bims-obesme 2025-08-17 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2025–08–17
eight papers selected by
Xiong Weng, University of Edinburgh

ICAM-1 identifies preadipocytes and restricts white adipogenesis by adhering immune cells.
Obesity-associated macrophages dictate adipose stem cell ferroptosis and visceral fat dysfunction by propagating mitochondrial fragmentation.
Adipocyte RNA-binding protein CELF1 promotes beiging of white fat through stabilizing Dio2 mRNA.
European and African ancestry-specific plasma protein-QTL and metabolite-QTL analyses identify ancestry-specific T2D effector proteins and metabolites.
Rewriting nuclear epigenetic scripts in mitochondrial diseases as a strategy for heteroplasmy control.
Glucose-dependent insulinotropic polypeptide receptor signaling in oligodendrocytes increases the weight-loss action of GLP-1R agonism.
Prevalent mesenchymal drift in aging and disease is reversed by partial reprogramming.
Dysregulation of GTPase-activating protein-binding protein1 in the pathogenesis of metabolic dysfunction-associated steatotic liver disease.

Cell Death Differ. 2025 Aug 15.

ICAM-1 identifies preadipocytes and restricts white adipogenesis by adhering immune cells.

Chunxing Zheng, Jiayin Ye, Qian Yang, Keli Liu, Cheng Chen, Jianchang Cao, Qing Li, Yueqing Xue, Hui Ma, Arnold B Rabson, Changshun Shao, Fei Hua, Lydia Sorokin, Gerry Melino, Yufang Shi, Ying Wang.

Adipose stem cell hierarchy was delineated by scRNA-seq analysis, revealing that ICAM-1, a glycoprotein that mediates cell-cell interaction, is a preadipocyte marker. However, the cellular and molecular mechanisms of how ICAM-1+ preadipocytes contribute to adipose tissue homeostasis in vivo remain unclear. To address this, Icam1+/CreERT2 mice were generated, and it was demonstrated that ICAM-1-expressing progenitors actively participated in developing and remodeling white adipose tissue. Under a high-fat diet, both proliferation and adipogenic differentiation of ICAM-1+ preadipocytes increased significantly. Interestingly, ICAM-1 plays a critical role in maintaining the interaction between preadipocytes and immune cells, acting as a checkpoint on white adipogenesis. Mice lacking ICAM-1 specifically in stromal cells exhibited worsened hyperplastic obesity, showing heightened fatty acid synthesis and lipid storage in adipose tissue, and the related insulin resistance. In human adipose tissue, ICAM-1 also marked committed preadipocytes and mediated adhesion between preadipocytes and immune cells. Thus, our study shows that ICAM-1 marks preadipocytes and curbs adipogenesis by facilitating adhesion between preadipocytes and immune cells.

DOI: https://doi.org/10.1038/s41418-025-01551-2
Nat Commun. 2025 Aug 14. 16(1): 7564

Obesity-associated macrophages dictate adipose stem cell ferroptosis and visceral fat dysfunction by propagating mitochondrial fragmentation.

Yan Tao, Jinhao Zang, Tianci Wang, Peixuan Song, Zixin Zhou, Huijie Li, Yalin Wang, Yiyang Liu, Haipeng Jie, Mei Kuang, Hui Zhao, Fuwu Wang, Shen Dai, Chun Guo, Faliang Zhu, Haiting Mao, Fengming Liu, Lining Zhang, Qun Wang.

Morbid obesity induces adipose stem cell (ASC) shortage that impairs visceral adipose tissue (VAT) homeostasis. Macrophages cooperate with ASCs to regulate VAT metabolism, their impact on ASC shortage remains elusive. TNF-α-induced protein 8-like 2 (TIPE2) is an important regulator in immune cells, its expression in VAT macrophages and function in macrophage-ASC crosstalk are largely unknown. Here, TIPE2 loss in VAT macrophages promotes ASC ferroptosis to aggravate diet-induced obesity and metabolic disorders in male mice, which can be corrected by macrophage-specific TIPE2 restoration in VAT. Mechanistically, TIPE2-deficient macrophages propagate mitochondrial fragmentation and reduce delivery of exosomal ferritin toward ASCs, resulting in mitochondrial ROS and Fe2+ overload that dictates ASC ferroptosis. TIPE2 interacts with IP3R to constrain IP3R-Ca2+-Drp1 axis, thereby preventing excessive mitochondrial fission and enabling macrophages to protect against ASC ferroptosis. This study reveals distinct obesity-associated macrophages that dictate ASC ferroptosis, and proposes macrophage TIPE2 as therapeutic target for obesity-related diseases.

DOI: https://doi.org/10.1038/s41467-025-62690-1
Nat Commun. 2025 Aug 11. 16(1): 7414

Adipocyte RNA-binding protein CELF1 promotes beiging of white fat through stabilizing Dio2 mRNA.

