bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–03–30
nineteen papers selected by
Xiong Weng, University of Edinburgh
  1. Discovery of a potent allosteric activator of DGKQ that ameliorates obesity-induced insulin resistance via the sn-1,2-DAG-PKCε signaling axis.
  2. Epigenetic editing at individual age-associated CpGs affects the genome-wide epigenetic aging landscape.
  3. Semaglutide and bariatric surgery induce distinct changes in the composition of mouse white adipose tissue.
  4. Identification of PTGR2 inhibitors as a new therapeutic strategy for diabetes and obesity.
  5. Dnmt3a overexpression disrupts skeletal muscle homeostasis, promotes an aging-like phenotype, and reduces metabolic elasticity.
  6. Haem biosynthesis regulates BCAA catabolism and thermogenesis in brown adipose tissue.
  7. The Balance of MFN2 and OPA1 in Mitochondrial Dynamics, Cellular Homeostasis, and Disease.
  8. A cellular assay to determine the fusion capacity of MFN2 variants linked to Charcot-Marie-Tooth disease of type 2 A.
  9. Changes in neurotensin signalling drive hedonic devaluation in obesity.
  10. The metabolic sensor LKB1 regulates ILC3 homeostasis and mitochondrial function.
  11. FOXM1 expression reverts aging chromatin profiles through repression of the senescence-associated pioneer factor AP-1.
  12. RIG-I-driven CDKN1A stabilization reinforces cellular senescence.
  13. TRIM15 drives chondrocyte senescence and osteoarthritis progression.
  14. Metabolic and transcriptional regulation of reproductive diapause in Arma chinensis.
  15. A novel anti-obesity peptide that targets the hypothalamus.
  16. Inhibition of basal IL-6 activity promotes subcutaneous fat retention in humans during fasting and postprandial states.
  17. A map of mitochondrial biology reveals the energy landscape of the human brain.
  18. Mechanism of non-coding RNA regulation of DNMT3A.
  19. NAT10-mediated N4-acetylcytidine modification in KLF9 mRNA promotes adipogenesis.
  1. Cell Metab. 2025 Mar 26. pii: S1550-4131(25)00113-5. [Epub ahead of print]
    Discovery of a potent allosteric activator of DGKQ that ameliorates obesity-induced insulin resistance via the sn-1,2-DAG-PKCε signaling axis.
    Zu-Guo Zheng, Yin-Yue Xu, Wen-Ping Liu, Yang Zhang, Chong Zhang, Han-Ling Liu, Xiao-Yu Zhang, Run-Zhou Liu, Yi-Ping Zhang, Meng-Ying Shi, Hua Yang, Ping Li.
      
    DOI:  https://doi.org/10.1016/j.cmet.2025.03.010
  2. Nat Aging. 2025 Mar 24.
    Epigenetic editing at individual age-associated CpGs affects the genome-wide epigenetic aging landscape.
    Sven Liesenfelder, Mohamed H Elsafi Mabrouk, Jessica Iliescu, Monica Varona Baranda, Athanasia Mizi, Juan-Felipe Perez-Correa, Martina Wessiepe, Argyris Papantonis, Wolfgang Wagner.
      Aging is reflected by genome-wide DNA methylation changes, which form the basis of epigenetic clocks, but it is largely unclear how these epigenetic modifications are regulated and whether they directly affect the aging process. In this study, we performed epigenetic editing at age-associated CpG sites to explore the consequences of interfering with epigenetic clocks. CRISPR-guided editing targeted at individual age-related CpGs evoked genome-wide bystander effects, which were highly reproducible and enriched at other age-associated regions. 4C-sequencing at age-associated sites revealed increased interactions with bystander modifications and other age-related CpGs. Subsequently, we multiplexed epigenetic editing in human T cells and mesenchymal stromal cells at five genomic regions that become either hypermethylated or hypomethylated upon aging. While targeted methylation seemed more stable at age-hypermethylated sites, both approaches induced bystander modifications at CpGs with the highest correlations with chronological age. Notably, these effects were simultaneously observed at CpGs that gain and lose methylation with age. Our results demonstrate that epigenetic editing can extensively modulate the epigenetic aging network and interfere with epigenetic clocks.
