bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–12–28
seven papers selected by
Xiong Weng, University of Edinburgh
  1. The protein denitrosylase SCoR2 regulates lipogenesis and fat storage.
  2. TMEM120A maintains adipose tissue lipid homeostasis through ER CoA channeling.
  3. SREBP1-mediated lipogenesis promotes dedifferentiation and senescence of vascular smooth muscle cells through epigenetic remodeling.
  4. Graded Calorie Restriction Causes Graded Slowing of Epigenetic Ageing in Mice.
  5. Senescent Mesenchymal Stromal Cells Differentially Alter Adipogenesis in Adipose Tissue, Skeletal Muscle, and Bone Marrow.
  6. Promising Results With NAD Supplementation in Rare Diseases With Premature Aging and DNA Damage.
  7. Germline epigenome editing identifies H3K9me3 as a mediator of intergenerational DNA methylation recovery in mice.
  1. Sci Signal. 2025 Dec 23. 18(918): eadv0660
    The protein denitrosylase SCoR2 regulates lipogenesis and fat storage.
    Nicholas M Venetos, Colin T Stomberski, Hua-Lin Zhou, Zhaoxia Qian, Precious J McLaughlin, Puneet K Bansal, John Feczko, Ilya Bederman, Hoa Nguyen, Alfred Hausladen, Joseph C Schindler, Zachary W Grimmett, Henri Brunengraber, Richard T Premont, Jonathan S Stamler.
      Lipid homeostasis is subject to control by posttranslational modification machinery, such as sirtuin deacetylases that reverse coenzyme A (CoA)-dependent acetylation. Here, we showed that a mammalian denitrosylase (SCoR2), which counteracts CoA-dependent S-nitrosylation, promoted both fat storage and lipogenesis to impair metabolic health. In mice, SCoR2 protein abundance correlated with body mass, and deleting or pharmacologically inhibiting SCoR2 prevented both diet-induced obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Loss of SCoR2 in adipocytes promoted the S-nitrosylation of the actin cytoskeletal regulator myosin 9, which inhibited the activity of the lipogenesis-promoting transcription factors PPARγ, SREBP1, and CEBPα to prevent fat storage. In hepatocytes, inhibition of SCoR2-mediated denitrosylation of lipogenic enzymes reduced fat synthesis and induced fat oxidation. In humans, an obesity-linked polymorphism was associated with increased SCoR2 mRNA expression, and in patient adipose and liver tissues, SCoR2 protein or mRNA abundance directly correlated with adipocyte size or MASLD. These results indicate that SCoR2 regulates nutrient metabolism, similar to sirtuins, and is a potential drug target for obesity and MASLD.
    DOI:  https://doi.org/10.1126/scisignal.adv0660
  2. Nat Commun. 2025 Dec 21.
    TMEM120A maintains adipose tissue lipid homeostasis through ER CoA channeling.
    Yoon Keun Cho, Junhyuck Lee, Yujin L Jeong, Minki Shim, Xuan Linh Mai, Chang Seomoon, Cheol Woon Jung, Yoon Ha Choi, Sik Namgoong, Young-Suk Jung, Sung Won Kwon, Juyong Lee, Je Kyung Seong, Sunghyouk Park, Emilio P Mottillo, James G Granneman, Dong-Kyu Lee, Jong Kyoung Kim, Yun-Hee Lee.
      Efficient fatty acid (FA) re-esterification is essential for lipid homeostasis in adipocytes, yet the mechanisms coordinating Coenzyme A (CoA) availability at the endoplasmic reticulum (ER)-a major site of lipid synthesis-remain unclear. Here, we identify TMEM120A as an ER-resident CoA-binding protein that regulates intracellular FA metabolism. TMEM120A interacts with the ER-localized acyl-CoA synthetase ACSL1 and ACSL3 to promote long-chain acyl-CoA synthesis and channeling into the ER, thereby facilitating FA re-esterification and lipid cycling during lipolysis. By relieving acyl-CoA-mediated feedback inhibition of lipolysis, TMEM120A enhances lipid turnover while protecting against ER stress and lipotoxicity. Adipocyte-specific deletion of Tmem120a in mice impairs lipolysis-induced energy expenditure and exacerbates inflammation and metabolic dysfunction under high-fat diet conditions. These findings establish TMEM120A as a critical regulator of ER CoA handling and lipid flux, revealing a previously unrecognized mechanism that links intracellular CoA dynamics to systemic energy balance and metabolic health.
