bims-mimead 2025-10-12 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–10–12
ten papers selected by
Rachel M. Handy, University of Guelph

Adipocyte Heparan Sulfate Determines Type 2 Diabetes Susceptibility in Mice via FGF1-Mediated Glucose Regulation.
Platelets impair the resolution of inflammation in atherosclerotic plaques in insulin-resistant mice after lipid-lowering.
Influence of obesity and IL-6 on human postprandial amino acid and protein metabolism at whole-body and tissue level.
Adipocyte-specific Mlkl knockout mitigates obesity-induced metabolic dysfunction by enhancing mitochondrial functions.
Muscle and liver insulin resistance are associated with distinct plasma protein profiles; data from the DiOGenes trial.
Early-life ketone body signalling promotes beige fat biogenesis through changes in histone acetylome and β-hydroxybutyrylome.
Adipocyte FMO3-derived TMAO induces WAT dysfunction and metabolic disorders by promoting inflammasome activation in ageing.
Antioxidant, Bioenergetic, and Metabolic Effects of Novel Mitochondria-Targeted Estrogens.
Effect of sweeteners and sweetness enhancers on weight management and gut microbiota composition in individuals with overweight or obesity: the SWEET study.
TERT expression attenuates metabolic disorders in obese mice by promoting adipose stem and progenitor cell expansion and differentiation.

Mol Metab. 2025 Oct 08. pii: S2212-8778(25)00174-7. [Epub ahead of print] 102267

Adipocyte Heparan Sulfate Determines Type 2 Diabetes Susceptibility in Mice via FGF1-Mediated Glucose Regulation.

Chung-Jui Yu, Ariane R Pessentheiner, Sihao Liu, Sarah Wax, Marissa L Maciej-Hulme, Chelsea D Painter, Bastian Ramms, Daniel R Sandoval, Anthony Quach, Natalie DeForest, G Michelle Ducasa, Chiara Tognaccini, Caroline Labib, Norah Al-Azzam, Friederike Haumann, Greg Trieger, Patrick Secrest, Amit Majithia, Aaron C Petrey, Kamil Godula, Annette R Atkins, Michael Downes, Ronald M Evans, Philip L S M Gordts.

Obesity is the principal driver of insulin resistance, and lipodystrophy is also linked with insulin resistance, emphasizing the vital role of adipose tissue in glucose homeostasis. The quality of adipose tissue expansion is a critical determinant of insulin resistance predisposition, with individuals suffering from metabolic unhealthy adipose expansion exhibiting greater risk. Adipocytes are pivotal in orchestrating metabolic adjustments in response to nutrient intake and cell intrinsic factors that positively regulate these adjustments are key to prevent Type-2 diabetes. Employing unique genetic mouse models, we established the critical involvement of heparan sulfate (HS), a fundamental element of the adipocyte glycocalyx, in upholding glucose homeostasis during dietary stress. Genetic models that compromise adipocyte HS accelerate the development of high-fat diet-induced hyperglycemia and insulin resistance, independent of weight gain. Mechanistically, we show that perturbations in adipocyte HS disrupts endogenous FGF1 signaling, a key nutrient-sensitive effector. Furthermore, compromising adipocyte HS composition detrimentally impacts FGF1-FGFR1-mediated endocrinization, with no significant improvement observed in glucose homeostasis. Our data establish adipocyte HS composition as a determinant of Type 2 diabetes susceptibility and the critical dependency of the endogenous adipocyte FGF1 metabolic pathway on HS.

DOI: https://doi.org/10.1016/j.molmet.2025.102267
JCI Insight. 2025 Oct 09. pii: e193593. [Epub ahead of print]

Platelets impair the resolution of inflammation in atherosclerotic plaques in insulin-resistant mice after lipid-lowering.

Maria Laskou, Sofie Delbare, Michael Gildea, Ada Weinstock, Vitor De Moura Virginio, Maxwell La Forest, Franziska Krautter, Casey Donahoe, Letizia Amadori, Natalia Eberhardt, Tessa J Barrett, Chiara Giannarelli, Jeffrey S Berger, Edward A Fisher.