    DOI:  https://doi.org/10.1038/s43587-025-00841-1
  3. Mol Metab. 2025 Mar 24. pii: S2212-8778(25)00033-X. [Epub ahead of print] 102126
    Semaglutide and bariatric surgery induce distinct changes in the composition of mouse white adipose tissue.
    Margo P Emont, Adam L Essene, Anton Gulko, Nadejda Bozadjieva-Kramer, Christopher Jacobs, Soumya Nagesh, Randy J Seeley, Linus T Tsai, Evan D Rosen.
      Adipose tissue is a central player in energy balance and glucose homeostasis, expanding in the face of caloric overload in order to store energy safely. If caloric overload continues unabated, however, adipose tissue becomes dysfunctional, leading to systemic metabolic compromise in the form of insulin resistance and type 2 diabetes. Changes in adipose tissue during the development of metabolic disease are varied and complex, made all the more so by the heterogeneity of cell types within the tissue. Here we present detailed comparisons of atlases of murine WAT in the setting of diet-induced obesity, as well as after weight loss induced by either vertical sleeve gastrectomy (VSG) or treatment with the GLP-1 receptor agonist semaglutide. We focus on identifying populations of cells that return to a lean-like phenotype versus those that persist from the obese state, and examine pathways regulated in these cell types across conditions. These data provide a resource for the study of the cell type changes in WAT during weight loss, and paint a clearer picture of the differences between adipose tissue from lean animals that have never been obese, versus those that have.
    DOI:  https://doi.org/10.1016/j.molmet.2025.102126
  4. EMBO Mol Med. 2025 Mar 21.
    Identification of PTGR2 inhibitors as a new therapeutic strategy for diabetes and obesity.
    Yi-Cheng Chang, Meng-Lun Hsieh, Hsiao-Lin Lee, Siow-Wey Hee, Chi-Fon Chang, Hsin-Yung Yen, Yi-An Chen, Yet-Ran Chen, Ya-Wen Chou, Fu-An Li, Yi-Yu Ke, Shih-Yi Chen, Ming-Shiu Hung, Alfur Fu-Hsin Hung, Jing-Yong Huang, Chu-Hsuan Chiu, Shih-Yao Lin, Sheue-Fang Shih, Chih-Neng Hsu, Juey-Jen Hwang, Teng-Kuang Yeh, Ting-Jen Rachel Cheng, Karen Chia-Wen Liao, Daniel Laio, Shu-Wha Lin, Tzu-Yu Chen, Chun-Mei Hu, Ulla Vogel, Daniel Saar, Birthe B Kragelund, Lun Kelvin Tsou, Yu-Hua Tseng, Lee-Ming Chuang.
      Peroxisome proliferator-activated receptor γ (PPARγ) is a master transcriptional regulator of systemic insulin sensitivity and energy balance. The anti-diabetic drug thiazolidinediones (TZDs) are potent synthetic PPARγ ligands with undesirable side effects, including obesity, fluid retention, and osteoporosis. 15-keto prostaglandin E2 (15-keto-PGE2) is an endogenous PPARγ ligand metabolized by prostaglandin reductase 2 (PTGR2). Here, we confirmed that 15-keto-PGE2 binds to and activates PPARγ via covalent binding. In patients with type 2 diabetes and obese mice, serum 15-keto-PGE2 levels were decreased. Administration of 15-keto-PGE2 improves glucose homeostasis and prevented diet-induced obesity in mice. Either genetic inhibition of PTGR2 or PTGR2 inhibitor BPRPT0245 protected mice from diet-induced obesity, insulin resistance, and hepatic steatosis without causing fluid retention and osteoporosis. In conclusion, inhibition of PTGR2 is a new therapeutic approach to treat diabetes and obesity through increasing endogenous PPARγ ligands while avoiding side effects including increased adiposity, fluid retention, and osteoporosis.
