bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–12–14
fourteen papers selected by
Xiong Weng, University of Edinburgh
  1. Paracrine stimulation of brown adipose tissue vascularization by adipocyte O-GlcNAc signaling.
  2. PTEN regulates vagal-insulin signaling to optimize autonomic output determining peripheral inflammatory and metabolic homeostasis.
  3. Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control.
  4. Adipose tissue-derived microRNAs as epigenetic modulators of type 2 diabetes.
  5. Dynamic changes in mitochondria support phenotypic flexibility of microglia.
  6. H3K36 Methylation as a Guardian of Epigenome Integrity.
  7. Bile acids regulate lipid metabolism through selective actions on fatty acid absorption.
  8. AGPAT2 acts at the crossroads of lipid biosynthesis and DRP1-mediated ER morphogenesis.
  9. The glycolytic enzyme PFKFB3 alleviates DNA damage and chondrocyte senescence in osteoarthritis.
  10. Pla2g7 regulates bone homeostasis via Alox12/12-HETE/Gpr31 signaling axis.
  11. Editing DNA methylation in vivo.
  12. Inferring cell differentiation maps from lineage tracing data.
  13. Dnmt3a2 expression during embryonic development is required for phenotypic stability.
  14. Neutrophils preserve energy storage in sympathetically activated adipocytes.
  1. Cell Rep. 2025 Dec 11. pii: S2211-1247(25)01450-0. [Epub ahead of print]44(12): 116678
    Paracrine stimulation of brown adipose tissue vascularization by adipocyte O-GlcNAc signaling.
    Luwen Li, Liwei Dong, Yaping Shan, Jintang Xie, Ting Song, Sai Zhang, Yun Kong, Shiqi Zhang, Chengwei Gu, Die Hu, Weijia Wang, Yunfan Yang.
      Brown adipose tissue (BAT) is extensively vascularized, which is essential for its physiological activities. The molecular mechanism that underpins BAT vascularization, however, remains poorly understood. This study presents evidence that acute cold exposure induces an elevation in total protein O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) in BAT. Ablation of O-GlcNAc transferase in brown adipocytes drastically impairs BAT vascularization. Mechanistic studies demonstrate that O-GlcNAcylation of specificity protein 1 in brown adipocytes enhances its transcriptional activity toward kielin/chordin-like protein (Kcp). Secreted KCP subsequently promotes BAT angiogenesis by paracrine activation of bone morphogenetic protein signaling. Furthermore, boosting O-GlcNAc signaling with glucosamine supplementation effectively augments BAT vascularization and thermogenesis. These findings thus uncover a previously unrecognized role of adipocyte O-GlcNAc signaling in the metabolism-driven regulation of BAT vascularization and function.
    Keywords:  BMP signaling; CP: metabolism; KCP; O-GlcNAc; brown adipose tissue; vascular system
    DOI:  https://doi.org/10.1016/j.celrep.2025.116678
  2. Nat Commun. 2025 Dec 10.
    PTEN regulates vagal-insulin signaling to optimize autonomic output determining peripheral inflammatory and metabolic homeostasis.
    Yu Zhe Li, Joe Eun Son, Nathaniel Vo, Catherine Bellisimo, Ju Hee Lee, Joshua Rapps, Evan Pollock-Tahiri, Martha Ghebreselassie, Chuck T Chen, Richard P Bazinet, Filio Billia, Akira Suzuki, Chi-Chung Hui, Tak W Mak, Hoon-Ki Sung, Paul Yoo, Minna Woo.
      The vagus nerve (VN) is a major component of the parasympathetic nervous system that regulates glucose and energy homeostasis. However, the specific molecular signaling pathways within the VN that regulates this homeostasis remain unclear. Here, we show that vagal neuron-specific deletion of phosphatase and tensin homolog (Pten), the endogenous negative regulator of PI3K, led to increased vagal output. Intriguingly, dopaminergic signaling genes were upregulated, correlating with elevated sympathetic nerve density and increased norepinephrine levels in adipose tissue of vagal Pten-deficient mice. These mice were also protected against high-fat diet-induced obesity, insulin resistance, and systemic inflammation. To investigate insulin-specific PI3K signaling within the VN, we generated mice with vagal neuron-specific insulin receptor deletion that resulted in exacerbation of metabolic defects, which was rescued by concomitant Pten deletion. In summary, we show that insulin-PI3K-PTEN axis within vagal neurons is essential in optimizing the autonomic output that determines peripheral inflammatory and metabolic homeostasis.
