bims-mimead 2026-07-26 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2026–07–26
eight papers selected by
Rachel M. Handy, University of Guelph and Universiteit Mastricht

The Divergent Effects of Nicotinamide Riboside and High-Intensity Exercise Training on Skeletal Muscle Epigenetic Aging.
Neonatal Overnutrition-Induced Adiposity and Glucose Intolerance are Associated with Impaired Lipolytic and Insulin Signaling in Adipose Tissue.
Tripartite ER-mitochondria-lipid droplets contact sites control adipocyte metabolic flexibility.
Acute mild cold exposure with shivering reduces 24 h glucose levels in individuals with type 2 diabetes but not prediabetes.
Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice.
Functional characterization of obesity using advanced 3D in vitro adipose tissue models.
VCD-induced estropause fails to enhance responsiveness to 17α-estradiol in adult female mice.
Single-cell atlas of the mouse ovary reveals molecular drivers of aging and senescence during the estropausal transition.

Aging Cell. 2026 Aug;25(8): e70638

The Divergent Effects of Nicotinamide Riboside and High-Intensity Exercise Training on Skeletal Muscle Epigenetic Aging.

Aino Heikkinen, Liina Uusitalo-Kylmälä, Ida Blom, Jørn Wulff Helge, Linn Gillberg, Robert Seaborne, Steen Larsen, Macsue Jacques, Robin Grolaux, Sari Aaltonen, Jaakko Kaprio, Birgitta W van der Kolk, Sini Heinonen, Nir Eynon, Kirsi H Pietiläinen, Riikka Kivelä, Eija Pirinen, Miina Ollikainen.

  Aging is accompanied by a decline in physiological function and increased vulnerability to disease, with mitochondrial dysfunction and epigenetic alterations recognized as key hallmarks. Nicotinamide riboside (NR), a vitamin B3 precursor to NAD+, and high-intensity interval training (HIIT) have both been proposed to ameliorate aging-related mitochondrial decline, but their effects on skeletal muscle epigenetic aging are not fully elucidated. Here, we assessed the impact of 5-month NR supplementation and 4-6 weeks HIIT on epigenetic age acceleration (EAA, via seven epigenetic clocks) in human skeletal muscle across three independent studies. NR supplementation was associated with reduced muscle EAA, particularly when measured with the PCHannum, MEAT, and DunedinPACE clocks, while HIIT produced opposite effects in some clocks, notably increasing pace of aging by DunedinPACE. Correlation analyses revealed that changes in skeletal muscle mitochondrial content correlated with changes in MEAT-derived EAA after NR and 6 weeks of HIIT. Together, these findings indicate that skeletal muscle epigenetic aging can be modulated by NR and HIIT interventions but in opposing directions, highlighting a potential link between mitochondrial abundance and epigenetic clocks. Further studies are warranted to clarify how NR and exercise regulate epigenetic aging. These results offer new insights into development of strategies for promoting epigenetic outcomes and healthy aging.

Keywords:  epigenetic aging; high‐intensity interval training; mitochondria; nicotinamide riboside; skeletal muscle; twins

DOI:  https://doi.org/10.1111/acel.70638
Arch Med Res. 2026 Jul 20. pii: S0188-4409(26)00121-9. [Epub ahead of print]57(7): 103499

Neonatal Overnutrition-Induced Adiposity and Glucose Intolerance are Associated with Impaired Lipolytic and Insulin Signaling in Adipose Tissue.

Camila F de Souza, Larissa Rugila S Stopa, Andressa B Martins, Ana Luiza M Wunderlich, Flaviane de Fatima Silva, Ayumi Cristina Medeiros Komino, Fábio Goulart de Andrade, Cristiane Mota Leite, Cassia Thaïs Bv Zaia, Fabio Bessa Lima, Ernane Torres Uchoa.

   BACKGROUND: Neonatal overnutrition induced by litter size reduction leads to obesity from childhood until adulthood. Increased adiposity in white adipose tissue (WAT) and glucose intolerance are obesity-related comorbidities. In this context, adiposity is regulated by lipogenesis and lipolysis, and glucose intolerance can result from insulin resistance and/or impaired insulin secretion by pancreatic β cells. Thus, this study assessed the lipolytic and insulin signaling pathways in the WAT in adult male rats overfed during lactation.
METHODS: Male rats were reared in either a small litter (SL) or a normal litter (NL). On postnatal day (PND) 73, the animals underwent a glucose tolerance test. The following day, they were euthanized by decapitation to collect retroperitoneal and epididymal WAT.
RESULTS: SL rats exhibited increased body weight, adipocyte area in both fat depots, and glucose intolerance. These animals also exhibited reduced expression of proteins involved in lipolytic regulation, such as adrenergic receptors β1, β3, Ser563pHSL, and FABP4, as well as proteins in the insulin signaling pathway, PI3Kp85 and GLUT4, in the retroperitoneal WAT, but not in the epididymal adipose tissue.
CONCLUSIONS: This study demonstrates that neonatal overnutrition leads to adult adiposity and glucose intolerance, which are associated with depot-specific molecular alterations in proteins involved in the lipolytic and insulin signaling pathways, particularly in retroperitoneal WAT.

