bims-mimead Biomed News
on Adipose tissue and metabolic disease
Issue of 2025–04–13
eleven papers selected by
Rachel M. Handy, University of Guelph
  1. Effect of Marked Weight Loss on Adipose Tissue Biology in People With Obesity and Type 2 Diabetes.
  2. Revisiting insulin-stimulated hydrogen peroxide dynamics reveals a cytosolic reductive shift in skeletal muscle.
  3. Histone chaperone HIRA facilitates transcription elongation to regulate insulin sensitivity and obesity-associated adipose expansion.
  4. Preadipocyte IL-13/IL-13Rα1 signaling regulates beige adipogenesis through modulation of PPARγ activity.
  5. GLP-1-mediated targeting of inflammation corrects obesogenic memory in male mice.
  6. Adipocyte size distribution: Mathematical model of a tissue property.
  7. NK cell-derived IFNγ mobilizes free fatty acids from adipose tissue to promote early B cell activation during viral infection.
  8. Estradiol (E2) concentration shapes the chromatin binding landscape of estrogen receptor alpha.
  9. Tirzepatide did not impact metabolic adaptation in people with obesity, but increased fat oxidation.
  10. Human proteome distribution atlas for tissue-specific plasma proteome dynamics.
  11. Miro1- a key player in β-cell function and mitochondrial dynamics under diabetes mellitus.
  1. Diabetes Care. 2025 Apr 10. pii: dc242739. [Epub ahead of print]
    Effect of Marked Weight Loss on Adipose Tissue Biology in People With Obesity and Type 2 Diabetes.
    Dmitri Samovski, Gordon I Smith, Hector Palacios, Terri Pietka, Anja Fuchs, Gary J Patti, Allah Nawaz, C Ronald Kahn, Samuel Klein.
       OBJECTIVE: Weight loss improves insulin sensitivity in people with obesity and type 2 diabetes. However, the mechanisms responsible for this effect are unclear. We hypothesized that alterations in adipose tissue biology and adipose tissue-related factors in plasma are involved in mediating the systemic metabolic benefits of weight loss.
    RESEARCH DESIGN AND METHODS: We evaluated blood and adipose tissue samples obtained from 10 adults with obesity and type 2 diabetes before and after marked (16-20%) weight loss and >50% increase in whole-body insulin sensitivity, assessed by using the hyperinsulinemic-euglycemic clamp procedure.
    RESULTS: Weight loss 1) decreased adipose tissue expression of genes related to extracellular matrix remodeling; 2) decreased adipose tissue expression of SERPINE 1, which encodes plasminogen activator inhibitor 1 (PAI-1); 3) did not decrease adipose tissue immune cell content or expression of genes involved in inflammation; 4) decreased adipose tissue ceramide content; 5) decreased plasma PAI-1 and leptin concentrations and increased plasma high-molecular weight (HMW) adiponectin; and 6) decreased plasma small extracellular vesicle (sEV) concentration and the sEV content of microRNAs proposed to inhibit insulin action, and completely reversed the inhibitory effect of plasma sEVs on insulin signaling in myotubes.
    CONCLUSIONS: These findings suggest that weight loss increases insulin sensitivity in people with obesity and type 2 diabetes by modifying adipose tissue biology, with concomitant alterations in circulating PAI-1, leptin, HMW adiponectin, and sEV microRNAs.
    DOI:  https://doi.org/10.2337/dc24-2739
  2. Redox Biol. 2025 Mar 25. pii: S2213-2317(25)00120-X. [Epub ahead of print]82 103607
    Revisiting insulin-stimulated hydrogen peroxide dynamics reveals a cytosolic reductive shift in skeletal muscle.
    Carlos Henríquez-Olguín, Samantha Gallero, Anita Reddy, Kaspar W Persson, Farina L Schlabs, Christian T Voldstedlund, Gintare Valentinaviciute, Roberto Meneses-Valdés, Casper M Sigvardsen, Bente Kiens, Edward T Chouchani, Erik A Richter, Thomas E Jensen.