    Keywords:  15-keto-PGE2; Diabetes; Obesity; PPARγ; PTGR2
    DOI:  https://doi.org/10.1038/s44321-025-00216-4
  5. iScience. 2025 Apr 18. 28(4): 112144
    Dnmt3a overexpression disrupts skeletal muscle homeostasis, promotes an aging-like phenotype, and reduces metabolic elasticity.
    Mamoru Oyabu, Yuto Ohira, Mariko Fujita, Kiyoshi Yoshioka, Runa Kawaguchi, Atsushi Kubo, Yukino Hatazawa, Hinako Yukitoshi, Huascar Pedro Ortuste Quiroga, Naoki Horii, Fumihito Miura, Hiromitsu Araki, Masaki Okano, Izuho Hatada, Hitoshi Gotoh, Tatsuya Yoshizawa, So-Ichiro Fukada, Yoshihiro Ogawa, Takashi Ito, Kengo Ishihara, Yusuke Ono, Yasutomi Kamei.
      Mammalian aging is reportedly driven by the loss of epigenetic information; however, its impact on skeletal muscle aging remains unclear. This study shows that aging mouse skeletal muscle exhibits increased DNA methylation, and overexpression of DNA methyltransferase 3a (Dnmt3a) induces an aging-like phenotype. Muscle-specific Dnmt3a overexpression leads to an increase in central nucleus-positive myofibers, predominantly in fast-twitch fibers, a shift toward slow-twitch fibers, elevated inflammatory and senescence markers, mitochondrial OXPHOS complex I reduction, and decreased basal autophagy. Dnmt3a overexpression resulted in reduced muscle mass and strength and impaired endurance exercise capacity with age, accompanied by an enhanced inflammatory signature. In addition, Dnmt3a overexpression reduced not only sensitivity to starvation-induced muscle atrophy but also the restorability from muscle atrophy. These findings suggest that increased DNA methylation disrupts skeletal muscle homeostasis, promotes an aging-like phenotype, and reduces muscle metabolic elasticity.
    Keywords:  Age; Epigenetics; Integrative aspects of cell biology; Model organism; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2025.112144
  6. Nat Metab. 2025 Mar 25.
    Haem biosynthesis regulates BCAA catabolism and thermogenesis in brown adipose tissue.
    Dylan J Duerre, Julia K Hansen, Steven V John, Annie Jen, Noah D Carrillo, Hoang Bui, Yutong Bao, Matias Fabregat, J Leon Catrow, Li-Yu Chen, Katherine A Overmyer, Evgenia Shishkova, Quentinn Pearce, Mark P Keller, Richard A Anderson, Vincent L Cryns, Alan D Attie, James E Cox, Joshua J Coon, Jing Fan, Andrea Galmozzi.
      The distinctive colour of brown adipose tissue (BAT) is attributed to its high content of haem-rich mitochondria. However, the mechanisms by which BAT regulates intracellular haem levels remain largely unexplored. Here we demonstrate that haem biosynthesis is the primary source of haem in brown adipocytes. Inhibiting haem biosynthesis results in an accumulation of the branched-chain amino acids (BCAAs) valine and isoleucine, owing to a haem-associated metabolon that channels BCAA-derived carbons into haem biosynthesis. Haem synthesis-deficient brown adipocytes display reduced mitochondrial respiration and lower UCP1 levels than wild-type cells. Although exogenous haem supplementation can restore intracellular haem levels and mitochondrial function, UCP1 downregulation persists. This sustained UCP1 suppression is linked to epigenetic regulation induced by the accumulation of propionyl-CoA, a byproduct of disrupted haem synthesis. Finally, disruption of haem biosynthesis in BAT impairs thermogenic response and, in female but not male mice, hinders the cold-induced clearance of circulating BCAAs in a sex-hormone-dependent manner. These findings establish adipose haem biosynthesis as a key regulator of thermogenesis and sex-dependent BCAA homeostasis.
    DOI:  https://doi.org/10.1038/s42255-025-01253-6
  7. Biomolecules. 2025 Mar 18. pii: 433. [Epub ahead of print]15(3):
    The Balance of MFN2 and OPA1 in Mitochondrial Dynamics, Cellular Homeostasis, and Disease.
