bims-mimead Biomed News
on Adipose tissue and metabolic disease
Issue of 2026–10–25
eight papers selected by
Rachel M. Handy, University of Guelph and Universiteit Mastricht
  1. Transient Adipose Inflammatory Remodeling during High-Dose Semaglutide-Induced Weight Loss and Regain.
  2. Synthesis, molecular dynamics, and functional analysis of mitochondria-targeted estrogens through estrogen receptors.
  3. A futile Na+ K+ transport cycle augments energy expenditure in beige adipocytes.
  4. Uncovering the transcriptional hallmarks of endothelial cell aging via integrated single-cell analysis.
  5. BMI as a partitioning factor for estradiol and estrone reference intervals in middle-aged men and postmenopausal women.
  6. Taurine lowers inflammaging by regulating the NLRP3 inflammasome in macrophages.
  7. BMI-anchored transcriptomics uncovers oxidative and inflammatory poles of obesity heterogeneity.
  8. Weight loss during intermittent fasting, not Mediterranean diet quality alone, is associated with lower inflammation: A randomized controlled trial.
  1. Endocrinol Metab (Seoul). 2026 Oct 22.
    Transient Adipose Inflammatory Remodeling during High-Dose Semaglutide-Induced Weight Loss and Regain.
    Mihye Seo, Vivi Julietta, Maria Averia, Shindy Soedono, Ellen Budiono, Hyeong Kyu Park, Kyoil Suh, Kae Won Cho.
       Background: Weight loss improves obesity-associated metabolic dysfunction, yet resolution of adipose inflammation may be incomplete and can reappear during weight regain. Whether high-dose semaglutide induces sustained immunological remodeling of adipose and hepatic tissues during weight cycling remains unclear.
    Methods: Male C57BL/6 mice with diet-induced obesity were treated with semaglutide (60 nmol/kg, intraperitoneally, every 3 days) or vehicle for 3 weeks, followed by drug withdrawal under continued high-fat diet feeding. Body weight, body composition, and glucose homeostasis were assessed during treatment and after weight regain. Inflammatory changes in visceral and subcutaneous adipose tissue and liver were analyzed by flow cytometry, histology, immunofluorescence, and gene expression profiling.
    Results: Semaglutide induced rapid fat mass-selective weight loss with preservation of lean mass and significantly improved fasting glucose, insulin levels, insulin sensitivity, and glucose tolerance. During treatment, visceral adipose tissue exhibited marked reductions in pro-inflammatory macrophages, crown-like structures, and inflammatory gene expression, whereas subcutaneous adipose tissue was minimally affected. Following withdrawal, mice rapidly regained weight and adiposity. Visceral adipose inflammation fully reverted, with macrophage infiltration and inflammatory gene expression comparable to chronically obese controls. Hepatic steatosis and inflammatory markers similarly returned to obese levels. Despite this tissue-level reversion, fasting glycemia and insulin levels remained partially improved.
    Conclusion: High-dose semaglutide induces robust metabolic improvement and transient suppression of visceral adipose inflammation during active treatment; however, these inflammatory changes are not sustained after withdrawal and largely revert with weight regain. In contrast, partial improvement in fasting glycemia persisted, suggesting differential durability between systemic metabolic adaptation and local inflammatory remodeling during pharmacological weight cycling.
    Keywords:  Adipose tissue; Inflammation; Obesity; Semaglutide; Weight loss; Weight regain
    DOI:  https://doi.org/10.3803/EnM.2026.2979
  2. J Steroid Biochem Mol Biol. 2026 Oct 19. pii: S0960-0760(26)00204-9. [Epub ahead of print]266 107138
    Synthesis, molecular dynamics, and functional analysis of mitochondria-targeted estrogens through estrogen receptors.
    Geovanni Alberto Ruiz-Romero, Magdiel Orozco-Valdivia, Javier I Wong-Romero, Ricardo Alberto González-Sánchez, Sergio Andrés Águila, Aldo Moreno-Ulloa, Rafael Vazquez-Duhalt, Kanchan Chauhan, Carolina Álvarez-Delgado.