      The intracellular redox state is crucial for insulin responses in peripheral tissues. Despite the longstanding belief that insulin signaling increases hydrogen peroxide (H2O2) production leading to reversible oxidation of cysteine thiols, evidence is inconsistent and rarely involves human tissues. In this study, we systematically investigated insulin-dependent changes in subcellular H2O2 levels and reversible cysteine modifications across mouse and human skeletal muscle models. Utilizing advanced redox tools-including genetically encoded H2O2 sensors and non-reducing immunoblotting-we consistently observed no increase in subcellular H2O2 levels following insulin stimulation. Instead, stoichiometric cysteine proteome analyses revealed a selective pro-reductive shift in cysteine modifications affecting insulin transduction related proteins, including Cys179 on GSK3β and Cys416 on Ras and Rab Interactor 2 (RIN2). Our findings challenge the prevailing notion that insulin promotes H2O2 generation in skeletal muscle and suggest that an insulin-stimulated pro-reductive shift modulates certain aspects of insulin signal transduction.
    DOI:  https://doi.org/10.1016/j.redox.2025.103607
  3. bioRxiv. 2025 Mar 25. pii: 2025.03.21.644577. [Epub ahead of print]
    Histone chaperone HIRA facilitates transcription elongation to regulate insulin sensitivity and obesity-associated adipose expansion.
    Danyang Wan, Ji-Eun Lee, Young-Kwon Park, Susanna Maisto, Christabelle Agyapong, Keiko Ozato, Oksana Gavrilova, Kai Ge.
      Adipose tissue is essential for maintaining glucose and lipid homeostasis in mammals. The histone chaperone HIRA has been reported to play a lineage- and stage-selective role during development. However, its role in adipose tissue development and function as well as its working mechanism remain unknown. Here we show that tissue-specific knockout of histone chaperone HIRA in mice impairs insulin sensitivity and alleviates adipose tissue expansion during high-fat diet-induced obesity, but only moderately affects embryonic development of adipose tissue. Mechanistically, HIRA is selectively required for expression of genes critical for insulin response and lipogenesis, rather than adipogenesis, in adipose tissue. By acute depletion of HIRA protein and by mapping HIRA genomic localization in adipocytes, we demonstrate that HIRA binds to promoters and enhancers of insulin response and lipogenesis genes and regulates their expression by facilitating transcription elongation. Our findings not only identify HIRA as an epigenomic regulator of insulin sensitivity, lipogenesis, and obesity-associated adipose expansion, but also reveal a novel mechanism by which HIRA regulates transcription.
    Bullet points: HIRA depletion reduces expression of insulin response and lipogenesis genes in adipose tissueHIRA depletion alleviates adipose tissue expansion during high-fat diet-induced obesityHIRA targets insulin response and lipogenesis genes in adipocytesAcute depletion of HIRA impairs transcription elongation on target genes.
    DOI:  https://doi.org/10.1101/2025.03.21.644577
  4. J Clin Invest. 2025 Apr 08. pii: e169152. [Epub ahead of print]
    Preadipocyte IL-13/IL-13Rα1 signaling regulates beige adipogenesis through modulation of PPARγ activity.
    Alexandra R Yesian, Mayer M Chalom, Nelson H Knudsen, Alec L Hyde, Jean Personnaz, Hyunjii Cho, Yae-Huei Liou, Kyle A Starost, Chia-Wei Lee, Dong-Yan Tsai, Hsing-Wei Ho, Jr-Shiuan Lin, Jun Li, Frank B Hu, Alexander S Banks, Chih-Hao Lee.