    DOI:  https://doi.org/10.1038/s41467-025-67870-7
  3. Nat Commun. 2025 Dec 26.
    SREBP1-mediated lipogenesis promotes dedifferentiation and senescence of vascular smooth muscle cells through epigenetic remodeling.
    Bowen Li, Kaixiang Zhou, Anan Yin, Yonghong Liu, Xichen Wang, Yujia Cui, Fangfang Liu, Qiurong Liu, Hongjing Zheng, Zhiqiang Mu, Kun Chen, Yuanming Wu, Yaoming Chang, Junxiang Bao.
      Real or simulated microgravity induces a senescence-like modification of carotid artery in both human and animal observations, with the mechanisms not fully elucidated. Here, we aim to elucidate the role of sterol regulatory element-binding protein 1 (SREBP1, encoded by Srebf1) mediated lipogenesis in the process. Pharmacological activation of SREBP1 directly triggers senescence-like transformation in vascular smooth muscle cells (VSMC), while silencing Srebf1 exerts an opposite effect. Mechanistically, SREBP1-mediated lipogenesis upregulates acetyl-CoA pool to increase histone acetylation, modifying the chromatin accessibility which limiting recruitment of SRF/myocardin complexes to CArG boxes of contractile genes and opening the chromatin accessibility of aging genes. Srebf1 knockdown and local delivery of lentivirus or AAV-mediated VSMC specific expressing sh-Srebf1 significantly attenuates the senescence-like transformation of VSMC both in vitro and in vivo. Our findings reveal a previously unrecognized feature of SREBP1-mediated lipogenesis in vascular biology and SM-induced carotid artery remodeling.
    DOI:  https://doi.org/10.1038/s41467-025-67534-6
  4. Aging Cell. 2026 Jan;25(1): e70342
    Graded Calorie Restriction Causes Graded Slowing of Epigenetic Ageing in Mice.
    Timothy P Moulds, Sharon E Mitchell, Xiaojing Yang, Wei Guo, Emily Chen, Peter D Adams, John R Speakman.
      DNA methylation variation is associated with chronological ageing. Calorie restriction (CR) prolongs lifespan and healthspan in many species. Our hypothesis is that CR has an impact on DNA methylation patterns with increased CR leading to slower epigenetic ageing. We studied the effects of graded CR in male C57BL/6J mice on liver DNA methylation. Mice were fed ad libitum (AL) in the dark-phase or restricted by 10%, 20%, 30% or 40% from 5-months old for 19-months. Livers were collected in surviving mice at 24-months old and DNA methylation measured. Comparisons were made to 8-month-old AL fed mice. DNA methylation was significantly related to graded CR in a subset of cytosine-guanine dinucleotide (CpG) sites. In a substantially similar subset of CpG sites, DNA methylation in 24-month-old mice fed 40CR moved towards the values in 8-month-old AL fed mice, resulting in an average effective epigenetic age of about 12-months, indicative of slower epigenetic ageing. DNA methylation at several CpG sites was sensitive to glucose intolerance and circulating insulin levels, consistent with the impact of this nutrient sensing pathway on ageing. We focussed on genes where multiple CpG sites were significant for DNA methylation change with CR and found many have been implicated in age-associated liver diseases. In summary, the benefits of CR include modification of epigenetic signatures in the direction of slower ageing, consistent with the life extending effects of CR. Whether this effect is causal for the life extension under CR, and the mechanism by which it occurs remain unanswered questions.
    Keywords:  DNA methylation; ageing; calorie restriction
    DOI:  https://doi.org/10.1111/acel.70342
  5. Obesity (Silver Spring). 2025 Dec 24.
    Senescent Mesenchymal Stromal Cells Differentially Alter Adipogenesis in Adipose Tissue, Skeletal Muscle, and Bone Marrow.
    Xu Zhang, Madison L Doolittle, Ting Fan, Utkarsh Tripathi, Yan Er Ng, Xinyi Jiang, João F Passos, Diana Jurk, David G Monroe, Tamara Tchkonia, James L Kirkland, Paul D Robbins, Sundeep Khosla, Nathan K LeBrasseur.
       OBJECTIVE: Aging alters mesenchymal stromal cell (MSC) function, leading to dysregulated adipogenesis across tissues through biased lineage commitment. Fat redistribution from adipose depots to skeletal muscle and bone marrow is common in aging, but the underlying mechanisms remain unclear. This study investigates how MSC senescence modulates adipogenesis.