    Paola Zanfardino, Alessandro Amati, Mirko Perrone, Vittoria Petruzzella.
      Mitochondrial dynamics, governed by fusion and fission, are crucial for maintaining cellular homeostasis, energy production, and stress adaptation. MFN2 and OPA1, key regulators of mitochondrial fusion, play essential roles beyond their structural functions, influencing bioenergetics, intracellular signaling, and quality control mechanisms such as mitophagy. Disruptions in these processes, often caused by MFN2 or OPA1 mutations, are linked to neurodegenerative diseases like Charcot-Marie-Tooth disease type 2A (CMT2A) and autosomal dominant optic atrophy (ADOA). This review explores the molecular mechanisms underlying mitochondrial fusion, the impact of MFN2 and OPA1 dysfunction on oxidative phosphorylation and autophagy, and their role in disease progression. Additionally, we discuss the divergent cellular responses to MFN2 and OPA1 mutations, particularly in terms of proliferation, senescence, and metabolic signaling. Finally, we highlight emerging therapeutic strategies to restore mitochondrial integrity, including mTOR modulation and autophagy-targeted approaches, with potential implications for neurodegenerative disorders.
    Keywords:  autophagy; mTOR signaling; mitochondria; mitochondrial dynamics; mitophagy; neurodegenerative diseases; oxidative phosphorylation; proliferation; senescence
    DOI:  https://doi.org/10.3390/biom15030433
  8. Sci Rep. 2025 Mar 22. 15(1): 9971
    A cellular assay to determine the fusion capacity of MFN2 variants linked to Charcot-Marie-Tooth disease of type 2 A.
    Chloe Barsa, Julian Perrin, Claudine David, Arnaud Mourier, Manuel Rojo.
      Charcot-Marie-Tooth Disease (CMT) is an inherited peripheral neuropathy with two main forms: demyelinating CMT1 and axonal CMT2. The most frequent subtype of CMT2 (CMT2A) is linked to mutations of MFN2, encoding a ubiquitously expressed GTP-binding protein anchored to the mitochondrial outer membrane and essential for mitochondrial fusion. The use of Next-Generation Sequencing has led to the identification of increasing numbers of MFN2 variants, yet many of them remain of unknown significance, depriving patients of a clear diagnosis. In this work, we establish a cellular assay allowing to assess the impact of 12 known MFN2 variants linked to CMT2A on mitochondrial fusion. The functional analysis revealed that out of the 12 selected MFN2 mutations, only six exhibited reduced fusion activity. The classification of MFN2 variants according to the results of the functional assay revealed a correlation between the fusion capacity, the age at onset of CMT2A and computational variant effect predictions relying on the analysis of the protein sequence. The functional assay and the results obtained will assist and improve the classification of novel MFN2 variants identified in patients.
    Keywords:  CMT2A; Charcot–Marie-Tooth disease; MFN2; Mitochondrial dynamics; Mitochondrial fusion; Single nucleotide variants; Variant effect predictor; Variants of unknown significance
    DOI:  https://doi.org/10.1038/s41598-025-93702-1
  9. Nature. 2025 Mar 26.
    Changes in neurotensin signalling drive hedonic devaluation in obesity.
    Neta Gazit Shimoni, Amanda J Tose, Charlotte Seng, Yihan Jin, Tamás Lukacsovich, Hongbin Yang, Jeroen P H Verharen, Christine Liu, Michael Tanios, Eric Hu, Jonathan Read, Lilly W Tang, Byung Kook Lim, Lin Tian, Csaba Földy, Stephan Lammel.