      Type 2 innate lymphoid cells (ILC2) regulate the proliferation of preadipocytes that give rise to beige adipocytes. Whether and how ILC2 downstream Th2 cytokines control beige adipogenesis remain unclear. We employed cell systems and genetic models to examine the mechanism through which interleukin-13 (IL-13), an ILC2-derived Th2 cytokine, controls beige adipocyte differentiation. IL-13 priming in preadipocytes drives beige adipogenesis by upregulating beige-promoting metabolic programs, including mitochondrial oxidative metabolism and PPARγ-related pathways. The latter is mediated by increased expression and activity of PPARγ through IL-13 receptor α1 (IL-13Rα1) downstream effectors, STAT6 and p38 MAPK, respectively. Il13 knockout (Il13KO) or preadipocyte Il13ra1 knockout (Il13ra1KO) mice are refractory to cold- or β-3 adrenergic agonist-induced beiging in inguinal white adipose tissue, whereas Il4 knockout mice show no defects in beige adipogenesis. Il13KO and Il13ra1KO mouse models exhibit increased body weight/fat mass and dysregulated glucose metabolism but have a mild cold intolerant phenotype, likely due to their intact brown adipocyte recruitment. We also find that genetic variants of human IL13RA1 are associated with body mass index and type 2 diabetes. These results suggest that IL-13 signaling-regulated beige adipocyte function may play a predominant role in modulating metabolic homeostasis rather than in thermoregulation.
    Keywords:  Adipose tissue; Cell biology; Glucose metabolism; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI169152
  5. Diabetes. 2025 Apr 11. pii: db241071. [Epub ahead of print]
    GLP-1-mediated targeting of inflammation corrects obesogenic memory in male mice.
    Stéphane Léon, Julie Benoit, Samantha Clark, Philippe Zizzari, Bin Yang, Isabelle Dugail, Fatiha Merabtene, Karine Clement, Louise Eygret, Nathalie Dupuy, Jean-Christophe Delpech, Moïra Rossitto, Matthias Mack, Thierry Lesté-Lasserre, Brian Finan, Daniela Cota, Carmelo Quarta.
      Obesity-induced biological changes often persist after weight loss and are difficult to reverse, a phenomenon known as 'obesogenic memory'. This enduring effect is associated with metabolic inflammation, particularly in adipose tissue. In this study, we characterise a mouse model of obesogenic memory and evaluate the efficacy of the unimolecular conjugate GLP-1/Dexa, which selectively and safely delivers the anti-inflammatory drug dexamethasone to GLP-1 receptor (GLP-1R)-expressing cells. We document that this precision pharmacological approach outperforms treatment with GLP-1 or dexamethasone alone, significantly reducing body weight, food intake, adiposity and markers of adipose tissue inflammation in male mice with obesogenic memory. In addition, we identify the CCR2/CCL2 inflammatory pathway as an important mediator of glucose intolerance and adipose tissue inflammation associated with obesogenic memory. Our findings suggest that targeting inflammation via GLP-1R signalling may be a promising therapeutic strategy to alleviate obesogenic memory and improve the long-term clinical management of metabolic diseases.
    DOI:  https://doi.org/10.2337/db24-1071
  6. Math Biosci. 2025 Apr 09. pii: S0025-5564(25)00059-8. [Epub ahead of print] 109433
    Adipocyte size distribution: Mathematical model of a tissue property.
    Aloïs Dauger, Hedi Soula, Chloe Audebert.
      White adipose tissue is in charge of storing excess of energy in form of lipids. The main cells involved in the process - the adipocytes - adapt their sizes up to 200μm of diameter to accomodate the storage. In addition, their size distribution is bimodal. A previous mathematical model based on lipid fluxes provided size distribution bimodality. However, the variability within cell population was not fully explored. In the previous model, bimodality was considered a consequence of a bistable distribution of cell sizes at equilibrium: meaning that adipocytes had to have two stable sizes. In this study, we first provide a computational method to evaluate equilbria taking into account cells variabilty. Our results suggest that this variability is key to provide realistic distributions. In addition, we show that size distribution with a proportion of cell with bi-stable profile are not in good agreement with the measurements. We find that mono-stable (i.e. one equilibrium size) profile within the adipose tissue is enough to explain bimodality and to reproduces qualitatively size distribution data. We thus show that bimodality of adipose tissue size distribution does not arise directly from cellular bi-stability but rather from a tissue property.
    Keywords:  Adipocytes; Cell variability; Obesity; Size distribution
    DOI:  https://doi.org/10.1016/j.mbs.2025.109433
  7. Nat Metab. 2025 Apr 11.
    NK cell-derived IFNγ mobilizes free fatty acids from adipose tissue to promote early B cell activation during viral infection.