  Insulin resistance impairs benefits of lipid-lowering treatment as evidenced by higher cardiovascular risk in individuals with type 2 diabetes versus those without. Because platelet activity is higher in insulin-resistant patients and promotes atherosclerosis progression, we questioned whether platelets impair inflammation resolution in plaques during lipid-lowering. In mice with obesity and insulin resistance, we induced advanced plaques, then implemented lipid-lowering to promote atherosclerotic plaque inflammation-resolution. Concurrently, mice were treated with either platelet-depleting or control antibodies for 3 weeks. Platelet activation and insulin resistance were unaffected by lipid-lowering. Both antibody-treated groups showed reduced plaque macrophages, but plaque cellular and structural composition differed. In platelet-depleted mice, scRNA seq revealed dampened inflammatory gene expression in plaque macrophages and an expansion of a subset of Fcgr4+ macrophages having features of inflammation-resolving, phagocytic cells. Necrotic core size was smaller and collagen content greater, resembling stable human plaques. Consistent with the mouse results, clinical data showed that patients with lower platelet counts had decreased pro-inflammatory signaling pathways in circulating non-classical monocytes after lipid-lowering. These findings highlight that platelets hinder inflammation-resolution in atherosclerosis during lipid-lowering treatment. Identifying novel platelet-targeted therapies following lipid-lowering treatment in individuals with insulin resistance may be a promising therapeutic approach to promote atherosclerotic plaque inflammation-resolution.

Keywords:  Atherosclerosis; Cardiology; Diabetes; Inflammation; Platelets; Vascular biology

DOI:  https://doi.org/10.1172/jci.insight.193593
J Clin Endocrinol Metab. 2025 Oct 09. pii: dgaf547. [Epub ahead of print]

Influence of obesity and IL-6 on human postprandial amino acid and protein metabolism at whole-body and tissue level.

Trinh Beckey, Signe Johanne Rasmussen, Mathilde Ehnhuus Brøgger-Jensen, Ana Rita Albuquerque de Almeida Tavanez, Anton Lund, Alexandra Vassilieva, Susanne Janum, Ulrik Winning Iepsen, Kirsten Møller, Bente Klarlund Pedersen, Gerrit Van Hall, Helga Ellingsgaard.

   CONTEXT: Sarcopenic obesity, the loss of muscle mass and function in people with obesity, may result from altered muscle protein synthesis and degradation. Chronic low-grade inflammation, particularly interleukin-6 (IL-6) has been implicated.
OBJECTIVE: To assess the role of IL-6 in protein and amino acid metabolism during fasting and postprandial states in humans with healthy weight or obesity at whole-body, skeletal muscle and subcutaneous adipose tissue levels.
METHODS: In this placebo-controlled, non-randomized, participant-blinded study, 12 men with healthy weight and 12 men with obesity received placebo (0.9% saline) or three weeks of IL-6 receptor (IL-6R) blockade with tocilizumab. Isotope dilution/incorporation techniques and arteriovenous balance measurements were applied in fasted and postprandial states. The trial was originally designed to examine IL-6 effects on fat storage (reported previously). Here, we present pre-specified exploratory outcomes on amino acid and protein turnover.
RESULTS: Obesity was associated with reduced meal-induced muscle-protein gain driven by impaired suppression of muscle protein degradation, and with reduced appearance of amino acids from meals. In both groups, IL-6R blockade increased fasting and postprandial plasma amino acids, and reduced postprandial plasma protein synthesis without affecting skeletal muscle protein turnover. In the healthy weight group, it also increased amino acid appearance from the meal and postprandial phenylalanine oxidation.
CONCLUSION: Obesity impairs meal-induced muscle-protein gain, through insufficient suppression of protein degradation. Basal IL-6 activity does not regulate muscle protein turnover but influences amino acid metabolism and protein synthesis in extra-muscular tissues.

Keywords:  Adipose Tissue; Meal; Protein Turnover; Skeletal Muscle; Stable Isotopes; Tocilizumab

DOI:  https://doi.org/10.1210/clinem/dgaf547
Cell Death Dis. 2025 Oct 06. 16(1): 683

Adipocyte-specific Mlkl knockout mitigates obesity-induced metabolic dysfunction by enhancing mitochondrial functions.

Juliette Tokgozoglu, Valeria Pistorio, Mirko Minini, Pierre-Antoine Soret, Virginie Steunou, Jean-Louis Delaunay, Julien Castel, Serge Luquet, Ivan Nemazanyy, Carine Beaupère, Laetitia Dinard, Tatiana Ledent, Aurore L'honoré, Sara Lemoinne, Chantal Housset, Philippe Lesnik, Vlad Ratziu, Bruno Fève, Tounsia Aït-Slimane, Axelle Cadoret, Nicolas Chignard, Jérémie Gautheron.