    DOI:  https://doi.org/10.1038/s41467-025-67192-8
  3. Nat Metab. 2025 Dec 08.
    Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control.
    Julien Chilloux, Francois Brial, Amandine Everard, David Smyth, Petros Andrikopoulos, Liyong Zhang, Hubert Plovier, Antonis Myridakis, Lesley Hoyles, José Maria Moreno-Navarrete, Jèssica Latorre Luque, Viviana Casagrande, Rossella Menghini, Blerina Ahmetaj-Shala, Christine Blancher, Laura Martinez-Gili, Selin Gencer, Jane F Fearnside, Richard H Barton, Ana Luisa Neves, Alice R Rothwell, Christelle Gérard, Sophie Calderari, Mark J Williamson, Julian E Fuchs, Lata Govada, Claire L Boulangé, Saroor Patel, James Scott, Mark Thursz, Naomi Chayen, Robert C Glen, Nigel J Gooderham, Jeremy K Nicholson, Massimo Federici, José Manuel Fernández-Real, Dominique Gauguier, Peter P Liu, Patrice D Cani, Marc-Emmanuel Dumas.
      The global type 2 diabetes epidemic is a major health crisis. Although the microbiome has roles in the onset of insulin resistance (IR), low-grade inflammation and diabetes, the microbial compounds controlling these processes remain to be discovered. Here, we show that the microbial metabolite trimethylamine (TMA) decouples inflammation and IR from diet-induced obesity by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4), a central kinase in the Toll-like receptor pathway sensing danger signals. TMA blunts TLR4 signalling in primary human hepatocytes and peripheral blood monocytic cells and rescues mouse survival after lipopolysaccharide-induced septic shock. Genetic deletion and chemical inhibition of IRAK4 result in metabolic and immune improvements in high-fat diets. Remarkably, our results suggest that TMA-unlike its liver co-metabolite trimethylamine N-oxide, which is associated with cardiovascular disease-improves immune tone and glycemic control in diet-induced obesity. Altogether, this study supports the emerging role of the kinome in the microbial-mammalian chemical crosstalk.
    DOI:  https://doi.org/10.1038/s42255-025-01413-8
  4. BMC Med. 2025 Dec 09. 23(1): 678
    Adipose tissue-derived microRNAs as epigenetic modulators of type 2 diabetes.
    Ratika Sehgal, Neele Haacke, Alice Maguolo, Fiorella A Solari, Markus Jähnert, Pascal Gottmann, Emma Nilsson, Allan Vaag, Pamela Fischer-Posovszky, Anja Werberger, Andreas L Birkenfeld, Andreas Fritsche, Hans-Ulrich Häring, Albert Sickmann, Heike Vogel, Charlotte Ling, Meriem Ouni, Annette Schürmann.
       BACKGROUND: White adipose tissue (WAT) dysfunction including an aberrant expression of miRNAs is strongly associated with the risk of developing type 2 diabetes (T2D), with limited evidence linking early changes in the WAT-derived miRNAs and T2D. The present study aims to identify early miRNome changes prognostic for T2D in mice and humans.
    METHODS: Gonadal (g) WAT of diabetes-resistant and diabetes-prone mice were subjected to multi-omics analyses (transcriptome, miRNome, methylome, proteome). Metabolic phenotypes linked with T2D were correlated with adipose tissue miRNA expression and DNA methylation from 14 monozygotic twin pairs discordant for T2D. Plasma miRNA levels from females at high risk of developing T2D (TÜF study) were included.