      Calorie-rich foods, particularly those that are high in fat and sugar, evoke pleasure in both humans and animals1. However, prolonged consumption of such foods may reduce their hedonic value, potentially contributing to obesity2-4. Here we investigated this phenomenon in mice on a chronic high-fat diet (HFD). Although these mice preferred high-fat food over regular chow in their home cages, they showed reduced interest in calorie-rich foods in a no-effort setting. This paradoxical decrease in hedonic feeding has been reported previously3-7, but its neurobiological basis remains unclear. We found that in mice on regular diet, neurons in the lateral nucleus accumbens (NAcLat) projecting to the ventral tegmental area (VTA) encoded hedonic feeding behaviours. In HFD mice, this behaviour was reduced and uncoupled from neural activity. Optogenetic stimulation of the NAcLat→VTA pathway increased hedonic feeding in mice on regular diet but not in HFD mice, though this behaviour was restored when HFD mice returned to a regular diet. HFD mice exhibited reduced neurotensin expression and release in the NAcLat→VTA pathway. Furthermore, neurotensin knockout in the NAcLat and neurotensin receptor blockade in the VTA each abolished optogenetically induced hedonic feeding behaviour. Enhancing neurotensin signalling via overexpression normalized aspects of diet-induced obesity, including weight gain and hedonic feeding. Together, our findings identify a neural circuit mechanism that links the devaluation of hedonic foods with obesity.
    DOI:  https://doi.org/10.1038/s41586-025-08748-y
  10. Cell Rep. 2025 Mar 21. pii: S2211-1247(25)00227-X. [Epub ahead of print]44(4): 115456
    The metabolic sensor LKB1 regulates ILC3 homeostasis and mitochondrial function.
    Diogo Fonseca-Pereira, Sena Bae, Slater L Clay, Monia Michaud, Meghan H MacDonald, Jonathan N Glickman, Wendy S Garrett.
      Group 3 innate lymphoid cells (ILC3s) are tissue-resident cells that sense environmental cues, control infections, and promote tissue homeostasis at mucosal surfaces. The metabolic sensor liver kinase B1 (LKB1) integrates intracellular stress, metabolism, and mitochondrial function to promote the development and effector functions of a variety of immune cells; however, the role of LKB1 in ILC3 function was unknown. Here, we show that LKB1 is crucial for adult ILC3 homeostasis, cytokine production, and mitochondrial function. ILC3-specific LKB1 deletion resulted in a reduced number of ILC3s and interleukin-22 (IL-22) production. LKB1-deficient ILC3s had decreased survival, mitochondrial dysfunction, cytoplasmic lipid accumulation, and altered bioenergetics. Using LKB1 downstream kinase modulators, we found that LKB1 regulation of ILC3 survival and IL-22 production requires signaling through microtubule affinity-regulating kinases (MARKs). Mechanistically, LKB1 deficiency resulted in increased reactive oxygen species (ROS) production and NFAT2 and PD-1 expression. Our work reveals that metabolic regulation of enteric ILC3 function by an LKB1-dependent signaling network is crucial for intestinal immunity and tissue homeostasis.
    Keywords:  CP: Immunology; CP: Metabolism; ILC3; LKB1; group 3 innate lymphoid cells; liver kinase B1; mitochondrial function
    DOI:  https://doi.org/10.1016/j.celrep.2025.115456
  11. Nat Commun. 2025 Mar 25. 16(1): 2931
    FOXM1 expression reverts aging chromatin profiles through repression of the senescence-associated pioneer factor AP-1.
    Fábio J Ferreira, Mafalda Galhardo, João M Nogueira, Joana Teixeira, Elsa Logarinho, José Bessa.
      Aging is characterized by changes in gene expression, some of which can drive deleterious cellular phenotypes and senescence. The transcriptional activation of senescence genes has been mainly attributed to epigenetic shifts, but the changes in chromatin accessibility and its underlying mechanisms remain largely elusive in natural aging. Here, we profiled chromatin accessibility in human dermal fibroblasts (HDFs) from individuals with ages ranging from neonatal to octogenarian. We found that AP-1 binding motifs are prevalent in elderly-specific accessible chromatin regions while neonatal-specific regions are highly enriched for TEAD binding motifs. We further show that TEAD4 and FOXM1 share a conserved transcriptional regulatory landscape controlled by a not previously described and age-dependent enhancer that loses accessibility with aging and whose deletion drives senescence. Finally, we demonstrate that FOXM1 ectopic expression in elderly cells partially resets chromatin accessibility to a youthful state due to FOXM1's repressive function on several members of the AP-1 complex, which is known to trigger the senescence transcriptional program. These results place FOXM1 at a top hierarchical level in chromatin remodeling required to prevent senescence.