      Estrogens play an important role in regulating mitochondrial function and cellular metabolism. Most of the effects of estrogens are mediated by estrogen receptors α and β (ERα and ERβ), located in various cellular compartments, including the mitochondria. The aim of this study was to validate the mitochondrial accumulation of mitochondria-targeted estrogens and determine whether their biological effects are mediated by ERs. Two mitochondria-targeted estrogen derivatives, mitoE2 and mitoEE2, were synthesized by covalently coupling a triphenylphosphonium (TPP) moiety to 17β-estradiol (E2) and 17α-ethynylestradiol (EE2), respectively, and were structurally characterized. Mitochondrial and cytosolic accumulation in MCF-7 cells was quantified by high resolution mass spectrometry. Cell viability assays were performed to assess the cytocompatibility of TPP. To investigate the binding of mitochondria-targeted estrogens to ERs molecular dynamics simulations were performed. Functional assays were assessed in vitro in the MCF-7 cell line through Manganese-dependent Superoxide Dismutase (MnSOD) activity assays using selective ER antagonists, and by gene expression analyses of mitochondrial-encoded cytochrome c oxidase COX1 and nuclear-encoded COX4. Both mitoE2 and mitoEE2 preferentially accumulated in mitochondria compared with the cytosol. The molecular dynamic simulations showed a thermodynamically stable binding to the ligand-binding domain of ERα and ERβ. In vitro analyses revealed that ERβ selectively mediates the inhibition of MnSOD activity induced by mitoE2 and that mitochondria-targeted estrogens differentially modulate COX1 and COX4 expression in a time-dependent manner. In conclusion, this work contributes to understanding the molecular mechanisms underlying the effects of mitochondria-targeted estrogens on mitochondrial function. Our findings support the need for further investigation to determine their role as modulators of mitochondrial processes and provide a mechanistic basis for future studies in additional cellular and disease-specific models.
    Keywords:  Cytochrome c oxidase; Estrogen; Estrogen receptor; Mitochondria-targeted estrogen; Superoxide dismutase
    DOI:  https://doi.org/10.1016/j.jsbmb.2026.107138
  3. Nat Metab. 2026 Oct 21.
    A futile Na+ K+ transport cycle augments energy expenditure in beige adipocytes.
    Qing Liu, Ying Cheng, Dandan Yan, Wenjie Wu, Zhenchuan Lei, Qiaoyun Long, Ziyu Zhao, Yuan Gao, Baile Wang, Tianshi Feng, Jihoon Shin, Jiayu Zhao, Shiting Zhao, Kang Chen, Kingyip Cheng, Xiaoqiang Yao, Ping Gu, Xuefei Gao, Ching-Lung Cheung, Shingo Kajimura, Pengtao Liu, Donghai Wu, Wei Sun, Jinfeng Xiao, Zexin Lin, Yi Wang, Maxwell Kwok, Ngar Yun Ellen Poon, Cheng Hu, Aimin Xu, Hannah Xiaoyan Hui.
      Uncoupling protein 1 (UCP1)-independent energy dissipation has been proven to serve physiological functions in beige adipocytes. Here we show that a futile sodium/potassium (Na+/K+) transport cycle is preferentially amplified in mouse and human beige adipocytes and contributes to UCP1-independent energy expenditure. In mice, cold exposure activates a sympathetic-thyroid hormone signaling axis that coordinatedly induces the Na+/K+-ATPase subunit ATP1A2 together with Na+ and K+ channels, increasing bidirectional ion flux across the plasma membrane while maintaining ionic balance. Atp1a2+Kcnk3+ adipocytes are detected in mouse inguinal white adipose tissue after cold exposure. Acute inhibition of Na+/K+-ATPase reduces energy expenditure in mouse and human beige adipocytes, whereas overexpressing Atp1a2 in murine adipocytes potentiates energy expenditure, independent of UCP1. Adipocyte-specific Atp1a2 deletion impairs thermogenic capacity and exacerbates diet-induced obesity in mice. Expression of a human ATP1A2 missense variant reduces ATP1A2-dependent respiration in mouse adipocytes. Together, these identify ion transport as a tunable ATP-consuming mechanism that expands the thermogenic repertoire of beige adipocytes.
    DOI:  https://doi.org/10.1038/s42255-026-01630-9
  4. Nat Aging. 2026 Oct 23.
    Uncovering the transcriptional hallmarks of endothelial cell aging via integrated single-cell analysis.
    Sarah Dobner, Lisa Kleissl, Fanni Tóth, Robert L Paxton, Irena Yordanova, Kveta Brazdilova, Cedric Vanluyten, Aleksandra Aizenshtadt, Hanna Tóth, Jake Burton, Aglaja Kopf, Vera Belyaeva, Katharina Ferencevic, Dunja A Al-Nuaimi, Mauriz A Lichtenstein, Georg E Winter, André F Rendeiro, Christoph Bock, Joanna Kalucka, Stefan Krauss, Selma Osmanagic-Myers, Laurens J Ceulemans, Georg Stary, Abdel Rahman Abdel Fattah, Laura P M H de Rooij.