Ting Zeng, Liuling Xiao, Jiajie Li, Han Wu, Xiaolong Guo, Fukang Zhu, Xinyu Yu, Yewei Cui, Xueya Zhao, Yumeng Wang, Ting Zhang, Weijiong He, Hongxiang Zeng, Xi Li.

RNA-binding proteins (RBPs) regulate diverse post-transcriptional processes and play roles in adipocyte development; however, their role in white fat beiging remains unclear. Here we identify CUG-BP Elav-like family member 1 (CELF1) as a key RBP promoting beiging of inguinal white adipose tissue in response to cold. Adipocyte-specific Celf1 deficiency impairs cold-induced thermogenic gene expression and reduces energy expenditure. Mechanistically, CELF1 binds to the 3'UTR of Dio2 mRNA and enhances its stability, promoting local triiodothyronine (T3) production. Notably, CELF1 expression is significantly reduced in subcutaneous fat of individuals with obesity and negatively correlates with BMI. CELF1 enhances isoproterenol-induced beige adipocyte activation and mitochondrial respiration in vitro, and Celf1 overexpression ameliorates diet-induced obesity and metabolic dysfunction. Hence, our study identifies CELF1 as a physiological regulator of metabolic stress in activating thermogenesis and promoting energy expenditure at the post-transcriptional level, highlighting its potential as a therapeutic target for obesity and metabolic diseases.

DOI: https://doi.org/10.1038/s41467-025-62740-8
Nat Commun. 2025 Aug 11. 16(1): 7412

European and African ancestry-specific plasma protein-QTL and metabolite-QTL analyses identify ancestry-specific T2D effector proteins and metabolites.

Chengran Yang, Priyanka Gorijala, Jigyasha Timsina, Lihua Wang, Menghan Liu, Ciyang Wang, William Brock, Yueyao Wang, Fumihiko Urano, Yun Ju Sung, Carlos Cruchaga.

In this study, we generated and integrated plasma proteomics and metabolomics with the genotype datasets of over 2300 European (EUR) and 400 African (AFR) ancestries to identify ancestry-specific multi-omics quantitative trait loci (QTLs). In total, we mapped 954 AFR pQTLs, 2848 EUR pQTLs, 65 AFR mQTLs, and 490 EUR mQTLs. We further applied these QTLs to ancestry-stratified type-2 diabetes (T2D) risk to pinpoint key proteins and metabolites underlying the disease-associated genetic loci. Using INTACT that combined trait-imputation and colocalization results, we nominated 270 proteins and 72 metabolites from the EUR set; seven proteins and one metabolite from the AFR set as molecular effectors of T2D risk in an ancestry-stratified manner. Here, we show that the integration of genetic and omic studies of different ancestries can be used to identify distinct effector molecular traits underlying the same disease across diverse ancestral groups.

DOI: https://doi.org/10.1038/s41467-025-62463-w
EMBO Mol Med. 2025 Aug 11.

Rewriting nuclear epigenetic scripts in mitochondrial diseases as a strategy for heteroplasmy control.

María J Pérez, Rocío B Colombo, Sebastián M Real, María T Branham, Sergio R Laurito, Carlos T Moraes, Lía Mayorga.

  Mitochondrial diseases, caused by mutations in nuclear or mitochondrial DNA (mtDNA), have limited treatment options. For mtDNA mutations, reducing the mutant-to-wild-type mtDNA ratio (heteroplasmy shift) is a promising strategy, though it currently faces challenges. Previous research showed that severe mitochondrial dysfunction triggers an adaptive nuclear epigenetic response, through changes in DNA methylation, absent or less important for subtle mitochondrial impairment. Therefore, we hypothesized that targeting nuclear DNA methylation could impair cells with high-mutant mtDNA load while sparing those with lower levels, reducing overall heteroplasmy. Using cybrid models harboring two disease-causing mtDNA mutations-m.13513 G > A and m.8344 A > G-at varying heteroplasmies, we discovered that both the mutation type and load distinctly shape the nuclear DNA methylome. We found this methylation pattern critical for the survival of high-heteroplasmy cells but not for low-heteroplasmy ones. Treatment with FDA-approved DNA methylation inhibitors selectively impacted high-heteroplasmy cybrids and reduced heteroplasmy. These findings were validated in cultured cells and xenografts. Our findings highlight nuclear DNA methylation as a key regulator of heteroplasmic cell survival and a potential therapeutic target for mitochondrial diseases.

Keywords:  DNA Methylation; Epigenetics; Heteroplasmy; Mitochondrial DNA; Mitochondrial Diseases

DOI:  https://doi.org/10.1038/s44321-025-00285-5
Cell Metab. 2025 Aug 08. pii: S1550-4131(25)00355-9. [Epub ahead of print]

Glucose-dependent insulinotropic polypeptide receptor signaling in oligodendrocytes increases the weight-loss action of GLP-1R agonism.

