bims-mimead Biomed News
on Adipose tissue and metabolic disease
Issue of 2025–08–31
six papers selected by
Rachel M. Handy, University of Guelph
  1. Epigenetic Programming of Estrogen Receptor in Adipocytes by High Fat Diet Regulates Obesity-Induced Inflammation.
  2. CRISPLD2, a novel insulin-sensitizing adipokine that alters adipocyte size.
  3. Single-cell DNA methylome and 3D genome atlas of human subcutaneous adipose tissue.
  4. Exercise-Induced Muscle-Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging.
  5. Inducible skeletal muscle-specific p53 deletion alleviates high-fat diet-induced insulin resistance by modulating mitochondria-associated membrane in obese mice.
  6. Intermittent Cold Exposure Induces Distinct Proteomic Signatures in White Adipose Tissue of Mice.
  1. JCI Insight. 2025 Aug 26. pii: e173423. [Epub ahead of print]
    Epigenetic Programming of Estrogen Receptor in Adipocytes by High Fat Diet Regulates Obesity-Induced Inflammation.
    Rui Wu, Fenfen Li, Shirong Wang, Jia Jing, Xin Cui, Yifei Huang, Xucheng Zhang, Jose A Carrillo, Zufeng Ding, Jiuzhou Song, Liqing Yu, Huidong Shi, Bingzhong Xue, Hang Shi.
      Adipose inflammation plays a key role in obesity-induced metabolic abnormalities. Epigenetic regulation, including DNA methylation, is a molecular link between environmental factors and complex diseases. Here we found that high fat diet (HFD) feeding induced a dynamic change of DNA methylome in mouse white adipose tissue (WAT) analyzed by reduced representative bisulfite sequencing. Interestingly, DNA methylation at the promoter of estrogen receptor α (Esr1) was significantly increased by HFD, concomitant with a down-regulation of Esr1 expression. HFD feeding in mice increased the expression of DNA methyltransferase 1 (Dnmt1) and Dnmt3a, and binding of DNMT1 and DNMT3a to Esr1 promoter in WAT. Mice with adipocyte-specific Dnmt1 deficiency displayed increased Esr1 expression, decreased adipose inflammation and improved insulin sensitivity upon HFD challenge; while mice with adipocyte-specific Dnmt3a deficiency showed a mild metabolic phenotype. Using a modified CRISPR/RNA-guided system to specifically target DNA methylation at the Esr1 promoter in WAT, we found that reducing DNA methylation at Esr1 promoter increased Esr1 expression, decreased adipose inflammation and improved insulin sensitivity in HFD-challenged mice. Our study demonstrated that DNA methylation at Esr1 promoter played an important role in regulating adipose inflammation, which may contribute to obesity-induced insulin resistance.
    Keywords:  Adipose tissue; Endocrinology; Epigenetics; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/jci.insight.173423
  2. Obesity (Silver Spring). 2025 Aug 26.
    CRISPLD2, a novel insulin-sensitizing adipokine that alters adipocyte size.
    Beth A Griesel, Kylie Williams, Nagib Ahsan, Philipp E Scherer, Ann Louise Olson, David P Sparling.
       OBJECTIVE: Both obesity and adipose tissue fibrosis are associated with insulin resistance, which can improve with weight loss. We previously found increased adipocyte-specific secretion of the novel adipokine CRISPLD2 during weight loss. In this study, we further explore the function of adipose CRISPLD2, which others suggest may regulate inflammation and fibrosis in a variety of tissues.
    METHODS: We designed mice with adipose-specific doxycycline-inducible overexpression of CRISPLD2 (CLD2AD) to assess adipose-specific effects on tissue structure and function on chow or high-fat diets. The effects of prolonged excess CRISPLD2 were determined after 7 months, including stromal vascular fraction analysis by single-cell RNA-seq. CRISPLD2 cell surface signaling was explored in 3T3-L1 adipocytes via transwell assays, and adipocyte binding partners were determined in unbiased binding screening by mass spectrometry.
    RESULTS: CLD2AD mice had decreased adipocyte size but unchanged fat mass. Long-term CRISPLD2 overexpression led to downregulation of collagen transcription and decreased fibrosis. CRISPLD2 induced Ifng transcription in adipocytes in vitro and bound multiple adipocyte cell surface proteins, including nucleolin. Finally, obese CLD2AD mice had decreased adipocyte size and improved glucose tolerance, with no change in fat mass.