    RESULTS: Adipose tissue of the diabetes-susceptible mice was less insulin sensitive with ~ 200 differentially expressed mature miRNAs compared to diabetes-resistant mice. Integrative analysis of miRNome-transcriptome-proteome identified 227 proteins involved in amino acid metabolism, inflammation, signalling pathways, and insulin resistance. More than 20 differentially expressed miRNAs are located in the imprinted region Dlk1-Gtl2 and Mest (miR-335) potentially regulated by DNA methylation. Imprinted miRNAs also exhibited similar alterations in adipose tissue from monozygotic twin pairs discordant for T2D, with miR-335 expression altered only in females. Moreover, plasma levels of miR-335-5p were negatively correlated with fasting blood glucose in females at high risk of developing T2D.
    CONCLUSIONS: Early alterations of WAT-derived miRNAs such as miR-335-5p could contribute to systemic metabolic changes associated with the risk of developing T2D.
    Keywords:  Adipose tissue; Discordant monozygotic twins; Epigenetics; Imprinting; MicroRNA (miRNA); Multiomics; New Zealand Obese (NZO) mice; Type 2 diabetes (T2D)
    DOI:  https://doi.org/10.1186/s12916-025-04560-7
  5. Nat Commun. 2025 Dec 12. 16(1): 11103
    Dynamic changes in mitochondria support phenotypic flexibility of microglia.
    Katherine Espinoza, Ari W Schaler, Daniel T Gray, Arielle R Sass, Adrian Escobar, Kamilia Moore, Megan E Yu, Casandra G Chamorro, Lindsay M De Biase.
      Microglial capacity to adapt to tissue needs is a hallmark feature of these cells. New studies show that mitochondria critically regulate the phenotypic adaptability of macrophages. To determine whether these organelles play similar roles in shaping microglial phenotypes, we generated transgenic mouse crosses to accurately visualize and manipulate microglial mitochondria. We find that brain-region differences in microglial attributes and responses to aging are accompanied by regional differences in mitochondrial mass and aging-associated mitochondrial remodeling. Microglial mitochondria are also altered within hours of LPS injections and microglial expression of inflammation-, trophic-, and phagocytosis-relevant genes is strongly correlated with expression of mitochondria-relevant genes. Finally, direct genetic manipulation of microglial mitochondria alters microglial morphology and leads to brain-region specific effects on microglial gene expression. Overall, this study advances our understanding of microglial mitochondria and supports the idea that mitochondria influence basal microglial phenotypes and phenotypic remodeling that takes place over hours to months.
    DOI:  https://doi.org/10.1038/s41467-025-66709-5
  6. Nat Commun. 2025 Dec 11.
    H3K36 Methylation as a Guardian of Epigenome Integrity.
    Reinnier Padilla, Gerry A Shipman, Cynthia Horth, Michel Gravel, Eric Bareke, Jacek Majewski.
      H3K36 methylation is a key epigenetic mark with critical roles in development and disease. Here, we systematically dissect its functions using CRISPR-engineered mouse mesenchymal stem cells lacking combinations of the five H3K36 methyltransferases, culminating in quintuple knockout cells devoid of H3K36me2/3. We show that H3K36me2 influences enhancer activity, supports the expression of their target genes, and safeguards active genes from encroachment of the repressive marks, H3K27me2/3. In addition, we find that the loss of H3K36me triggers redistribution of large heterochromatic H3K9me3 domains into euchromatin, in part mediated by SUV39H1, leading to global epigenomic remodelling, constitutive heterochromatin erosion, and a collapse of 3D genome organization. Parallel analyses in human HNSCC cells overexpressing the H3K36M oncohistone reveal conserved disruptions to the epigenome and chromatin architecture. Together, these results establish H3K36 methylation as a pivotal regulator of chromatin state and genomic structure.
    DOI:  https://doi.org/10.1038/s41467-025-66365-9
  7. Cell Metab. 2025 Dec 11. pii: S1550-4131(25)00494-2. [Epub ahead of print]
    Bile acids regulate lipid metabolism through selective actions on fatty acid absorption.