    Mia Krapić, Inga Kavazović, Sanja Mikašinović, Karlo Mladenić, Fran Krstanović, Gönül Seyhan, Sabine Helmrath, Elena Camerini, Ilija Brizić, Fleur S Peters, Marc Schmidt-Supprian, Bojan Polić, Tamara Turk Wensveen, Felix M Wensveen.
      The immune system plays a major role in the regulation of adipose tissue homeostasis. Viral infection often drives fat loss, but how and why this happens is unclear. Here, we show that visceral adipose tissue transiently decreases adiposity following viral infection. Upon pathogen encounter, adipose tissue upregulates surface expression of ligands for activating receptors on natural killer cells, which drives IFNγ secretion. This cytokine directly stimulates adipocytes to shift their balance from lipogenesis to lipolysis, which leads to release of lipids in circulation, most notably of free fatty acids. The free fatty acid oleic acid stimulates early-activated B cells by promoting oxidative phosphorylation. Oleic acid promoted expression of co-stimulatory B7 molecules on B cells and promoted their ability to prime CD8+ T cells. Inhibiting lipid uptake by activated B cells impaired CD8+ T cell responses, causing an increase of viral replication in vivo. Our findings uncover a previously unappreciated mechanism of metabolic adaptation to infection and provide a better understanding of the interactions between immune cells and adipose tissue in response to inflammation.
    DOI:  https://doi.org/10.1038/s42255-025-01273-2
  8. J Biol Chem. 2025 Apr 09. pii: S0021-9258(25)00348-5. [Epub ahead of print] 108499
    Estradiol (E2) concentration shapes the chromatin binding landscape of estrogen receptor alpha.
    Amy L Han, Kiran Vinod-Paul, Satyanarayan Rao, Heather M Brechbuhl, Carol A Sartorius, Srinivas Ramachandran, Peter Kabos.
      How transcription factors (TF) selectively occupy a minute subset of their binding sites from a sizeable pool of putative sites in large mammalian genomes remains an important unanswered question. In part, nucleosomes help by creating formidable barriers to TF binding. TF concentration itself plays a crucial role in the competition between TFs and nucleosomes. With nuclear receptors, the ligand adds another layer of complexity. Estrogen receptor alpha (ER) is a classic example where its main ligand estradiol (E2) can modulate ER binding on chromatin. Here, we show a shift in ER binding as a function of E2 concentration. As E2 concentration increases by two orders of magnitude, ER levels decrease, and ER binding localizes to promoter-distal sites with strong ER motifs. At low E2 levels, abundant levels of ER are present in the nucleus, and ER binding occurs mostly at sites without a canonical ER binding motif, in cooperation with other TFs like STAT1. We propose that E2's effect on ER activity plays a major role in defining genome-wide ER binding profiles. Thus, variations in E2 concentrations in ER-positive breast tumors could be a significant factor driving heterogeneity in tumor phenotype, treatment response, and potentially drug resistance.
    Keywords:  Breast cancer; STAT1; chromatin biology; estradiol; estrogen receptor
    DOI:  https://doi.org/10.1016/j.jbc.2025.108499
  9. Cell Metab. 2025 Apr 03. pii: S1550-4131(25)00114-7. [Epub ahead of print]
    Tirzepatide did not impact metabolic adaptation in people with obesity, but increased fat oxidation.
    Eric Ravussin, Guillermo Sanchez-Delgado, Corby K Martin, Robbie A Beyl, Frank L Greenway, Libbey S O'Farrell, William C Roell, Hui-Rong Qian, Jing Li, Hiroshi Nishiyama, Axel Haupt, Edward J Pratt, Shweta Urva, Zvonko Milicevic, Tamer Coskun.
      Tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, promoted significant body weight reduction in the phase 3 clinical trials. We conducted a preclinical study and a phase 1 clinical trial (NCT04081337) to understand potential mechanisms mediating tirzepatide-induced weight loss in mice and people with obesity. In calorie-restricted, obese mice, chronic treatment with tirzepatide reduced the drop in energy expenditure that occurred in vehicle-treated and pair-fed mice, indicating that tirzepatide attenuated metabolic adaptation. Respiratory exchange ratio also decreased in tirzepatide-treated mice, indicating increased fat oxidation. In the clinical trial, tirzepatide appeared to have no impact on metabolic adaptation but led to increased fat oxidation and reductions in appetite and calorie intake during an ad libitum test meal (vs. placebo). This is the first study to provide insights into the mechanisms of action of tirzepatide on weight loss with respect to calorie intake, energy expenditure, and macronutrient utilization.