    CONCLUSIONS: These data suggest a model wherein CRISPLD2 can both regulate adipose tissue fibrosis and improve insulin sensitivity.
    DOI:  https://doi.org/10.1002/oby.24342
  3. Nat Genet. 2025 Aug 20.
    Single-cell DNA methylome and 3D genome atlas of human subcutaneous adipose tissue.
    Zeyuan Johnson Chen, Sankha Subhra Das, Asha Kar, Seung Hyuk T Lee, Kevin D Abuhanna, Marcus Alvarez, Mihir G Sukhatme, Zitian Wang, Kyla Z Gelev, Matthew G Heffel, Yi Zhang, Oren Avram, Elior Rahmani, Sriram Sankararaman, Markku Laakso, Sini Heinonen, Hilkka Peltoniemi, Eran Halperin, Kirsi H Pietiläinen, Chongyuan Luo, Päivi Pajukanta.
      The cell-type-level epigenomic landscape of human subcutaneous adipose tissue (SAT) is not well characterized. Here, we elucidate the epigenomic landscape across SAT cell types using snm3C-seq. We find that SAT CG methylation (mCG) displays pronounced hypermethylation in myeloid cells and hypomethylation in adipocytes and adipose stem and progenitor cells, driving nearly half of the 705,063 differentially methylated regions (DMRs). Moreover, TET1 and DNMT3A are identified as plausible regulators of the cell-type-level mCG profiles. Both global mCG profiles and chromosomal compartmentalization reflect SAT cell-type lineage. Notably, adipocytes display more short-range chromosomal interactions, forming complex local 3D genomic structures that regulate transcriptional functions, including adipogenesis. Furthermore, adipocyte DMRs and A compartments are enriched for abdominal obesity genome-wide association study (GWAS) variants and polygenic risk, while myeloid A compartments are enriched for inflammation. Together, we characterize the SAT single-cell-level epigenomic landscape and link GWAS variants and partitioned polygenic risk of abdominal obesity and inflammation to the SAT epigenome.
    DOI:  https://doi.org/10.1038/s41588-025-02300-4
  4. Pharmaceuticals (Basel). 2025 Aug 19. pii: 1222. [Epub ahead of print]18(8):
    Exercise-Induced Muscle-Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging.
    Amelia Tero-Vescan, Hans Degens, Antonios Matsakas, Ruxandra Ștefănescu, Bianca Eugenia Ősz, Mark Slevin.
      Regular physical activity induces a dynamic crosstalk between skeletal muscle and adipose tissue, modulating the key molecular pathways that underlie metabolic flexibility, mitochondrial function, and inflammation. This review highlights the role of myokines and adipokines-particularly IL-6, irisin, leptin, and adiponectin-in orchestrating muscle-adipose tissue communication during exercise. Exercise stimulates AMPK, PGC-1α, and SIRT1 signaling, promoting mitochondrial biogenesis, fatty acid oxidation, and autophagy, while also regulating muscle hypertrophy through the PI3K/Akt/mTOR and Wnt/β-catenin pathways. Simultaneously, adipose-derived factors like leptin and adiponectin modulate skeletal muscle metabolism via JAK/STAT3 and AdipoR1-mediated AMPK activation. Additionally, emerging exercise mimetics such as the mitochondrial-derived peptide MOTS-c and myostatin inhibitors are highlighted for their roles in increasing muscle mass, the browning of white adipose tissue, and improving systemic metabolic function. The review also addresses the role of anti-inflammatory compounds, including omega-3 polyunsaturated fatty acids and low-dose aspirin, in mitigating NF-κB and IL-6 signaling to protect mitochondrial health. The resulting metabolic flexibility, defined as the ability to efficiently switch between lipid and glucose oxidation, is enhanced through repeated exercise, counteracting age- and disease-related mitochondrial and functional decline. Together, these adaptations demonstrate the importance of inter-tissue signaling in maintaining energy homeostasis and preventing sarcopenia, obesity, and insulin resistance. Finally, here we propose a stratified treatment algorithm based on common age-related comorbidities, offering a framework for precision-based interventions that may offer a promising strategy to preserve metabolic plasticity and delay the age-associated decline in cardiometabolic health.
