adipocyte nuclei of different sizes, we identify distinct adipocyte subpopulations categorized by size and functionality. These subpopulations follow two divergent trajectories, adaptive and pathological, with their prevalence varying by depot. Specifically, we identify a key molecular feature of dysfunctional hypertrophic adipocytes, a global shutdown in gene expression, along with elevated stress and inflammatory responses. Furthermore, our differential gene expression analysis reveals distinct contributions of adipocyte subpopulations to the overall pathophysiology of adipose tissue. Our study establishes a robust snRNA-seq method, providing novel insights into the biological processes involved in adipose tissue remodeling during obesity, with broader applicability across diverse biological systems.
    Keywords:  adipocytes; cell biology; genetics; genomics; mouse; obesity; snRNA-seq
    DOI:  https://doi.org/10.7554/eLife.97981
  4. Nat Aging. 2025 Jan 13.
    Somatic mutation as an explanation for epigenetic aging.
    Zane Koch, Adam Li, Daniel S Evans, Steven Cummings, Trey Ideker.
      DNA methylation marks have recently been used to build models known as epigenetic clocks, which predict calendar age. As methylation of cytosine promotes C-to-T mutations, we hypothesized that the methylation changes observed with age should reflect the accrual of somatic mutations, and the two should yield analogous aging estimates. In an analysis of multimodal data from 9,331 human individuals, we found that CpG mutations indeed coincide with changes in methylation, not only at the mutated site but with pervasive remodeling of the methylome out to ±10 kilobases. This one-to-many mapping allows mutation-based predictions of age that agree with epigenetic clocks, including which individuals are aging more rapidly or slowly than expected. Moreover, genomic loci where mutations accumulate with age also tend to have methylation patterns that are especially predictive of age. These results suggest a close coupling between the accumulation of sporadic somatic mutations and the widespread changes in methylation observed over the course of life.
    DOI:  https://doi.org/10.1038/s43587-024-00794-x
  5. Nat Rev Genet. 2025 Jan 13.
    Epigenetic ageing clocks: statistical methods and emerging computational challenges.
    Andrew E Teschendorff, Steve Horvath.
      Over the past decade, epigenetic clocks have emerged as powerful machine learning tools, not only to estimate chronological and biological age but also to assess the efficacy of anti-ageing, cellular rejuvenation and disease-preventive interventions. However, many computational and statistical challenges remain that limit our understanding, interpretation and application of epigenetic clocks. Here, we review these computational challenges, focusing on interpretation, cell-type heterogeneity and emerging single-cell methods, aiming to provide guidelines for the rigorous construction of interpretable epigenetic clocks at cell-type and single-cell resolution.
    DOI:  https://doi.org/10.1038/s41576-024-00807-w
  6. iScience. 2025 Jan 17. 28(1): 111562
    Ablation of PI3Kγ in neurons protects mice from diet-induced obesity MASLD and insulin resistance.
    Angela Molinaro, Arianna Mazzoli, Andrea Usseglio Gaudi, Amit Chand Gupta, Vagner Ramon Rodrigues Silva, Damien Ramel, Muriel Laffargue, Johan Ruud, Barbara Becattini, Giovanni Solinas.
      Mice with genetic ablation of PI3Kγ are protected from diet-induced obesity. However, the cell type responsible for PI3Kγ action in obesity remains unknown. We generated mice with conditional deletion of PI3Kγ in neurons using the nestin promoter to drive the expression of the Cre recombinase (PI3KγNest mice) and investigated their metabolic phenotype in a model of diet-induced obesity. On a chow diet, lean PI3KγNest mice display reduced linear growth and a normal metabolic phenotype. PI3KγNest mice were largely protected from diet-induced obesity and liver steatosis and showed improved glucose tolerance and insulin sensitivity. This phenotype was associated with increased phosphorylation of hormone-sensitive lipase (HSL) at protein kinase A (PKA) sites in white fat. It is concluded that PI3Kγ action in diet-induced obesity depends on its activity in neurons controlling adipose tissue lipolysis. Future clinical studies on PI3Kγ inhibitors capable of crossing the brain-blood barrier will reveal the relevance of these findings to humans.
    Keywords:  Molecular biology; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2024.111562
  7. Nat Commun. 2025 Jan 17. 16(1): 752
    Single-cell transcriptome atlas of lamprey exploring Natterin- induced white adipose tissue browning.
    Yue Pang, Yating Qin, Zeyu Du, Qun Liu, Jin Zhang, Kai Han, Jiali Lu, Zengbao Yuan, Jun Li, Shanshan Pan, Xinrui Dong, Mengyang Xu, Dantong Wang, Shuo Li, Zhen Li, Yadong Chen, Zhisheng Zhao, Zhe Zhang, Shunqin Chuan, Yue Song, Mingjie Sun, Xiaodong Jia, Zhangyong Xia, Liping Zhan, Zhen Yue, Wei Cui, Jun Wang, Ying Gu, Ming Ni, Huanming Yang, Xun Xu, Xin Liu, Qingwei Li, Guangyi Fan.
      Lampreys are early jawless vertebrates that are the key to understanding the evolution of vertebrates. However, the lack of cytomic studies on multiple lamprey organs has hindered progress in this field. Therefore, the present study constructed a comprehensive cell atlas comprising 604,460 cells/nuclei and 70 cell types from 14 lamprey tissue samples. Comparison of cellular evolution across species revealed that most lamprey cell types are homologous to those in jawed vertebrates. We discovered acinar- and islet-like cell populations despite the lack of parenchymal organs in lampreys, providing evidence of pancreatic function in vertebrates. Furthermore, we investigated the heterogeneity of lamprey immune cell populations. Natterin was highly expressed in granulocytes, and NATTERIN was localized to the lipid droplets. Moreover, we developed a transgenic mouse model expressing Natterin to elucidate the role of NATTERIN in lipid metabolism, whereas the browning of white adipose tissue was induced. These findings elucidate vertebrate cellular evolution and advance our understanding of adipose tissue plasticity and metabolic regulation in lampreys.