      Endothelial cells (ECs) are critical regulators of vascular function and exhibit tissue-specialized roles. During aging, these cells become dysfunctional, resulting in increased susceptibility to cardiovascular disease. Although single-cell transcriptomics has revealed extensive endothelial heterogeneity, a comprehensive atlas of human EC transcriptomes over the course of the adult human lifespan has been lacking. Here, we present the Human Aging Endothelial Cell Atlas (HAECA), a harmonized single-cell transcriptomic compendium of over 375,000 ECs from 12 human tissues throughout adulthood. We identified age-associated transcriptional shifts, including a decline in angiogenic gene expression in venous ECs and widespread alterations in extracellular matrix and mechanotransduction-associated signatures. Furthermore, we uncovered a p21-linked transcriptional program in ECs, which we linked to cellular senescence in both in vitro and in vivo models. Together, our study provides a high-resolution transcriptomic reference of the human endothelium across tissues and age.
    DOI:  https://doi.org/10.1038/s43587-026-01247-3
  5. Eur J Endocrinol. 2026 Oct 19. pii: lvag194. [Epub ahead of print]
    BMI as a partitioning factor for estradiol and estrone reference intervals in middle-aged men and postmenopausal women.
    M Kruijt, R de Mutsert, A van Hylckama Vlieg, F R Rosendaal, J J Hillebrand, M den Heijer, A C Heijboer.
       INTRODUCTION: Estrogens play a large role in female and male physiology and are routinely determined in the clinical setting. For interpretation, distinct reference intervals are applied for men, pre---, and postmenopausal women. Adipose tissue is a potent producer of estrogens and influences the circulating estrogen concentrations, although its impact on estrogen reference intervals is currently unknown.
    METHOD: We determined estradiol and estrone concentrations in 6,671 middle-aged participants of a large cohort oversampled for persons with BMI >27 kg/m2. We investigated partitioning based on sex, age, menopausal status, and BMI by assessing the proportion of subgroups outside each limit of a shared 95% reference interval (ideally 2.5%) and calculating reference intervals for justified subgroups according to CLSI EP28-A3c.
    RESULTS: As expected, the strongest partitioning factor was sex, followed by menopausal status for women. When using a shared reference interval for all BMI categories, 4.9% and 5.2% of values in men with obesity and 11.4% and 7.7% of values in postmenopausal women with obesity fell above the reference interval for estradiol and estrone, respectively. Within postmenopausal women differences in the upper reference limit were found, being 138, 157, and 210 pmol/L for estradiol and 32, 41, and 74 pmol/L for estrone for normal weight, overweight, and obesity, respectively.
    DISCUSSION: Laboratory professionals and clinicians should be aware that BMI affects estrogen concentrations to such extent that it may influence clinical interpretation. Ideally their reference intervals should be stratified by BMI category to reflect the increased estrogen concentrations associated with higher BMI.
    Keywords:  BMI; estradiol; estrone; partitioning; reference intervals
    DOI:  https://doi.org/10.1093/ejendo/lvag194
  6. Cell. 2026 Oct 23. pii: S0092-8674(26)01207-9. [Epub ahead of print]
    Taurine lowers inflammaging by regulating the NLRP3 inflammasome in macrophages.
    Chenyang Guan, Seungjin Ryu, Mingze Dong, Yitao Zhu, Rae Maeda, Yun-Hee Youm, Subhasis Mohanty, Hee-Hoon Kim, Lucie Orliaguet, Tamara Dlugos, Steven R Smith, Eric Ravussin, Janset Onyuru, Hal M Hoffman, Stephan Siebel, Andrew Wang, Yaqiu Wang, Yuval Kluger, Albert C Shaw, Thirumala-Devi Kanneganti, Nathan LeBrasseur, Yuki Sugiura, Vishwa Deep Dixit.
      Whether a decline in taurine drives aging is debated, and despite high millimolar intracellular concentrations, its function as a potential guardian of cytosolic homeostasis is unclear. Here, we show that aging increases circulating taurine concentrations in humans and mice. Further elevating taurine in aged mice enhances health span, engaging anti-inflammatory pathways previously linked to youthfulness, and reduces mortality from sepsis and inflammasome-mediated inflammation, suggesting an enantiostatic response. Mechanistically, diverse NLRP3-specific "danger signals" induce taurine efflux from macrophages as a proximal step to activate the inflammasome and the resultant pyroptosis. Taurine restoration in macrophages prevents NLRP3-induced trans-Golgi network disassembly, thereby suppressing NLRP3 inflammasome activation. Conversely, lowering taurine biosynthesis combined with reduced bioavailability in macrophages exacerbated inflammasome activation. In humans, sustained caloric restriction elevates adipose tissue taurine and is accompanied by lower inflammation. Together, we identify taurine as an immunometabolic rheostat that links danger sensing to NLRP3 inflammasome activation, suggesting taurine-based strategies to alleviate inflammaging and inflammasomopathies.