    Keywords:  IL-6; adipokines; adiponectin; irisin; leptin; metabolic flexibility; mitochondrial biogenesis; myokines; skeletal muscle–adipose tissue crosstalk
    DOI:  https://doi.org/10.3390/ph18081222
  5. Redox Biol. 2025 Aug 20. pii: S2213-2317(25)00341-6. [Epub ahead of print]86 103828
    Inducible skeletal muscle-specific p53 deletion alleviates high-fat diet-induced insulin resistance by modulating mitochondria-associated membrane in obese mice.
    Soyoung Park, Jin Ki Jung, Jung-Yoon Heo, Themis Thoudam, Su-Yeon Jeong, Seok-Hui Kang, Chang-Hoon Woo, Hyoung Chul Choi, In-Kyu Lee, Jinmyoung Dan, Jongsoon Lee, Jae-Ryong Kim, So-Young Park.
      p53 has been implicated in metabolic regulation, but its role in obesity-induced skeletal muscle insulin resistance remains incompletely understood. This study aimed to determine the functional contribution of skeletal muscle p53 to insulin resistance and mitochondrial dysfunction, particularly in the context of obesity. We demonstrate that inducible, skeletal muscle-specific deletion of p53 (iMp53 KO) significantly improves insulin sensitivity in high-fat diet (HFD)-induced obese mice, with no effect in chow-fed controls. This metabolic improvement was accompanied by enhanced mitochondrial respiration and membrane potential, as well as reduced mitochondrial calcium overload in palmitate-treated C2C12 myotubes. Electron microscopy and immunoblotting revealed a marked reduction in mitochondria-associated membrane (MAM) area and decreased levels of MAM components (IP3R, VDAC, GRP75) in iMp53 KO muscle. Co-immunoprecipitation assays demonstrated physical interactions between p53 and MAM proteins, supporting a role for p53 in promoting MAM formation under obese conditions. Consistently, skeletal muscle from patients with type 2 diabetes exhibited elevated expression of both p53 and MAM markers, with a positive correlation between them. These findings suggest that p53 plays an important role in modulating ER-mitochondrial contacts and mitochondrial homeostasis in skeletal muscle and suggest its contribution to obesity-induced insulin resistance. This study provides new mechanistic insight into the pathological role of p53 in muscle metabolism.
    Keywords:  Insulin resistance; Mitochondria-associated membrane; Obesity; Skeletal muscle; p53
    DOI:  https://doi.org/10.1016/j.redox.2025.103828
  6. Int J Mol Sci. 2025 Aug 15. pii: 7898. [Epub ahead of print]26(16):
    Intermittent Cold Exposure Induces Distinct Proteomic Signatures in White Adipose Tissue of Mice.
    Elena Elsukova, Tatiana Zamay, Anna Kichkailo, Andrey Yakunenkov, Dmitry V Veprintsev, Zoran Minic, Maxim V Berezovski, Yury Glazyrin.
      Adipose tissue exhibits dynamic metabolic and structural changes in response to environmental stimuli, including temperature fluctuations. While continuous cold exposure has been extensively studied, the molecular effects of prolonged intermittent cold exposure (ICE) remain poorly characterized. Here, we present a proteomic analysis of inguinal white adipose tissue (IWAT) from mice subjected to a 16-week regimen of short-term daily ICE (6 °C for 6 h, 5 days per week) without compensatory caloric intake. Mass spectrometry identified 1108 proteins, with 140 differentially expressed between experimental and control groups. ICE significantly upregulated mitochondrial proteins associated with lipid and carbohydrate catabolism, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and lipogenesis, including LETM1, AIFM1, PHB, PHB2, ACOT2, NDUA9, and ATP5J. These changes reflect enhanced metabolic activity and mitochondrial remodeling. In contrast, proteins linked to oxidative stress, insulin resistance, inflammation, and extracellular matrix remodeling were downregulated, such as HMGB1, FETUA, SERPH1, RPN1, and AOC3. Notably, gamma-synuclein (SYUG), which inhibits lipolysis, was undetectable in ICE-treated samples. Our findings support the hypothesis that ICE promotes thermogenic reprogramming and metabolic rejuvenation in subcutaneous fat through activation of futile cycles and mitochondrial restructuring. This study offers molecular insights into adaptive thermogenesis and presents intermittent cold exposure as a potential strategy to mitigate adipose tissue aging.
    Keywords:  adipose tissue; futile cycles; intermittent cold exposure; mitochondrial remodeling; proteomics; thermogenesis
    DOI:  https://doi.org/10.3390/ijms26167898
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