    DOI:  https://doi.org/10.1038/s41467-025-56153-w
  8. Nat Metab. 2025 Jan 16.
    Proline exacerbates hepatic gluconeogenesis via paraspeckle-dependent mRNA retention.
    Yurong Zhao, Xinxin Chai, Junxuan Peng, Yi Zhu, Rong Dong, Junwei He, Linghao Xia, Sishuo Liu, Jingzhou Chen, Zhengping Xu, Chi Luo, Jinghao Sheng.
      Type 2 diabetes (T2D) is a global health issue characterized by abnormal blood glucose levels and is often associated with excessive hepatic gluconeogenesis. Increased circulating non-essential amino acids (NEAAs) are consistently observed in individuals with T2D; however, the specific contribution of each amino acid to T2D pathogenesis remains less understood. Here, we report an unexpected role of the NEAA proline in coordinating hepatic glucose metabolism by modulating paraspeckle, a nuclear structure scaffolded by the long non-coding RNA Neat1. Mechanistically, proline diminished paraspeckles in hepatocytes, liberating the retained mRNA species into cytoplasm for translation, including the mRNAs of Ppargc1a and Foxo1, contributing to enhanced gluconeogenesis and hyperglycaemia. We further demonstrated that the proline-paraspeckle-mRNA retention axis existed in diabetic liver samples, and intervening in this axis via paraspeckle restoration substantially alleviated hyperglycaemia in both female and male diabetic mouse models. Collectively, our results not only delineated a previously unappreciated proline-instigated, paraspeckle-dependent mRNA-retention mechanism regulating gluconeogenesis, but also spotlighted proline and paraspeckle as potential targets for managing hyperglycaemia.
    DOI:  https://doi.org/10.1038/s42255-024-01206-5
  9. Nat Aging. 2025 Jan 10.
    Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence.
    Hao Yang, Tongyao Wang, Chenglang Qian, Huijing Wang, Dong Yu, Meifang Shi, Mengwei Fu, Xueguang Liu, Miaomiao Pan, Xingyu Rong, Zhenming Xiao, Xiejiu Chen, Anaguli Yeerken, Yonglin Wu, Yufan Zheng, Hui Yang, Ming Zhang, Tao Liu, Peng Qiao, Yifan Qu, Yong Lin, Yiqin Huang, Jianliang Jin, Nan Liu, Yumei Wen, Ning Sun, Chao Zhao.
      Gut microbiota plays a crucial role in the host health in the aging process. However, the mechanisms for how gut microbiota triggers cellular senescence and the consequent impact on human aging remain enigmatic. Here we show that phenylacetylglutamine (PAGln), a metabolite linked to gut microbiota, drives host cellular senescence. Our findings indicate that the gut microbiota alters with age, which leads to increased production of phenylacetic acid (PAA) and its downstream metabolite PAGln in older individuals. The PAGln-induced senescent phenotype was verified in both cellular models and mouse models. Further experiments revealed that PAGln induces mitochondrial dysfunction and DNA damage via adrenoreceptor (ADR)-AMP-activated protein kinase (AMPK) signaling. Blockade of ADRs as well as senolytics therapy impede PAGln-induced cellular senescence in vivo, implying potential anti-aging therapies. This combined evidence reveals that PAGln, a naturally occurring metabolite of human gut microbiota, mechanistically accelerates host cellular senescence.
    DOI:  https://doi.org/10.1038/s43587-024-00795-w
  10. Nat Metab. 2025 Jan 16.
    Recommendations for mitochondria transfer and transplantation nomenclature and characterization.
    Jonathan R Brestoff, Keshav K Singh, Katia Aquilano, Lance B Becker, Michael V Berridge, Eric Boilard, Andrés Caicedo, Clair Crewe, José Antonio Enríquez, Jianqing Gao, Åsa B Gustafsson, Kazuhide Hayakawa, Maroun Khoury, Yun-Sil Lee, Daniele Lettieri-Barbato, Patricia Luz-Crawford, Heidi M McBride, James D McCully, Ritsuko Nakai, Jiri Neuzil, Martin Picard, Alexander G Rabchevsky, Anne-Marie Rodriguez, Shiladitya Sengupta, Alexander J Sercel, Toshio Suda, Michael A Teitell, Alain R Thierry, Rong Tian, Melanie Walker, Minghao Zheng.
      Intercellular mitochondria transfer is an evolutionarily conserved process in which one cell delivers some of their mitochondria to another cell in the absence of cell division. This process has diverse functions depending on the cell types involved and physiological or disease context. Although mitochondria transfer was first shown to provide metabolic support to acceptor cells, recent studies have revealed diverse functions of mitochondria transfer, including, but not limited to, the maintenance of mitochondria quality of the donor cell and the regulation of tissue homeostasis and remodelling. Many mitochondria-transfer mechanisms have been described using a variety of names, generating confusion about mitochondria transfer biology. Furthermore, several therapeutic approaches involving mitochondria-transfer biology have emerged, including mitochondria transplantation and cellular engineering using isolated mitochondria. In this Consensus Statement, we define relevant terminology and propose a nomenclature framework to describe mitochondria transfer and transplantation as a foundation for further development by the community as this dynamic field of research continues to evolve.
    DOI:  https://doi.org/10.1038/s42255-024-01200-x
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