    Alvin P Chan, Kelsey E Jarrett, Rochelle W Lai, Madelaine C Brearley-Sholto, Angela S Cheng, Maria O Taveras, Anne M Iwata, Michelle E Steel, Andrew Lau, Emily C Whang, John P Kennelly, Yajing Gao, Gabriella E Rubert, Heidi M Schmidt, Emily P Smith, Baolong Su, Kevin J Williams, Elizabeth J Tarling, Thomas Q de Aguiar Vallim.
      Intestinal lipid absorption, the entry point for fats into the body, requires the coordinated actions of bile acids and lipases. Here, we uncover distinct yet cooperative roles of bile acids in driving the differential uptake of dietary fatty acids. We first decreased the bile acid pool size by disrupting the rate-limiting enzyme in bile acid synthesis, Cyp7a1, using liver-directed gene editing in mice. Compared with lipase inhibition, reduced bile acids prevented diet-induced obesity, increased anorectic hormones, suppressed excessive eating, and improved systemic lipid metabolism. Remarkably, decreasing bile acids selectively reduced the absorption of saturated fatty acids but preserved polyunsaturated fatty acids. By targeting additional bile acid enzymes, we identified specific functions of individual bile acid species. Mechanistically, we show that cholic acid preferentially solubilizes polyunsaturated fatty acids into mixed micelles for intestinal uptake. Our studies demonstrate that bile acids can selectively control fatty acid uptake, revealing insights for future interventions in metabolic diseases.
    Keywords:  CYP2A12; CYP2C70; CYP7A1; CYP8B1; GLP-1; bile acids; fatty acids; lipid absorption; lipogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2025.11.010
  8. Nat Commun. 2025 Dec 12.
    AGPAT2 acts at the crossroads of lipid biosynthesis and DRP1-mediated ER morphogenesis.
    Yoshihiro Adachi, Mauricio Torres, Allen H Hunter, Woo Jung Cho, Meixia Pan, Xianlin Han, Guangwei Du, Ling Qi, Miho Iijima, Hiromi Sesaki.
      The morphology of the endoplasmic reticulum (ER), characterized by central sheets and peripheral tubules, is controlled by membrane-shaping proteins. However, the role of lipids in ER morphogenesis remains elusive, despite the ER being the major site for lipid synthesis. Here, by examining the role of eighteen phosphatidic acid (PA)-generating enzymes in ER morphology, we identify lysophosphatidic acid acyltransferase 2 (AGPAT2) as a critical factor in mouse and human cells. AGPAT2 produces PA in the glycerophospholipid/triacylglycerol biosynthesis pathway, and its mutations cause congenital generalized lipodystrophy. We find that AGPAT2-generated PA drives ER tubulation through gene knockout, 3D structural analysis by FIB-SEM, super-resolution microscopy, lipidomics, AlphaFold, and in vitro reconstitutions of ER tubulation and AGPAT2 activity. AGPAT2 interacts with and supplies PA to the PA-binding, dynamin-related GTPase, DRP1, which subsequently tubulates the ER in a manner independent of GTP hydrolysis and oligomerization, distinct from its function in mitochondrial division. Consistently, the reduction of PA levels by ectopic expression of a PA phosphatase, LIPIN1, transforms ER tubules into sheets. Our results reveal an unforeseen interplay between lipid biosynthesis and membrane organization in the ER.
    DOI:  https://doi.org/10.1038/s41467-025-66474-5
  9. Cell Death Discov. 2025 Dec 08.
    The glycolytic enzyme PFKFB3 alleviates DNA damage and chondrocyte senescence in osteoarthritis.
    Bo Liu, Chenzhong Wang, Ziyu Weng, Yi Yang, Yi Shi, Chi Zhang.