    DOI:  https://doi.org/10.1038/s41467-025-57503-4
  12. Sci China Life Sci. 2025 Mar 24.
    RIG-I-driven CDKN1A stabilization reinforces cellular senescence.
    Cui Wang, Xiaoyu Jiang, Hong-Yu Li, Jianli Hu, Qianzhao Ji, Qiaoran Wang, Xiaoqian Liu, Daoyuan Huang, Kaowen Yan, Liyun Zhao, Yanling Fan, Si Wang, Shuai Ma, Juan Carlos Izpisua Belmonte, Jing Qu, Guang-Hui Liu, Weiqi Zhang.
      The innate immune signaling network follows a canonical format for signal transmission. The innate immune pathway is crucial for defense against pathogens, yet its mechanistic crosstalk with aging processes remains largely unexplored. Retinoic acid-inducible gene-I (RIG-I), a key mediator of antiviral immunity within this pathway, has an enigmatic role in stem cell senescence. Our study reveals that RIG-I levels increase in human genetic and physiological cellular aging models, and its accumulation drives cellular senescence. Conversely, CRISPR/Cas9-mediated RIG-I deletion or pharmacological inhibition in human mesenchymal stem cells (hMSCs) confers resistance to senescence. Mechanistically, RIG-I binds to endogenous mRNAs, with CDKN1A mRNA being a prominent target. Specifically, RIG-I stabilizes CDKN1A mRNA, resulting in elevated CDKN1A transcript levels and increased p21Cip1 protein expression, which precipitates senescence. Collectively, our findings establish RIG-I as a post-transcriptional regulator of senescence and suggest potential targets for the mitigation of aging-related diseases.
    Keywords:  RIG-I; aging; human stem cell; innate immune pathway; senescence
    DOI:  https://doi.org/10.1007/s11427-024-2844-8
  13. Sci Transl Med. 2025 Mar 26. 17(791): eadq1735
    TRIM15 drives chondrocyte senescence and osteoarthritis progression.
    Zhuang Li, Weituo Zhang, Xiao Ying Wei, Jun Zheng Hu, Xinyue Hu, Haoyang Liu, Jun Lu, Shuying Shen, Ming-Liang Ji.
      Osteoarthritis (OA) is a prevalent joint disease characterized by pain, disability, and loss of physical function, posing a challenge to public health. However, molecular mechanisms of OA pathogenesis have not been fully described. We report that tripartite motif containing 15 (TRIM15) is a regulator in chondrocyte senescence and OA. Our study revealed heightened expression of TRIM15 in chondrocytes of senescent cartilage from patients with OA and in aged wild-type mice. Using gain- and loss-of-function studies, we found that TRIM15 facilitated human chondrocyte senescence. Conditional deletion of Trim15 in mouse chondrocytes severely impaired skeletal growth, partially because of impaired embryonic chondrocyte senescence. Compared with conditionally knocked out Col2a1-CreERT2/Trim15flox/flox mice, Trim15flox/flox control mice exhibited accelerated OA phenotypes, increased senescence markers, and senescence-associated secretory phenotype during aging. Mechanistically, TRIM15 bound with yes-associated protein (YAP) and mediated K48-linked YAP ubiquitination at K254, which interrupted the interaction between YAP and angiomotin, leading to enhanced YAP nuclear translocation. Dysregulation of TRIM15-YAP and transcriptional coactivator with PDZ-binding motif (TAZ) signaling promoted OA progression in both the surgery-induced and natural aging-induced mouse OA model. Intra-articular injection of adeno-associated virus 5 (AAV5)-Trim15 shRNA decelerated OA progression in mice. In particular, YAP and TAZ protein amounts were increased in chondrocytes of patients with OA. Our preclinical results demonstrated that the AAV5-TRIM15 shRNA treatment protected human OA explants against degeneration through inhibiting chondrocyte senescence. Together, our findings underscore the potential of targeting TRIM15 in reshaping the aging cartilage microenvironment and suggest a promising therapeutic avenue for OA.