Obesity is a global epidemic characterized by chronic low-grade inflammation and metabolic dysfunction, with adipose tissue playing a pivotal role in these processes. The mixed lineage kinase domain-like pseudokinase (MLKL) is a critical mediator of necroptosis but also exhibits noncanonical roles in metabolic regulation. This study aimed to investigate the adipocyte-specific functions of MLKL in obesity. Using adipocyte-specific Mlkl knockout (MlklAdi-KO) mice, we observed reduced susceptibility to high-fat diet (HFD)-induced obesity, enhanced glucose tolerance, and improved insulin sensitivity. MlklAdi-KO mice showed elevated energy expenditure independent of changes in food intake or locomotor activity, correlating with increased mitochondrial function and reduced lipid accumulation in white adipose tissue (WAT). Transcriptomic analyses of WAT revealed significant modulation of pathways linked to oxidative phosphorylation, inflammation, and lipid metabolism. Furthermore, metabolomic profiling highlighted reductions in TCA cycle intermediates, acylcarnitines, and pro-inflammatory amino acids in MlklAdi-KO mice under HFD conditions. These findings were accompanied by improved hepatic lipid profiles and decreased steatosis, underscoring systemic benefits of adipocyte-specific Mlkl deletion. Mechanistically, Mlkl deficiency altered adipocyte differentiation. These results position MLKL as a promising therapeutic target for obesity and related metabolic disorders, emphasizing the need for future studies using conditional knockout and overexpression models to explore its cell-specific and noncanonical functions in metabolic regulation.

DOI: https://doi.org/10.1038/s41419-025-08004-1
J Clin Endocrinol Metab. 2025 Oct 10. pii: dgaf562. [Epub ahead of print]

Muscle and liver insulin resistance are associated with distinct plasma protein profiles; data from the DiOGenes trial.

Esther J Kemper, Ellen E Blaak, Michiel E Adriaens, Ruth C R Meex.

   CONTEXT: Insulin resistance (IR) can develop in multiple organs, representing distinct etiologies towards cardiometabolic disease.
OBJECTIVE: This study aimed to investigate which proteins and pathways are specific for liver IR or muscle IR in individuals with overweight or obesity of the Diet, Obesity, and Genes (DiOGenes) cohort (n = 535) (NCT00390637, ClinicalTrials.gov).
METHODS: First, independent associations between muscle and liver IR and protein abundance levels were assessed. In the analysis we corrected for study centre, sex, BMI and age, whereby the analyses on liver IR were adjusted for muscle IR and vice versa. Differentially abundant proteins were then subjected to pathway enrichment analysis.
RESULTS: Muscle IR was associated with 160 proteins and liver IR was associated with 81 proteins. Of these, 12 were shared between both forms of IR. Pathway enrichment analysis identified 51 enriched pathways for muscle IR, characterized by a strong inflammatory profile, including chemokine signalling, IL-6 signalling and complement system related pathways. In contrast, liver IR was associated with 11 enriched pathways, primarily related to the complement system.
CONCLUSION: Understanding the processes underlying these distinct IR phenotypes could inform the development of personalized prevention strategies.

Keywords:  Obesity; liver; pathway enrichment analysis; proteomics; skeletal muscle; tissue-specific insulin resistance

DOI:  https://doi.org/10.1210/clinem/dgaf562
Nat Metab. 2025 Oct 09.

Early-life ketone body signalling promotes beige fat biogenesis through changes in histone acetylome and β-hydroxybutyrylome.

Chung-Lin Jiang, Pei-Hsiang Lai, Po-Cheng Yang, Chia-Jung Lien, Hsueh-Ping Catherine Chu, Jian-Da Lin, Sung-Jan Lin, I-Shing Yu, Fu-Jung Lin.

Infants undergo distinct ketogenesis during the preweaning period, yet its physiological implications remain unclear. Here, we show that preweaning ketosis promotes beige fat biogenesis and improves health outcomes in adulthood. Loss of ketogenesis in neonatal mice by early weaning or ablation of Hmgcs2 hinders beige adipogenesis, subsequently exacerbating metabolic dysregulation in high-fat diet-induced obesity. Enhanced ketogenesis during lactation through exogenous ketone supplements enhances energy expenditure, beige fat formation, and mitochondrial biogenesis and respiration. Using single-cell RNA sequencing, we identified a subset of β-hydroxybutyrate-responsive adipocyte progenitor cells (APCs) expressing Cd81 that showed high beige adipogenic potential. Enhanced ketogenesis promotes the recruitment of beige APCs and their differentiation into beige adipocytes. Mechanistically, ketogenesis-derived βHB induces a switch in the histone acetylome and β-hydroxybutyrylome for transcriptional activation of beige fat biogenesis genes. Notably, enhanced ketogenesis during lactation alleviates adverse metabolic effects predisposed by parental obesity. Our study highlights that targeting preweaning ketosis to drive beige adipogenesis may offer a therapeutic approach to combat obesity and metabolic diseases in adulthood.