      Chondrocyte senescence is a key driver of osteoarthritis (OA) progression. This study examined the role of the glycolytic enzyme PFKFB3 in regulating chondrocyte senescence during OA. Using a destabilization of the medial meniscus (DMM) mouse model, we found that PFKFB3 expression was reduced in human and mouse OA cartilage and in hydrogen peroxide-treated chondrocytes. PFKFB3 knockdown or overexpression in primary chondrocytes was achieved through RNA interference or lentiviral delivery, followed by RNA sequencing and molecular analyses. PFKFB3 loss impaired DNA damage repair, activated NF-κB signaling, elevated pro-inflammatory cytokines, and promoted chondrocyte senescence, whereas PFKFB3 overexpression enhanced DNA repair and alleviated OA severity. Pharmacologic inhibition of NF-κB reduced inflammatory and senescent phenotypes in PFKFB3-deficient chondrocytes. These findings indicate that PFKFB3 regulates chondrocyte senescence via NF-κB signaling and DNA damage responses, suggesting PFKFB3 as a potential therapeutic target for OA.
    DOI:  https://doi.org/10.1038/s41420-025-02903-0
  10. Nat Commun. 2025 Dec 10.
    Pla2g7 regulates bone homeostasis via Alox12/12-HETE/Gpr31 signaling axis.
    Jiayan Jin, Zeyu Zheng, Jiaxuan Gu, Qibin Zhang, Zhikun Xu, Zhenhua Feng, Siyue Tao, Shumin He, Jiao Cheng, Jian Wang, Hou-Feng Zheng, Shishi Li, Fengdong Zhao, Jian Chen.
      Bone homeostasis mainly depends on the equilibrium of osteoclasts and osteoblasts, overactivated osteoclasts play a pivotal role in the progression of osteoporosis. Here, we revealed that Pla2g7 (phospholipase A2 group VII) was positively correlated with bone resorption in clinic. By single-cell RNA-seq data analysis, Pla2g7 was found highly enriched in osteoclasts along the developmental trajectory, which promoted osteoclast differentiation. Inhibition of Pla2g7 by Darapladib impaired both human and mice osteoclast differentiation, meanwhile, Pla2g7-deficient mice showed higher bone mass and restored the ovariectomy-induced bone loss. Mechanistically, we identified that Alox12 (arachidonate 12-lipoxygenase) mediated-arachidonic acid metabolism is a key determinant in Pla2g7 enhanced osteoclast differentiation. Its metabolite 12-HETE (12-hydroxyeicosatetraenoic acid) activated Gpr31 to regulate osteoclast formation via p38 MAPK pathway and mitochondrial energy metabolism. Collectively, our study uncovers an Alox12/12-HETE/Gpr31 axis that regulates Pla2g7-induced osteoclast differentiation, and provides a new insight for osteoporosis treatment.
    DOI:  https://doi.org/10.1038/s41467-025-66285-8
  11. Nat Commun. 2025 Dec 10.
    Editing DNA methylation in vivo.
    Richard Pan, Jingwei Ren, Xinyue Chen, Luis F Flores, Rachel V L Gonzalez, Andre Antonio Adonnino, Brandon Lofts, Jennifer Waldo, Julian Halmai, Orrin Devinsky, Kyle Fink, X Shawn Liu.
      DNA methylation is a crucial epigenetic mechanism that regulates gene expression. Precise editing of DNA methylation has emerged as a promising tool for dissecting its biological function. However, challenges in delivery have limited most applications of DNA methylation editing to in vitro systems. Here, we develop two transgenic mouse lines harboring an inducible dCas9-DNMT3A or dCas9-TET1 editor to enable tissue-specific DNA methylation editing in vivo. We demonstrate that targeted methylation of the Psck9 promoter in the liver of dCas9-DNMT3A mice results in decreased Pcsk9 expression and a subsequent reduction in serum low-density lipoprotein cholesterol level. Targeted demethylation of the Mecp2 promoter in dCas9-TET1 mice reactivates Mecp2 expression from the inactive X chromosome and rescues neuronal nuclear size in Mecp2+/- mice. Genome-wide sequencing analyses reveal minimal transcriptional off-targets, demonstrating the specificity of the system. These results demonstrate the feasibility and versatility of methylation editing, to functionally interrogate DNA methylation in vivo.
    DOI:  https://doi.org/10.1038/s41467-025-67222-5
  12. Nat Methods. 2025 Dec 08.
    Inferring cell differentiation maps from lineage tracing data.