    METHODS: Primary MSCs were isolated from mouse skeletal muscle (FAPs), adipose tissue (APCs), and bone marrow (BMSCs). Single-cell RNA sequencing was performed to compare transcriptional profiles among these populations. In vitro adipogenic differentiation and DNA damage-induced senescence assays were conducted, and the effects of autologous conditioned media from senescent MSCs on adipogenesis were assessed.
    RESULTS: Transcriptional analyses revealed that FAPs and APCs share greater similarity with each other than with BMSCs. All MSC types exhibited adipogenic potential and developed a robust senescence-associated secretory phenotype (SASP) upon senescence induction. Conditioned media from senescent MSCs enhanced adipogenesis in BMSCs but inhibited adipogenesis in FAPs and APCs, revealing tissue-specific paracrine effects.
    CONCLUSIONS: MSC senescence reprograms adipogenic bias in a tissue-dependent, non-cell autonomous manner, contributing to age-related fat redistribution among adipose tissue, skeletal muscle, and bone marrow. Understanding these mechanisms may provide new therapeutic approaches for improving tissue composition and function in the context of aging.
    Keywords:  adipogenesis; mesenchymal stromal cells; senescence; senescence‐associated secretory phenotype
    DOI:  https://doi.org/10.1002/oby.70119
  6. Aging Cell. 2026 Jan;25(1): e70319
    Promising Results With NAD Supplementation in Rare Diseases With Premature Aging and DNA Damage.
    Vilhelm A Bohr.
      Nicotinamide adenine dinucleotide (NAD) has garnered significant attention in recent years due to its central role in cellular metabolism and its potential as a supplement to promote health and longevity. While numerous human studies indicate that NAD supplementation offers benefits with minimal or no side effects, some studies show no observable advantages. This discrepancy highlights the importance of identifying individuals who are most likely to benefit from NAD-based interventions. One critical factor in the efficacy of NAD supplementation relates to its declining levels in certain individuals, driven by various causes of NAD depletion. NAD is a vital substrate for numerous enzymatic processes, notably those involving poly-ADP-ribose polymerase (PARP) enzymes. PARP enzymes, especially PARP1, play a pivotal role in DNA repair by detecting and signaling DNA damage. Excessive activation of PARP, hyperparylation, is frequently observed in DNA repair disorders where DNA damage accumulates due to defective repair mechanisms. This hyperparylation has been implicated in the pathogenesis of several premature aging diseases. Such conditions often involve defective DNA repair pathways, elevated parylation levels, and associated mitochondrial dysfunction, factors that contribute to accelerated cellular aging. In model systems that mimic these disorders, as well as in emerging human studies, NAD supplementation has demonstrated promising benefits, including improved DNA repair capacity and improved mitochondrial function. These findings suggest that NAD supplementation could serve as an effective intervention for rare genetic diseases characterized by premature aging and DNA repair deficiencies. More broadly, these insights open new avenues for general aging research.
    DOI:  https://doi.org/10.1111/acel.70319
  7. Nat Commun. 2025 Dec 25. 16(1): 11200
    Germline epigenome editing identifies H3K9me3 as a mediator of intergenerational DNA methylation recovery in mice.
    Takuro Horii, Sumiyo Morita, Shinjiro Hino, Yuko Hino, Hiroto S Fukushima, Ryosuke Kobayashi, Mika Kimura, Mitsuyoshi Nakao, Yoichi Mizukami, Azusa Inoue, Izuho Hatada.
      Inter/transgenerational epigenetic inheritance is a crucial and controversial theory that could reshape the concept of genetics. To investigate this theory directly, we invent a system for targeted reprogramming of epigenetic memory in mouse sperm. Using this system, we erase DNA methylation at the differentially methylated region of the H19 gene (H19-DMR) in sperm, which causes Silver-Russell syndrome-like phenotypes in F1 offspring. Although DNA methylation is fully lost in the sperm, it is partially restored during pre-implantation development, suggesting the existence of epigenetic memory that instructs de novo DNA methylation. Importantly, targeted removal of histone modifications in zygotes reveals that tri-methylation at lysine 9 of histone H3 (H3K9me3), which is deposited shortly after fertilization, is required for the subsequent de novo DNA methylation at the H19-DMR. Thus, our study provides a robust germline editing tool, which reveals partial intergenerational inheritance and no transgenerational inheritance at the model locus. Furthermore, we identify H3K9me3 as a mediator for DNA methylation recovery also acting at imprinted loci.
    DOI:  https://doi.org/10.1038/s41467-025-67488-9
This page is being maintained by Thomas Krichel. It was last updated on 2025‒12‒28 at 13:33.