Robert Hansford, Sophie Buller, Anthony H Tsang, Simon Benoit, Anna G Roberts, Emmy Erskine, Thomas Brown, Valentina Pirro, Frank Reimann, Norio Harada, Nobuya Inagaki, Ricardo J Samms, Johannes Broichhagen, David J Hodson, Alice Adriaenssens, Soyoung Park, Clemence Blouet.

  The next generation of obesity medicines harness the activity of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptors (GIPR and GLP-1R), but their mechanism of action remains unclear. Here, we report that the GIPR is enriched in oligodendrocytes and GIPR signaling bidirectionally regulates oligodendrogenesis. In mice with adult-onset deletion of GIPR in oligodendrocytes, GIPR agonism fails to enhance the weight-loss effects of GLP-1R agonism. Mechanistically, GIPR agonism increases brain access of GLP-1R agonists, and GIPR signaling in oligodendrocytes is required for this effect. In addition, we show that vasopressin neurons of the paraventricular hypothalamus are necessary for the weight-loss response to GLP-1R activation, targeted by peripherally administered GLP-1R agonists via their axonal compartment, and this access is increased by activation of the GIPR in oligodendrocytes. Collectively, our findings identify a novel mechanism by which incretin therapies may function to promote synergistic weight loss in the management of excess adiposity.

Keywords:  blood-brain barrier; glucose-dependent insulinotropic peptide; hypothalamus; incretin; median eminence; obesity; oligodendrocytes; weight loss

DOI:  https://doi.org/10.1016/j.cmet.2025.07.009
Cell. 2025 Aug 11. pii: S0092-8674(25)00853-0. [Epub ahead of print]

Prevalent mesenchymal drift in aging and disease is reversed by partial reprogramming.

Jinlong Y Lu, William B Tu, Ronghui Li, Mingxi Weng, Bhargav D Sanketi, Baolei Yuan, Pradeep Reddy, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte.

  The loss of cellular and tissue identity is a hallmark of aging and numerous diseases, but the underlying mechanisms are not well understood. Our analysis of gene expression data from over 40 human tissues and 20 diseases reveals a pervasive upregulation of mesenchymal genes across multiple cell types, along with an altered composition of stromal cell populations, denoting a "mesenchymal drift" (MD). Increased MD correlates with disease progression, reduced patient survival, and an elevated mortality risk, whereas suppression of key MD transcription factors leads to epigenetic rejuvenation. Notably, Yamanaka factor-induced partial reprogramming can markedly reduce MD before dedifferentiation and gain of pluripotency, rejuvenating the aging transcriptome at the cellular and tissue levels. These findings provide mechanistic insight into the underlying beneficial effects of partial reprogramming and offer a framework for developing interventions to reverse age-related diseases using the partial reprogramming approach.

Keywords:  Yamanaka factors; aging; chronic kidney disease; epithelial-mesenchymal transition; fibrosis; heart failure; idiopathic pulmonary fibrosis; metabolic dysfunction-associated steatohepatitis; partial reprogramming; rejuvenation

DOI:  https://doi.org/10.1016/j.cell.2025.07.031
Nat Commun. 2025 Aug 14. 16(1): 7570

Dysregulation of GTPase-activating protein-binding protein1 in the pathogenesis of metabolic dysfunction-associated steatotic liver disease.

Qinqin Ouyang, Jiaqi Su, Yixuan Li, Haiping Liao, Haiying Guo, Yanan Sun, Xiaoyu Wang, Juan Chen, Josephine Thinwa, Wen-Xing Ding, Herbert Tilg, Fazheng Ren, Hao Zhang, Rong Liu.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are two common liver disorders characterized by abnormal lipid accumulation. Our study found reduced levels of GTPase-activating protein-binding protein1 (G3BP1) in patients with MASLD and MASH, suggesting its involvement in these liver disorders. Hepatocyte-specific G3BP1 knockout (G3BP1 HKO) male mice had more severe MASLD and MASH than their corresponding controls. Intriguingly, the G3BP1 HKO MASLD model male mice exhibit dysregulated autophagy, and biochemical analyses demonstrated that G3BP1 promotes autophagosome-lysosome fusion through direct interactions with the SNARE proteins STX17 and VAMP8. We also show that hepatic knockout of G3BP1 promotes de novo lipogenesis, and ultimately found that G3BP1 is required for the nuclear translocation of the well-known liver-lipid-regulating transcription factor TFE3. Taken together, our results suggest that G3BP1 should be investigated as a potential target for developing medical interventions to treat MASLD and MASH.

DOI: https://doi.org/10.1038/s41467-025-63022-z