    Palash Sashittal, Richard Y Zhang, Benjamin K Law, Henri Schmidt, Alexander Strzalkowski, Adriano Bolondi, Michelle M Chan, Benjamin J Raphael.
      During development, cells differentiate through a hierarchy of increasingly restricted cell types, a process that is summarized by a cell differentiation map. Recent technologies profile lineages and cell types at scale, but existing methods to infer cell differentiation maps from these data rely on heuristic models with restrictive assumptions about the developmental process. Here we introduce a quantitative framework to evaluate cell differentiation maps and develop an algorithm, called Carta, that infers an optimal differentiation map from single-cell lineage tracing data. The key insight in Carta is to balance the tradeoff between the complexity of the map and the number of unobserved cell type transitions on the lineage tree. We show that, in models of mammalian trunk development and mouse hematopoiesis, Carta identifies important features of development that are not revealed by other methods, including convergent differentiation of cell types, progenitor differentiation dynamics and new intermediate progenitors.
    DOI:  https://doi.org/10.1038/s41592-025-02903-z
  13. Commun Biol. 2025 Dec 08.
    Dnmt3a2 expression during embryonic development is required for phenotypic stability.
    Minmin Liu, Guillermo Urrutia, Rachel Shereda, Galen Hostetter, Stacey L Thomas, Gangning Liang, Peter A Jones.
      Proper function and switching of regulatory elements are essential for vertebrate development and are regulated by DNA methylation. We use isoform-specific knockouts of the de novo methyltransferase Dnmt3a1 and Dnmt3a2 to probe their roles during embryogenesis and postnatal development. Mice lacking Dnmt3a1 show minimal embryonic methylation loss but are smaller and die postnatally. In contrast, Dnmt3a2-/- mice exhibit widespread hypomethylation at enhancers, CTCF sites and imprinted genes, which are largely repaired postnatally. These mice are viable but display sporadic abnormalities including anophthalmia, hydrocephalus, hydronephrosis and male infertility due to absence of sperm. Interestingly, the fertile Dnmt3a2-/- mice produce sperm with sporadic imprinting defects. These findings suggest that the two isoform have distinct, developmentally regulated roles, with Dnmt3a2 being crucial for maintaining proper methylation of regulatory elements, especially for enhancers, CTCF sites and imprinted genes, and preventing stochastic phenotypic outcomes after birth.
    DOI:  https://doi.org/10.1038/s42003-025-09311-1
  14. Nature. 2025 Dec 10.
    Neutrophils preserve energy storage in sympathetically activated adipocytes.
    Seunghwan Son, Cindy Xu, Haipeng Fu, Churaibhon Wisessaowapak, Joseph M Valentine, Garam An, Janice Jang, Maddox Dinh, Yang Dai, Weiwei Fan, Ruth T Yu, Michael Downes, Wei Ying, Yuliya Skorobogatko, Ronald M Evans, Alan R Saltiel.
      Adipose tissue maintains energy homeostasis by storing lipids during nutrient surplus and releasing them through lipolysis in times of energy demand1,2. While lipolysis is essential for short-term metabolic adaptation, prolonged metabolic stress requires adaptive changes that preserve energy reserves2,3. Here we report that β3-adrenergic activation of adipocytes induces a transient and depot-specific infiltration of neutrophils into white adipose tissue (WAT), particularly in lipid-rich visceral WAT. Neutrophil recruitment requires the stimulation of both lipolysis and p38 MAPK in adipocytes, and is mediated by the secretion of leukotriene B4. Recruited neutrophils undergo activation in situ, and locally secrete IL-1β, which suppresses lipolysis and limits excessive energy loss. Neutrophil depletion or blockade of IL-1β production increases lipolysis, leading to reduced WAT mass after repeated β3-adrenergic stimulation. Together, these findings reveal a role of neutrophil-derived IL-1β in preserving lipid stores during metabolic stress, highlighting a physiological function of innate immune cells in limiting lipid loss and maintaining energy homeostasis.
    DOI:  https://doi.org/10.1038/s41586-025-09839-6
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