DOI: https://doi.org/10.1038/s42255-025-01378-8
Nat Commun. 2025 Oct 06. 16(1): 8873

Adipocyte FMO3-derived TMAO induces WAT dysfunction and metabolic disorders by promoting inflammasome activation in ageing.

Thashma Ganapathy, Juntao Yuan, Melody Yuen-Man Ho, Kelvin Ka-Lok Wu, Md Moinul Hoque, Baomin Wang, Xiaomu Li, Kai Wang, Martin Wabitsch, Xuejia Feng, Yongxia Niu, Kekao Long, Qizhou Lian, Yuyan Zhu, Kenneth King-Yip Cheng.

Trimethylamine N-oxide (TMAO) contributes to cardio-metabolic diseases, with hepatic flavin-containing monooxygenase 3 (FMO3) recognized as its primary source. Here we demonstrate that elevated adipocyte FMO3 and its derived TMAO trigger white adipose tissue (WAT) dysfunction and its related metabolic disorders in ageing. In adipocytes, ageing or p53 activation upregulates FMO3 and TMAO levels. Adipocyte-specific ablation of FMO3 attenuates TMAO accumulation in WAT and circulation, leading to enhanced glucose metabolism and energy and lipid homeostasis in ageing and obese mice. These improvements are associated with reduced senescence, fibrosis and inflammation in WAT. Proteomics analysis identified TMAO-interacting proteins involved in inflammasome activation in adipocytes and macrophages. Mechanistically, TMAO binds to the central inflammasome adaptor protein ASC, promoting caspase-1 activation and interleukin-1β production. Our findings uncover a pivotal role for adipocyte FMO3 in modulating TMAO production and WAT dysfunction by promoting inflammasome activation in ageing via an autocrine and paracrine manner.

DOI: https://doi.org/10.1038/s41467-025-63905-1
J Mol Endocrinol. 2025 Oct 09. pii: JME-25-0081. [Epub ahead of print]

Antioxidant, Bioenergetic, and Metabolic Effects of Novel Mitochondria-Targeted Estrogens.

Geovanni Alberto Ruiz-Romero, Johanna Bernáldez-Sarabia, Magdiel Orozco-Valdivia, Jessica Yazbel Romero-Rico, Pablo Garrido, Gonzalo Isaí Flores-Acosta, Alfredo Martínez, Carolina Álvarez-Delgado.

  Estrogens are steroid hormones that regulate antioxidant and mitochondrial bioenergetic metabolism in addition to activating nuclear genomic pathways. Concentrating these effects within the mitochondria is a novel strategy for ameliorating mitochondrial dysfunction, which is characteristic of cancer, metabolic, and neurodegenerative diseases. The use of synthetic mitochondria-targeted estrogens containing a triphenylphosphonium group may provide a basis for improving mitochondrial function in these conditions. Here, we evaluate the effects of two compounds, one derived from 17β-estradiol (mitoE2) and the other from 17α-ethinylestradiol (mitoEE2) on cell viability in MCF-7 and CCD-1112Sk cells. We further examine their influence on the activities of superoxide dismutase (MnSOD), citrate synthase (CS), cytochrome c oxidase (COX), and ATP synthase, as well as in the glycolytic reserve and cellular respiration. In both cellular models, cell viability assays indicated that MitoE2 was well tolerated below 500 nM, while MitoEE2 allowed treatments up to 100 nM for up to 24 hours. We found that the molecules act differently on enzymatic targets. Exposure of MCF-7 cells to mitoE2 resulted in reduced MnSOD activity. Pretreatment with MitoE2 or MitoEE2 restored the viability of MCF-7 cells exposed to H2O2-induced oxidative damage to levels comparable to untreated controls. Additionally, MitoEE2 increased the activities of CS and COX. Both mitochondria-targeted estrogens increased glycolytic reserve and mitochondrial respiration, as determined by extracellular flux assays. Overall, these findings suggest that the antioxidant and bioenergetic effects observed encourage further investigation into their potential as therapeutic strategies for conditions linked to mitochondrial dysfunction.

