bims-mimead Biomed News
on Adipose tissue and metabolic disease
Issue of 2025–06–29
eight papers selected by
Rachel M. Handy, University of Guelph
  1. Housing matters: experimental variables shaping metabolism in obese mice.
  2. Macrophage-Expressed Micropeptide Smim30 Maintains Adipose Tissue Insulin Sensitivity and Safeguards Systemic Metabolic Homeostasis.
  3. Skeletal Muscle Mitochondria Contain Nuclear-Encoded RNA Species Prior to and Following Adaptation to Exercise Training in Rats.
  4. Lipidomic profiling of human adiposomes identifies specific lipid shifts linked to obesity and cardiometabolic risk.
  5. Obesity drives depot-specific vascular remodeling in male white adipose tissue.
  6. Metabolic Messengers: oestradiol.
  7. Dietary control of peripheral adipose storage capacity through membrane lipid remodelling.
  8. Exercise-induced mitochondrial protection in skeletal muscle of ovariectomized mice: A myogenic E2 synthesis-independent mechanism.
  1. Mol Metab. 2025 Jun 17. pii: S2212-8778(25)00097-3. [Epub ahead of print] 102190
    Housing matters: experimental variables shaping metabolism in obese mice.
    Béatrice So-Yun Choi, Jacob Bak Holm, Asker Brejnrod, Even Fjære, Zhongkui Xia, Marie-Louise Allingbjerg, Ida Søgaard Larsen, David Møbjerg Kristensen, Morten Dall, Lene Secher Myrmel, Janne Koch, Niels Banhos Danneskiold-Samsøe, Otto Kalliokoski, Jonas T Treebak, Liang Xiao, Axel Kornerup Hansen, Helle Sørensen, Lise Madsen, Manimozhiyan Arumugam, Karsten Kristiansen, Benjamin A H Jensen.
      Diet-induced obesity in mice is an important model for investigating host-diet interactions as well as dietary and pharmacological treatments of metabolic diseases. Experimental reproducibility is, however, a recurrent challenge. To determine key controllable experimental drivers of mouse metabolism, we distributed 338 C57BL/6JBomTac mice (males and females) into six research units across two countries, divided them into a variety of housing conditions (i.e., diets, cage types, temperatures, group-housing vs. single-housing) and kept 26 reference mice at the vendor. We applied linear mixed models to rank the influence of each variable on metabolic phenotype (i.e., body weight gain, glucose intolerance, liver, and visceral adipose tissue weight). Group-housing was the most potent driver of metabolic dysfunction apart from sex and diet. Accordingly, single-housed mice exhibited reduced weight gain (∼50%), increased energy expenditure, and diminished respiratory exchange ratio concomitant with improved glucose tolerance (∼20%) compared to their group-housed counterparts. Our results may aid in clarifying the impact of experimental design and promote rational, transparent reporting to increase reproducibility.
    Keywords:  animal models; high-fat diet; housing conditions; reproducibility; sex differences; thermoneutrality
    DOI:  https://doi.org/10.1016/j.molmet.2025.102190
  2. Diabetes. 2025 Jun 23. pii: db240721. [Epub ahead of print]
    Macrophage-Expressed Micropeptide Smim30 Maintains Adipose Tissue Insulin Sensitivity and Safeguards Systemic Metabolic Homeostasis.
    Yonghe Ma, Yu Shi, Kaiyuan Wu, Ping Li, Nikhil Gupta, Chengfei Jiang, Hang Sun, Xiangbo Ruan, Tyler Finley, Jing Wu, Chengyu Liu, Haiming Cao.
      A growing number of micropeptides (miPs) have been identified in recent years, but their biological roles remain largely unexplored. We identified a conserved 6-kDa miP, named small integral membrane protein 30 (SMIM30), as a potential metabolic regulator. To study the physiological function of Smim30, we generated a loss-of-function mouse strain using the CRISPR/Cas9-mediated knock-in strategy. When fed both normal chow and high-fat diets, these mice exhibited elevated blood glucose and insulin levels, with reduced insulin sensitivity. We further showed that Smim30 loss in adipose tissue drove systemic insulin resistance, although intriguingly, adipocyte-expressed Smim30 was dispensable in this effect. Instead, Smim30 was mainly expressed in adipose tissue-residential macrophages, and loss of Smim30 led to increased macrophage infiltration and production of proinflammatory cytokines and chemokines. Smim30 also modulated inflammatory responses in ex vivo/in vitro macrophage systems, which are conserved in both humans and mice. The results indicate that Smim30 plays a key role in maintaining adipose tissue insulin sensitivity and safeguarding systemic metabolic homeostasis, offering potential as both a diagnostic biomarker and therapeutic target for metabolic disorders.