    Keywords:  NLRP3; aging; antiinflammation; caloric restriction; immunometabolism; inflammaging; inflammasome; lifespan; taurine; taurine efflux
    DOI:  https://doi.org/10.1016/j.cell.2026.09.061
  7. Mol Metab. 2026 Oct 22. pii: S2212-8778(26)00146-8. [Epub ahead of print] 102462
    BMI-anchored transcriptomics uncovers oxidative and inflammatory poles of obesity heterogeneity.
    Su Yin-Yuan, Bundalian Linnaeus, Chen Yin-Cheng, Gjermeni Erind, Gille Benedikt, Richter Sandy, Jasaszwili Mariami, Palma-Vera Sergio Eliseo, Hoffmann Anne, Ghosh Adhideb, Wolfrum Christian, Blüher Matthias, Peleg Shahaf, Garten Antje, Le Duc Diana, Lin Chen-Ching.
       BACKGROUND: BMI remains the dominant clinical index of obesity, but does not resolve adipose molecular programs that distinguish metabolic resilience from vulnerability.
    METHODS: Among 1,479 available human visceral adipose RNA-seq profiles, 1,298 samples from individuals with BMI 30-60 were included in the primary modeling cohort. Using BMI as a phenotypic anchor, we fit a LASSO regression model to derive transcriptome-predicted BMI and applied the resulting BMI-anchored transcriptomic model to mouse selection lines with divergent obesity phenotypes. In humans, directional discordance between measured and predicted BMI was used to define transcriptome-derived metabolically healthy obesity-like (MHO-like) and metabolically unhealthy obesity-like (MUO-like) states and to characterize pathophysiologic variation beyond measured BMI.
    RESULTS: Model-selected genes converged on immune, metabolic, mitochondrial, growth, structural-remodeling, and proteostasis programs. Cross-species application showed that BMI-anchored transcriptomic scores more closely tracked adipose-tissue content than body-size condition factor, distinguishing lipid-anabolic and inflammatory features of obesity-prone DU6 mice from the oxidative-catabolic phenotype of DU6P mice characterized by increased muscle mass. Gene-level associations with the transcriptomic score mirrored DU6-associated expression changes, linking the cross-species axis to an obesity-vulnerable adipose state. In humans, MHO-like individuals showed enhanced mitochondrial energy-production programs and more favorable glycemic and lipid profiles, whereas MUO-like individuals showed stress-adaptive metabolic remodeling and greater cardiometabolic medication use. In a separate, non-overlapping validation cohort, projection onto the primary-cohort PCA space retained a signal associated with insulin resistance that remained essentially unchanged after adjustment for sex.
    CONCLUSIONS: These findings support a conserved adipose transcriptomic axis linking oxidative metabolic resilience to healthier obesity and lipid-inflammatory remodeling to metabolic vulnerability.
    Keywords:  BMI-anchored transcriptomic model; adipose tissue metabolism; adipose transcriptomics; cross-species model; obesity; visceral adipose tissue
    DOI:  https://doi.org/10.1016/j.molmet.2026.102462
  8. Cell Metab. 2026 Oct 21. pii: S1550-4131(26)00392-X. [Epub ahead of print]
    Weight loss during intermittent fasting, not Mediterranean diet quality alone, is associated with lower inflammation: A randomized controlled trial.
    Moritz V Warmbrunn, Valeria Tosti, Raaj Kishore Biswas, Beatrice Bertozzi, Maria Lastra Cagigas, Nicola Veronese, Francesco Spelta, Laura Piccio, Richard D Head, Richard R Rodrigues, Dayna S Early, Yanjiao Zhou, Giorgio Trinchieri, Giovanni Fiorito, Luigi Fontana.
      Whether the anti-inflammatory effects of a Mediterranean diet reflect diet quality itself or accompanying weight loss is unclear. In a 16-week randomized controlled-feeding trial, 53 adults (77% female; mean age 54.7 years) with metabolic risk factors received a fully provided Mediterranean diet or their habitual western diet for 8 weeks, then added twice-weekly fasting days for a further 8 weeks. The primary outcome, high-sensitivity C-reactive protein, did not change during the diet-only phase despite clear dietary separation. After fasting began, C-reactive protein fell in the Mediterranean-diet group relative to controls, alongside greater weight loss, improved insulin sensitivity, and lower blood pressure; lipid improvements had already emerged during the diet-only phase. Multi-omic analyses showed parallel reductions in inflammatory signaling, with gut microbiome composition largely stable. Thus, diet quality alone does not lower inflammation over 8 weeks; negative energy balance and weight loss during fasting appear to be the stronger drivers. This study was registered at ClinicalTrials.gov (NCT02148458).
    Keywords:  LDL-cholesterol; Mediterranean diet; alternate-day fasting; cardiovascular disease risk; diet quality; hsCRP; inflammation; intermittent fasting; metabolism; weight loss
    DOI:  https://doi.org/10.1016/j.cmet.2026.09.017
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