Keywords:  antioxidant effects; estrogens; mitochondria-targeted estrogens; mitochondrial metabolism; oxygen consumption rate

DOI:  https://doi.org/10.1530/JME-25-0081
Nat Metab. 2025 Oct 07.

Effect of sweeteners and sweetness enhancers on weight management and gut microbiota composition in individuals with overweight or obesity: the SWEET study.

Michelle D Pang, Louise Kjølbæk, Jacco J A J Bastings, Sabina Stoffer Hjorth Andersen, Alexander Umanets, Mônica Maurer Sost, Santiago Navas-Carretero, Kyriakos Reppas, Graham Finlayson, Charo E Hodgkins, Marta Del Álamo, Tony Lam, Hariklia Moshoyiannis, Edith J M Feskens, Tanja C M Adam, Gijs H Goossens, Jason C G Halford, Joanne A Harrold, Yannis Manios, J Alfredo Martinez, Ellen E Blaak, Anne Raben.

Consumption of sweeteners and sweetness enhancers (S&SEs) is a popular strategy to reduce sugar intake, but the role of S&SEs in body weight regulation and gut microbiota composition remains debated. Here, we show that S&SEs in a healthy diet support weight loss maintenance and beneficial gut microbiota shifts in adults with overweight or obesity. In this multi-centre, randomized, controlled trial, we included 341 adults and 38 children with overweight or obesity. Adults followed a 2-month low-energy diet for ≥5% weight loss, followed by a 10-month healthy ad libitum diet with <10% energy from sugars. One group replaced sugar-rich products with S&SE products (S&SEs group), while the other did not (sugar group). Primary outcomes included changes in body weight and gut microbiota composition at 1 year. Secondary outcomes included changes in cardiometabolic parameters. The S&SEs group, compared to the sugar group, maintained greater weight loss at 1 year (1.6 ± 0.7 kg, P = 0.029) and exhibited distinct gut microbiota shifts, with increased short-chain fatty acid and methane-producing taxa (q ≤ 0.05). No significant differences were observed in cardiometabolic markers or in children. Overall, our findings indicate that prolonged consumption of S&SEs in a healthy diet is a safe strategy for obesity management. ClinicalTrial.gov identifier: NCT04226911 .

DOI: https://doi.org/10.1038/s42255-025-01381-z
Mol Metab. 2025 Oct 03. pii: S2212-8778(25)00169-3. [Epub ahead of print] 102262

TERT expression attenuates metabolic disorders in obese mice by promoting adipose stem and progenitor cell expansion and differentiation.

Laura Braud, Manuel Bernabe, Julien Vernerey, Antonio M A Miranda, Andrea Dominguez, Dmitri Churikov, Manon Richaud, Frédéric Jourquin, Liam Mc Allan, Christophe Lachaud, Jesus Gil, Will Scott, Vincent Géli.

   BACKGROUND AND AIMS: Adipose tissue (AT) senescence, induced by obesity or aging, leads to a reduced capacity for tissue remodeling and a chronic pro-inflammatory state, which leads to the onset of metabolic pathologies. Cellular senescence is triggered by various stresses, in particular excessive shortening of telomeres, which activates the p21 pathway and leads to the arrest of the cell cycle. We used the mouse model p21+/Tert expressing TERT from the Cdkn1a locus to investigate whether counteracting telomere shortening by telomerase (TERT) specifically in pre-senescent cells could improve obesity-induced metabolic disorders.
RESULTS: Our study demonstrates that conditional expression of TERT reduces insulin-resistance and glucose intolerance associated with obesity. In AT, this is accompanied by a decrease in the number of senescent p21-positive cells, very short telomeres, and oxidative DNA damage. Single nucleus RNA-seq data reveal TERT expression attenuates senescence induced by HFD in particular in adipose stem and progenitor cells (ASPC). We demonstrate that ASPC expansion and differentiation are promoted in p21+/Tert obese mice, thereby improving AT plasticity. Furthermore, we show that TERT expression enhances mitochondrial function and alleviates oxidative stress in ASPC. This process contributes to the AT hyperplasia with increased number of adipocytes which has been shown to have a protective effect against obesity-associated metabolic disorders CONCLUSIONS: These results underscore TERT's role in mitigating obesity-related metabolic dysfunction. Conditional TERT expression may therefore represent as a promising therapeutic strategy for obesity-associated metabolic disorders.

Keywords:  adipose-stem-cells; obesity; senescence; telomerase; telomeres

DOI:  https://doi.org/10.1016/j.molmet.2025.102262