    ARTICLE HIGHLIGHTS: Understanding the role of micropeptides (miPs) in metabolic regulation could enhance insights into metabolic diseases and open new pathways for treatment. Small integral membrane protein 30 (Smim30), an adipose tissue macrophage-expressed miP, maintains insulin sensitivity and safeguards systemic metabolic homeostasis. Smim30 modulates inflammatory responses and macrophage-adipocyte communication in adipose tissue. Smim30 could serve as a potential diagnostic biomarker and therapeutic target for metabolic disorders.
    DOI:  https://doi.org/10.2337/db24-0721
  3. FASEB J. 2025 Jul 15. 39(13): e70702
    Skeletal Muscle Mitochondria Contain Nuclear-Encoded RNA Species Prior to and Following Adaptation to Exercise Training in Rats.
    Jessica L Silver, Séverine Lamon, Stella Loke, Gisella Mazzarino, Larry Croft, Mark Ziemann, Megan Soria, Glenn D Wadley, Adam J Trewin.
      Skeletal muscle mitochondria adaptation to exercise training is mediated by molecular factors that are not fully understood. Mitochondria import over 1000 proteins encoded by the nuclear genome, but the RNA population resident within the organelle is generally thought to be exclusively encoded by the mitochondrial genome. However, recent in vitro evidence suggests that specific nuclear-encoded miRNAs and other noncoding RNAs (ncRNAs) can reside within the mitochondrial matrix. Whether these are present in mitochondria of skeletal muscle tissue, and whether this is affected by endurance training-a potent metabolic stimulus for mitochondrial adaptation-remains unknown. Rats underwent 4 weeks of moderate-intensity treadmill exercise training, then were humanely killed and tissues were collected for molecular profiling. Mitochondria from gastrocnemius skeletal muscle were isolated by immunoprecipitation, further purified, and then the resident RNA was sequenced to assess the mitochondrial transcriptome. Exercise training elicited typical transcriptomic responses and functional adaptations in skeletal muscle, including increased mitochondrial respiratory capacity. We identified 24 nuclear-encoded coding or noncoding RNAs in purified mitochondria, in addition to 50 nuclear-encoded miRNAs that met a specified abundance threshold. Although none were differentially expressed in the exercise vs. control group at FDR < 0.05, exploratory analyses suggested that the abundance of 3 miRNAs was altered (p < 0.05) in mitochondria isolated from trained compared with sedentary skeletal muscle. We report the presence of a specific population of nuclear-encoded RNAs in the mitochondria isolated from rat skeletal muscle tissue, which could play a role in regulating exercise adaptations and mitochondrial biology.
    Keywords:  exercise; mitochondria; skeletal muscle; transcriptome
    DOI:  https://doi.org/10.1096/fj.202500157R
  4. JCI Insight. 2025 Jun 23. pii: e191872. [Epub ahead of print]10(12):
    Lipidomic profiling of human adiposomes identifies specific lipid shifts linked to obesity and cardiometabolic risk.
    Abeer M Mahmoud, Imaduddin Mirza, Elsayed Metwally, Mohammed H Morsy, Giorgia Scichilone, Monica C Asada, Amro Mostafa, Francesco M Bianco, Mohamed M Ali, Mario A Masrur, Chandra Hassan, Brian T Layden.