    DOI:  https://doi.org/10.1126/scitranslmed.adq1735
  14. iScience. 2025 Mar 21. 28(3): 111761
    Metabolic and transcriptional regulation of reproductive diapause in Arma chinensis.
    Maosen Zhang, Weiwei He, Yuyan Li, Junjie Chen, Nicholas M Teets, Lisheng Zhang.
      Diapause enables insects to survive unfavorable conditions through metabolic and developmental adjustments. We investigated metabolic regulation during reproductive diapause in the predatory stinkbug Arma chinensis using transcriptomic and metabolomic analyses. Our study revealed 9,254 differentially expressed genes and 493 significantly changed metabolites across diapause stages. Key metabolic pathways including glutathione metabolism, TCA cycle, glycolysis, and lipid metabolism underwent substantial reorganization. The pre-diapause phase showed increased energy consumption and lipid accumulation, while the maintenance phase exhibited restructuring of amino acid and glucose metabolism. We identified stage-specific metabolic signatures and potential regulatory mechanisms, including the roles of glutathione metabolism in redox regulation and insulin signaling in diapause control. This comprehensive characterization of metabolic reprogramming during A. chinensis diapause provides insights for improving biocontrol agent production and storage strategies.
    Keywords:  Entomology; Genetics; Omics
    DOI:  https://doi.org/10.1016/j.isci.2025.111761
  15. Nat Rev Endocrinol. 2025 Mar 24.
    A novel anti-obesity peptide that targets the hypothalamus.
    Senegal Carty.
      
    DOI:  https://doi.org/10.1038/s41574-025-01104-0
  16. Cell Rep Med. 2025 Mar 22. pii: S2666-3791(25)00115-6. [Epub ahead of print] 102042
    Inhibition of basal IL-6 activity promotes subcutaneous fat retention in humans during fasting and postprandial states.
    Beckey Trinh, Signe Johanne Rasmussen, Mathilde Ehnhuus Brøgger-Jensen, Christoph Andreas Engelhard, Anton Lund, Ana Rita Tavanez, Alexandra Vassilieva, Susanne Janum, Ulrik Winning Iepsen, Bente Kiens, Kirsten Møller, Bente Klarlund Pedersen, Gerrit Van Hall, Helga Ellingsgaard.
      Interleukin-6 (IL-6) knockout mice and humans treated with IL-6 receptor blockade gain adipose tissue mass. This study investigates whether basal IL-6 activity (resting IL-6 levels) influences fat storage during fasting and postprandial states. Using stable-isotope tracer techniques and IL-6 receptor blockade with tocilizumab, we examine fat kinetics in humans. Blocking basal IL-6 activity reduces fasting whole-body lipolysis, decreases hormone-sensitive lipase (HSL) phosphorylation and fatty acid release in adipose tissue, and impairs postprandial fatty acid uptake in the leg. These results suggest diminished fatty acid uptake and oxidation in skeletal muscle, along with enhanced fatty acid entrapment in adipose tissue, which may account for the increased adiposity in the absence of IL-6 activity. Additionally, IL-6 blockade increases the escape of meal-derived fatty acids into the bloodstream. Whether this affects fatty acid storage and lipotoxicity in other tissues warrants further investigation. This study was registered at ClinicalTrials.gov (NCT04687540).
    Keywords:  fasting; fatty acids; homeostasis; humans; interleukin-6; isotopes; lipolysis; nutrients; obesity; tocilizumab
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102042
  17. Nature. 2025 Mar 26.
    A map of mitochondrial biology reveals the energy landscape of the human brain.
      
    Keywords:  Brain; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-00872-z
  18. Epigenetics Chromatin. 2025 Mar 28. 18(1): 15
    Mechanism of non-coding RNA regulation of DNMT3A.
    Jonathan E Sandoval, Nancy V N Carullo, Aaron J Salisbury, Jeremy J Day, Norbert O Reich.