    Keywords:  GIP; GLP-1; adaptive thermogenesis; energy balance; energy expenditure; energy intake; fat oxidation; obesity; sleeping metabolic rate; weight loss
    DOI:  https://doi.org/10.1016/j.cmet.2025.03.011
  10. Cell. 2025 Apr 04. pii: S0092-8674(25)00286-7. [Epub ahead of print]
    Human proteome distribution atlas for tissue-specific plasma proteome dynamics.
    Erik Malmström, Lars Malmström, Simon Hauri, Tirthankar Mohanty, Aaron Scott, Christofer Karlsson, Carlos Gueto-Tettay, Emma Åhrman, Shahab Nozohoor, Bobby Tingstedt, Sara Regner, Peter Elfving, Leif Bjermer, Andreas Forsvall, Alexander Doyle, Mattias Magnusson, Ingrid Hedenfalk, Päivi Kannisto, Christian Brandt, Emma Nilsson, Lars B Dahlin, Johan Malm, Adam Linder, Emma Niméus, Johan Malmström.
      The plasma proteome is maintained by the influx and efflux of proteins from surrounding organs and cells. To quantify the extent to which different organs and cells impact the plasma proteome in healthy and diseased conditions, we developed a mass-spectrometry-based proteomics strategy to infer the tissue origin of proteins detected in human plasma. We first constructed an extensive human proteome atlas from 18 vascularized organs and the 8 most abundant cell types in blood. The atlas was interfaced with previous RNA and protein atlases to objectively define proteome-wide protein-organ associations to infer the origin and enable the reproducible quantification of organ-specific proteins in plasma. We demonstrate that the resource can determine disease-specific quantitative changes of organ-enriched protein panels in six separate patient cohorts, including sepsis, pancreatitis, and myocardial injury. The strategy can be extended to other diseases to advance our understanding of the processes contributing to plasma proteome dynamics.
    Keywords:  biomarkers; human proteome atlas; mass spectrometry; organ dysfunction; plasma proteome; plasma proteome dynamics; tissue damage; tissue origin; tissue protein
    DOI:  https://doi.org/10.1016/j.cell.2025.03.013
  11. Mitochondrion. 2025 Apr 07. pii: S1567-7249(25)00036-4. [Epub ahead of print] 102039
    Miro1- a key player in β-cell function and mitochondrial dynamics under diabetes mellitus.
    Srikanth Kavyashree, Kannan Harithpriya, Kunka Mohanram Ramkumar.
      Mitochondrial health is crucial for the survival and function of β-cells, preserving glucose homeostasis and effective insulin production. Miro1, a mitochondrial Rho GTPase1 protein, plays an essential role in maintaining thequality of mitochondria by regulating calcium homeostasis and mitophagy. In this review, we aim to explore the dysfunction of Miro1 in type 2 diabetes mellitus (T2DM) and its contribution to impaired Ca2+ signaling, which increases oxidative stress in β-cells. This dysfunction is the hallmark of T2DM pathogenesis, leading to insufficient insulin production and poor glycemic control. Additionally, we discuss the role of Miro1 in modulating insulin secretion and inflammation, highlighting its effect on modulating key signaling cascades in β-cells. Altogether, enhancing Miro1 function and activity could alleviate mitochondrial dysfunction, reducing oxidative stress-mediated damage, and improving pancreatic β-cell survival. Targeting Miro1 by Small molecules or gene-editing approaches could provide effective strategies for restoring cell function and insulin secretion in diabetic individuals. Exploring the deeper knowledge of Miro1 functions and interactions could lead to novel therapeutic advances in T2DM management.
    Keywords:  Diabetes Mellitus; Miro1; Mitochondrial Dynamics; RHOT1; β-cells
    DOI:  https://doi.org/10.1016/j.mito.2025.102039
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