      BACKGROUNDObesity, a growing health concern, often leads to metabolic disturbances, systemic inflammation, and vascular dysfunction. Emerging evidence suggests that adipose tissue-derived extracellular vesicles (adiposomes) may propagate obesity-related complications. However, their lipid composition and effect on cardiometabolic state remain unclear.METHODSThis study examined the lipid composition of adiposomes in 122 participants (75 in obesity group, 47 in lean group) and its connection to cardiometabolic risk. Adiposomes were isolated via ultracentrifugation and characterized using nanoparticle tracking and comprehensive lipidomic analysis by mass spectrometry. Cardiometabolic assessments included anthropometry, body composition, glucose-insulin homeostasis, lipid profiles, inflammatory markers, and vascular function.RESULTSCompared with lean controls, individuals with obesity exhibited elevated adiposome release and shifts in lipid composition, including higher ceramides, free fatty acids, and acylcarnitines, along with reduced levels of phospholipids and sphingomyelins. These alterations strongly correlated with increased BMI, insulin resistance, systemic inflammation, and impaired vascular function. Pathway enrichment analyses highlight dysregulation in glycerophospholipid and sphingolipid metabolism, bile secretion, proinflammatory pathways, and vascular contractility. Machine-learning models utilizing adiposome lipid data accurately classified obesity and predicted cardiometabolic conditions, such as diabetes, hypertension, dyslipidemia, and liver steatosis, achieving accuracy above 85%.CONCLUSIONObesity profoundly remodels the adiposome lipid landscape, linking lipid changes to inflammation, metabolic dysfunction, and vascular impairment. These findings underscore adiposome lipids as biomarkers for obesity and related cardiometabolic disorders, supporting personalized interventions and offering therapeutic value in risk stratification and treatment.FUNDINGThis project was supported by NIH grants R01HL161386, R00HL140049, P30DK020595 (PI: AMM), R01DK104927, and P30DK020595 as well as by a VA Merit Award (1I01BX003382, PI: BTL).
    Keywords:  Adipose tissue; Inflammation; Lipidomics; Metabolism; Obesity; Vascular biology
    DOI:  https://doi.org/10.1172/jci.insight.191872
  5. Nat Commun. 2025 Jun 25. 16(1): 5392
    Obesity drives depot-specific vascular remodeling in male white adipose tissue.
    Sana S Hasan, David John, Martina Rudnicki, Ibrahim AlZaim, Daniel Eberhard, Iris Moll, Jacqueline Taylor, Christian Klein, Maximilian von Heesen, Lena-Christin Conradi, Ralf H Adams, Eckhard Lammert, Joanna Kalucka, Christiana Ruhrberg, Stefanie Dimmeler, Andreas Fischer.
      Obesity-driven pathological expansion of white adipose tissue (WAT) is a key driver of endothelial dysfunction. However, early vascular alterations associated with over-nutrition also serve to exacerbate WAT dysfunction. Here, we conduct a single-cell transcriptomic analysis of WAT endothelium to delineate endothelial heterogeneity and elucidate vascular alterations and its consequence in a male murine model of obesity. We demarcate depot-specific differences in subcutaneous (sWAT) and visceral WAT (vWAT) endothelium through in sillico analysis and further corroboration of our findings. Moreover, we identify a sWAT-specific fenestrated endothelial cell (EC) subtype, which declines in obese conditions. Utilizing systemic anti-VEGFA blockade and genetic Vegfa manipulation, we demonstrate that VEGFA is necessary for maintaining fenestration in sWAT. Additionally, we detect this fenestrated EC subtype in male human WAT, which undergoes reduction in individuals with obesity. Collectively, this atlas serves as a valuable tool for future studies to decipher the functional significance of different WAT EC subtypes.
    DOI:  https://doi.org/10.1038/s41467-025-60910-2
  6. Nat Metab. 2025 Jun;7(6): 1114-1122
    Metabolic Messengers: oestradiol.
    Andrea L Hevener, Stephanie M Correa.
      Oestradiol (E2), a steroid hormone derived from cholesterol, has long been recognized for its central role in female reproduction and pathobiology of menopause. However, accumulating evidence underscores a critical role for E2 in the regulation of systemic metabolism in both women and men. The metabolic actions of E2 are predominantly mediated by oestrogen receptor α (encoded by ESR1), a nuclear receptor with heritable expression patterns and tissue-specific transcript levels highly correlated with indices of metabolic health in both sexes. Here we provide an overview of the cell-specific actions of E2 and its receptors (α and β) in modulating key metabolic pathways. We contextualize these mechanistic preclinical studies with epidemiological data linking the menopausal transition to a marked rise of metabolic disease risk and provide evidence that E2 replacement mitigates this risk by preserving metabolic health.
    DOI:  https://doi.org/10.1038/s42255-025-01317-7
  7. Nat Metab. 2025 Jun 27.
    Dietary control of peripheral adipose storage capacity through membrane lipid remodelling.
    Marcus J Tol, Yuta Shimanaka, Alexander H Bedard, Jennifer Sapia, Liujuan Cui, Mariana Colaço-Gaspar, Peter Hofer, Alessandra Ferrari, Kevin Qian, John P Kennelly, Stephen D Lee, Yajing Gao, Xu Xiao, Jie Gao, Julia J Mack, Thomas A Weston, Kevin J Williams, Baolong Su, Calvin Pan, Aldons J Lusis, Daniel P Pike, Alex Reed, Natalia Milosevich, Benjamin F Cravatt, Makoto Arita, Stephen G Young, David A Ford, Rudolf Zechner, Stefano Vanni, Peter Tontonoz.