Keywords:  Insulin resistance; Lipolysis; Litter size reduction; Obesity

DOI:  https://doi.org/10.1016/j.arcmed.2026.103499
EMBO J. 2026 Jul 22.

Tripartite ER-mitochondria-lipid droplets contact sites control adipocyte metabolic flexibility.

Marie Palard, Gilliane Chadeuf, Maxime Carpentier, Clotilde C N Renaud, Samuel Frey, Mikael Croyal, Rola Shaaban, Samy Hadjadj, Chloe Cloteau, Naima El Khallouki, Perrine Bomme, Soazig Le Lay, Manuel Majrouh, Perrine Paul-Gilloteaux, Alexandre Humbert, Christine Durand, Nicolas Bertocchini, Laurence Dubreil, Yoann Combot, Antria Antreou, Cedric Le May, Simon Ducheix, Bertrand Cariou, Francesca Giordano, Jennifer Rieusset, Abdou Rachid Thiam, Xavier Prieur.

Adipocyte dysfunction is a major driver of obesity-associated cardiometabolic disease, underscoring the need to understand how lipid storage and mobilization are regulated and disrupted. The ER-anchored protein Seipin governs lipid droplet (LD) biogenesis and ER-LD and ER-mitochondria (MAM) contacts, and its loss impairs calcium transfer and causes lipodystrophy. Here, we investigated whether Seipin coordinates MAM and ER-LD remodeling during adipocyte lipid handling. In subcutaneous adipose tissue from inducible Seipin-knockout mice, electron microscopy and proximity ligation assays revealed that feeding reduces MAMs while increasing ER-LD and mitochondria-LD contacts, a remodeling abolished by Seipin deficiency. Lipid loading elevated tripartite MAM-LD contacts in controls but not knockouts. Fluorescence recovery after photobleaching showed that impaired triglyceride transfer to LDs in Seipin-deficient cells was rescued by the MAM-LD-stabilizing peptide 'Linker-ER-Mi', in a calcium-dependent manner. During adipogenesis and lipid loading, MAM-LD contacts increased, whereas MAM-cytosolic mitochondria contacts declined; however, obesity blunted this remodeling. Furthermore, disrupting membrane contact sites impaired lipid flux, lipolysis, and insulin signaling. Taken together, these findings identify MAM-LD as regulators of adipocyte metabolic flexibility.

DOI: https://doi.org/10.1038/s44318-026-00876-z
Diabetologia. 2026 Jul 20.

Acute mild cold exposure with shivering reduces 24 h glucose levels in individuals with type 2 diabetes but not prediabetes.

Dzhansel Hashim, Johanna A Jörgensen, Tineke van de Weijer, Denis P Blondin, Patrick Schrauwen, Joris Hoeks.