       BACKGROUND: De novo DNA methylation by DNMT3A is a fundamental epigenetic modification for transcriptional regulation. Histone tails and regulatory proteins regulate DNMT3A, and the crosstalk between these epigenetic mechanisms ensures appropriate DNA methylation patterning. Based on findings showing that Fos ecRNA inhibits DNMT3A activity in neurons, we sought to characterize the contribution of this regulatory RNA in the modulation of DNMT3A in the presence of regulatory proteins and histone tails.
    RESULTS: We show that Fos ecRNA and mRNA strongly correlate in primary cortical neurons on a single cell level and provide evidence that Fos ecRNA modulation of DNMT3A at these actively transcribed sites occurs in a sequence-independent manner. Further characterization of the Fos ecRNA-DNMT3A interaction showed that Fos-1 ecRNA binds the DNMT3A tetramer interface and clinically relevant DNMT3A substitutions that disrupt the inhibition of DNMT3A activity by Fos-1 ecRNA are restored by the formation of heterotetramers with DNMT3L. Lastly, using DNMT3L and Fos ecRNA in the presence of synthetic histone H3 tails or reconstituted polynucleosomes, we found that regulatory RNAs play dominant roles in the modulation of DNMT3A activity.
    CONCLUSION: Our results are consistent with a model for RNA regulation of DNMT3A that involves localized production of short RNAs binding to a nonspecific site on the protein, rather than formation of localized RNA/DNA structures. We propose that regulatory RNAs play a dominant role in the regulation of DNMT3A catalytic activity at sites with increased production of regulatory RNAs.
    Keywords:  Allostery; Cancer; DNA methylation; DNA methyltransferase 3A (DNMT3A); DNMT3L; Epigenetics; Gene regulation; Protein-RNA interactions
    DOI:  https://doi.org/10.1186/s13072-025-00574-w
  19. Cell Death Differ. 2025 Mar 23.
    NAT10-mediated N4-acetylcytidine modification in KLF9 mRNA promotes adipogenesis.
    Xinxing Wan, Linghao Wang, Md Asaduzzaman Khan, Lin Peng, Xiaoying Sun, Xuan Yi, Zhouqi Wang, Ke Chen.
      Dysfunctional adipogenesis is a major contributor of obesity. N-acetyltransferase 10 (NAT10) plays a crucial role in regulating N4-acetylcysteine (ac4C) modification in tRNA, 18SrRNA, and mRNA. As the sole "writer" in the ac4C modification process, NAT10 enhances mRNA stability and translation efficiency. There are few reports on the relationship between NAT10 and adipogenesis, as well as obesity. Our study revealed a significant upregulation of NAT10 in adipose tissues of obese individuals and high-fat diet-fed mice. Furthermore, our findings revealed that the overexpression of NAT10 promotes adipogenesis, while its silencing inhibits adipogenesis in both human adipose tissue-derived stem cells (hADSCs) and 3T3-L1 cells. These results indicate the intimate relationship between NAT10 and obesity. After silencing mouse NAT10 (mNAT10), we identified 30 genes that exhibited both hypo-ac4C modification and downregulation in their expression, utilizing a combined approach of acRIP-sequencing (acRIP-seq) and RNA-sequencing (RNA-seq). Among these genes, we validated KLF9 as a target of NAT10 through acRIP-PCR. KLF9, a pivotal transcription factor that positively regulates adipogenesis. Our findings showed that NAT10 enhances the stability of KLF9 mRNA and further activates the CEBPA/B-PPARG pathway. Furthermore, a dual-luciferase reporter assay demonstrated that NAT10 can bind to three motifs of mouse KLF9 and one motif of human KLF9. In vivo studies revealed that adipose tissue-targeted mouse AAV-NAT10 (AAV-shRNA-mNAT10) inhibits adipose tissue expansion in mice. Additionally, Remodelin, a specific NAT10 inhibitor, significantly reduced body weight, adipocyte size, and adipose tissue expansion in high-fat diet-fed mice by inhibiting KLF9 mRNA ac4C modification. These findings provide novel insights and experimental evidence of the prevention and treatment of obesity, highlighting NAT10 and its downstream targets as potential therapeutic targets.
    DOI:  https://doi.org/10.1038/s41418-025-01483-x
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