      Genetic and dietary cues are known drivers of obesity, yet how they converge at the molecular level is incompletely understood. Here we show that PPARγ supports hypertrophic expansion of adipose tissue via transcriptional control of LPCAT3, an endoplasmic reticulum (ER)-resident O-acyltransferase that selectively enriches diet-derived omega-6 polyunsaturated fatty acids (n-6 PUFAs) in the membrane lipidome. In mice fed a high-fat diet, lowering membrane n-6 PUFA levels through genetic or dietary interventions results in aberrant adipose triglyceride (TG) turnover, ectopic fat deposition and insulin resistance. Additionally, we detail a non-canonical adaptive response in 'lipodystrophic' Lpcat3-/- adipose tissues that engages a futile lipid cycle to increase metabolic rate and offset lipid overflow to ectopic sites. Live-cell imaging, lipidomics and molecular dynamics simulations reveal that adipocyte LPCAT3 activity enriches n-6 arachidonate in the phosphatidylethanolamine (PE)-dense ER-lipid droplet interface. Functionally, this localized PE remodelling optimizes TG storage by driving the formation of large droplets that exhibit greater resistance to adipose TG lipase activity. These findings highlight the PPARγ-LPCAT3 axis as a mechanistic link between dietary n-6 PUFA intake, adipose expandability and systemic energy balance.
    DOI:  https://doi.org/10.1038/s42255-025-01320-y
  8. Redox Biol. 2025 Jun 21. pii: S2213-2317(25)00248-4. [Epub ahead of print]85 103735
    Exercise-induced mitochondrial protection in skeletal muscle of ovariectomized mice: A myogenic E2 synthesis-independent mechanism.
    Xu Tian, Yi Hu, Tao Li, Fangfang Yu, Tingting Li, Xiangyang Tian, Yiwei Feng, Qiuling Zhong, Yifan Meng, Wei Chen, Rengfei Shi.
       BACKGROUND: Skeletal muscle, a 17β-estradiol (E2)-sensitive tissue, is prone to accelerated aging due to postmenopausal E2 deficiency and subsequent mitochondrial dysfunction. While exogenous E2 treatment has been shown to protect against mitochondrial damage in ovariectomized rodents, the impact of exercise-induced local E2 production in skeletal muscle on mitochondrial function remains to be determined. This study investigated exercise-mediated mitochondrial protection in ovariectomized mice and the contribution of myogenic E2.
    METHODS: Female C57BL/6J mice (8-week-old) were divided into Sham, OVX, and OVX + ET groups (N = 12). OVX mice underwent bilateral ovariectomy, with the OVX + ET group performing 8 weeks of treadmill exercise starting 10 weeks post-surgery. Functional tests (grip strength, fatigue resistance) and gastrocnemius analyses (morphology, mitochondrial function, E2/antioxidant levels, and protein expression) were conducted. Parallel experiments in muscle-specific aromatase knockout (MS-ARO-CKO) mice included E2 supplementation via subdermal pellets.
    RESULTS: 18 weeks after ovariectomy (OVX), C57BL/6J mice exhibited significant reductions in grip strength (∼30 %), rotarod performance (∼57 %), and grid hanging performance (∼92 %). Concomitantly, OVX led to marked decreases in mitochondrial respiration (p < 0.05) and antioxidant capacity (p < 0.05) in the gastrocnemius muscle, accompanied by alterations in mitochondrial quality control and antioxidant signaling proteins (p < 0.05). Exercise intervention effectively attenuated these OVX-induced deficits, accompanied by a 66 % increase in E2 levels and upregulation of aromatase (ARO) activity and expression (p < 0.05). In MS-ARO-CKO mice model, exercise failed to improve the impaired antioxidant capacity induced by OVX. However, exercise, similar to estrogen supplementation, restored mitochondrial function and related protein expression abnormalities induced by OVX (p < 0.05).
    CONCLUSIONS: Our findings demonstrate that the protective effects of exercise on skeletal muscle mitochondria involve multiple mechanisms, independent myogenic E2 Synthesis, providing novel insights for improving skeletal muscle health in postmenopausal women.
    Keywords:  Exercise training; Mitochondrial function; Muscle weakness; Myogenic 17β-estradiol
    DOI:  https://doi.org/10.1016/j.redox.2025.103735
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