   AIMS/HYPOTHESIS: Repeated cold exposure with shivering has been proposed as a potential strategy to enhance glucose metabolism by increasing energy expenditure and substrate utilisation. However, acute effects/benefits of cold-induced shivering on glucose homeostasis in metabolically compromised individuals are unknown. Here, we aimed to determine whether cold exposure at two different intensities improves 24 h glucose homeostasis in individuals with prediabetes and type 2 diabetes.
METHODS: In a randomised crossover trial conducted in the South Limburg/Maastricht region of the Netherlands, men and postmenopausal women with prediabetes (n=12) and stable type 2 diabetes (n=12), aged 40-75 years, body mass index ≥27 and ≤35 kg/m2, non-smoking and sedentary, underwent two whole-body cold exposure sessions using a water-perfused suit. Session order was randomised using an online randomisation tool (randomizer.org); participants were masked to the cold exposure intensity received, but investigators were not. Sessions were designed to elicit ~1.5-fold (mild, 15°C) and ~2.5-fold (moderate, 4°C) increases in resting metabolic rate (RMR). Continuous glucose monitoring assessed interstitial glucose concentrations over 24 h periods before and after each intervention, with controlled diet and activity. Shivering was confirmed via indirect calorimetry and electromyography.
RESULTS: In both study groups and periods, RMR increased significantly vs baseline (p<0.001 for all). In prediabetes, the increase in the final 1 h of cold was 1.53 × RMR in mild and 1.94 × RMR in moderate cold. In type 2 diabetes, the increase was 1.57 × RMR and 2.09 × RMR in the final 1 h of mild and moderate cold, respectively. In prediabetes, neither mild nor moderate cold exposure altered mean 24 h glucose levels. In contrast, after mild cold exposure the type 2 diabetes group exhibited a significant reduction in mean 24 h glucose levels (-0.6 ± 0.5 mmol/l, p=0.003) and fasting glucose (-0.6 ± 0.8 mmol/l, p=0.019), as well as an increase in time in normal range (+8.8 ± 10.3%, p=0.013) and reduced time in hyperglycaemia (-10.9 ± 12.9%, p=0.014). Moderate cold did not significantly affect any of the glucose outcomes in type 2 diabetes. Baseline fasting glucose, age and ALT levels were predictors of the glucose-lowering response, suggesting greater benefits in individuals who have higher baseline glucose levels, are younger and/or have more optimal liver health, i.e. lower ALT.
CONCLUSIONS/INTERPRETATION: Acute mild cold exposure with shivering reduced 24 h glucose levels in individuals with type 2 diabetes. No changes were observed in prediabetes. The observed effects appear to depend on baseline metabolic status rather than acute substrate utilisation during cold exposure. These findings support the potential of cold exposure as an adjunct non-pharmacological therapy for type 2 diabetes, although further mechanistic studies and validation in larger cohorts are warranted.
TRIAL REGISTRATION: ClinicalTrials.gov NCT05576025 FUNDING: Dutch Organisation for Knowledge and Innovation in Health, Healthcare and Well-being (ZonMw): 09120012010062.

Keywords:  Cold; Continuous glucose monitoring; Glucose homeostasis; Lifestyle intervention; Metabolism; Prediabetes; Type 2 diabetes

DOI:  https://doi.org/10.1007/s00125-026-06809-z
Nat Aging. 2026 Jul 24.

Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice.

Mariah F Calubag, Ismail Ademi, Cara L Green, Dulmalika N H Manchanayake, Hashan S M Jayarathne, Ryan N Marshall, Sandra M Le, Penelope Lialios, Lucia E Breuer, Shoshana Yakar, Reji Babygirija, Michelle M Sonsalla, Isaac Grunow, Chung-Yang Yeh, Yang Liu, Bailey A Knopf, Sarah Yandell, Charles I Opara, William A Ricke, Teresa T Liu, Mark P Keller, Alan D Attie, Marianna Sadagurski, Dudley W Lamming.

Dietary protein is a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction are mediated by reduced intake of dietary branched-chain amino acids (leucine, valine and isoleucine) and restriction of the branched-chain amino acids is sufficient to extend healthspan and lifespan in mice. Here we find that valine restriction (Val-R) improves metabolic health in C57BL/6J mice, promotes leanness and glycemic control across ages, and reduces frailty, cancer prevalence and senescent cell burden in both sexes while increasing median male lifespan by 23%. Assessing gene relationships across tissues, we identified a liver gene module enriched in mitochondrial pathways and increased mitochondrial respiration in Val-R-fed male mice. Our results demonstrate that Val-R improves multiple aspects of healthspan in mice of both sexes, extends lifespan in male mice and suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.

DOI: https://doi.org/10.1038/s43587-026-01169-0
Biomaterials. 2026 Jul 09. pii: S0142-9612(26)00470-9. [Epub ahead of print]336 124446

Functional characterization of obesity using advanced 3D in vitro adipose tissue models.

Vera M Pieters, Kyle S Nguyen, Penney M Gilbert, Alison P McGuigan.

  Obesity represents a complex systemic disease resulting in the global metabolic syndrome epidemic, yet our understanding of the underlying mechanisms in adipose tissue driving obesity remains limited. As the primary cellular targets of increased caloric intake, adipocytes undergo dramatic morphological and functional changes that trigger systemic metabolic dysfunction. To study the dysfunctional obese adipocyte phenotype in vitro, revolutionary three-dimensional (3D) adipocyte models have shown to be uniquely capable of recapitulating the lipid-laden, hypertrophic adipocyte characteristic of obesity. This feature makes 3D in vitro platforms powerful alternatives to traditional two-dimensional monolayer systems where the large, spherical and buoyant adipocytes simply detach. These sophisticated 3D in vitro New Approach Methodologies (NAMs) now enable researchers to dissect the multifactorial nature of obesity through diverse functional assays that validate individual disease hallmarks and assess therapeutic interventions. However, the field faces a critical challenge: integrating multiple disease-relevant readouts into holistic interpretations that can unlock novel adipocyte-targeting mechanisms. This review provides a comprehensive roadmap of cutting-edge 3D adipose tissue systems, showcasing how these NAMs can revolutionize biological and drug target discovery in obesity research. We examine the functional assays that define these models' capabilities, address key interpretative challenges, and explore transformative opportunities to amplify their impact through high-throughput approaches and scalable functional platforms that will accelerate the next generation of obesity therapies.

Keywords:  Assay development; Disease-relevant readouts; New Approach Methodologies (NAMs); Obesity; Three-dimensional (3D) in vitro adipose tissue models

DOI:  https://doi.org/10.1016/j.biomaterials.2026.124446
Geroscience. 2026 Jul 22.

VCD-induced estropause fails to enhance responsiveness to 17α-estradiol in adult female mice.

Sean R Janovic, Roberto Santín-Márquez, José V V Isola, Camila R C de Brito, Roshini Sathiaseelan, Jessica D Hense, Subhasri Biswas, Heather C Rice, Samim A Mondal, Michael B Stout.

  17α-estradiol (17α-E2) extends median lifespan and improves metabolic homeostasis in male mice through estrogen receptor α (ERα)-dependent mechanisms, but female mice are largely unresponsive unless ovariectomized or subjected to chronic high-fat feeding. Whether the gradual hormonal transition of natural reproductive aging similarly unmasks female responsiveness to 17α-E2 remains unknown. We tested whether 4-vinylcyclohexene diepoxide (VCD)-induced depletion of the ovarian reserve would render female mice responsive to 17α-E2 by treating wild-type (WT) and ERα knockout (ERαKO) littermates with VCD followed by 16 weeks of 17α-E2 administration. VCD-induced estropause was confirmed by elevated FSH, anestrus, and reduced ovarian size, but did not adversely affect metabolic phenotypes in WT mice. 17α-E2 treatment elicited modest improvements in adiposity and glucose tolerance, suppressed circulating IL-1β and IL-6, and reversed estropause-induced uterine atrophy in WT mice, but failed to rescue endometrial fibrosis. All 17α-E2-mediated effects were absent in ERαKO mice. These findings demonstrate that estropause does not unmask broad female responsiveness to 17α-E2 and indicate that the sex-specific actions of 17α-E2 extend beyond competitive receptor occupancy by endogenous 17β-E2.

Keywords:  17α-estradiol; Estrogen receptor α; Estropause; Menopause; Ovary; Uterus

DOI:  https://doi.org/10.1007/s11357-026-02434-1
Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2600323123

Single-cell atlas of the mouse ovary reveals molecular drivers of aging and senescence during the estropausal transition.

Xifan Wang, Jiping Yang, Chen Jin, Xizhe Wang, Daniela Contreras, Melody Devos, Maggie M Kane, Michael G Rosenfeld, Yousin Suh.

  Reproductive aging in mice leads to estropause, characterized by estrous cycle irregularity and eventual cessation, yet its underlying mechanism remains unclear. Here, we present a comprehensive single-cell atlas of mouse ovaries across precisely defined reproductive stages-from young (regular cycling) through the estropausal transition (regular vs. irregular cycling) to post-estropause (acyclic)-and of ovary-specific senescent cells defined by high senescence-associated β-galactosidase activity. We mapped transcriptomic dynamics of ovarian aging and characterized the molecular features of ovarian senescent cells. Our analyses revealed that during the estropausal transition, irregularly cycling ovaries exhibited accelerated aging and cellular senescence features compared with regularly cycling counterparts, including increased transcriptional noise, altered conserved aging pathways such as oxidative phosphorylation and proteostasis, hormone dysregulation in granulosa cells, and elevated expression of the senescence marker Cdkn1a and senescence-associated secretory phenotype factors. This atlas delineates the cellular and molecular hallmarks of mouse ovarian aging and ovary-specific senescent cells, providing a resource for understanding the mechanisms underlying the estropausal transition.

Keywords:  aging; cellular senescence; estropausal transition; ovary; single-cell RNA-seq

DOI:  https://doi.org/10.1073/pnas.2600323123