bims-mimead 2025-05-25 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–05–25
ten papers selected by
Rachel M. Handy, University of Guelph

Sex- and depot-specific differences in cellular insulin responsiveness during adipose expansion.
Effect of acute exercise and exercise training on the ability of insulin to clear branched-chain amino acids from plasma in obesity and type 2 diabetes.
Serpina3c Mitigates Adipose Tissue Inflammation by Inhibiting the HIF1α-Mediated Endoplasmic Reticulum Overoxidation in Adipocytes.
Low Intensity Pulsed Ultrasounds Modulate Adipose Stem Cells Differentiation.
Exploring adipose tissue-derived extracellular vesicles in inter-organ crosstalk: Implications for metabolic regulation and adipose tissue function.
Unravelling cysteine-deficiency-associated rapid weight loss.
De novo serine biosynthesis is protective in mitochondrial disease.
Skeletal Muscle as a Mediator of Interorgan Crosstalk During Exercise: Implications for Aging and Obesity.
Succinate reduces biological activity and mitochondrial function of human adipose-derived stem cells.
Estrogen induces the alternative activation of macrophages through binding to estrogen receptor-alpha.

Life Sci. 2025 May 20. pii: S0024-3205(25)00378-9. [Epub ahead of print]375 123743

Sex- and depot-specific differences in cellular insulin responsiveness during adipose expansion.

Mathis Neuhaus, Karin G Stenkula.

   BACKGROUND: Adipose tissue distribution, metabolism, and expansion capacity exhibit notable sex- and depot-specific differences. Herein, we monitored adipocyte traits related to insulin responsiveness and glucose transport during adipose expansion in visceral and subcutaneous fat from male and female mice.
MATERIALS AND METHODS: Adipocytes were isolated from perigonadal and inguinal adipose tissue of chow-fed female and male C57Bl6/J mice and assessed for adipocyte size distribution using a coulter counter; glucose uptake and cytosolic volume were measured using glucose tracer assays. GLUT1, GLUT4, and IRS-1 protein levels were assessed by western blot. Pharmacological inhibition (BAY876) of GLUT1 and GLUT4 was used to resolve their respective contribution to cellular glucose transport.
KEY FINDINGS: Independent of adiposity or sex, visceral adipocytes were larger and displayed higher glucose transport, cytosolic volume, and GLUT4 levelsthan subcutaneous adipocytes. GLUT1 content was higher in subcutaneous than visceral adipocytes in both sexes. Pharmacological inhibition confirmed that GLUT1 contributes to <10 % of adipocyte glucose uptake, while GLUT4 facilitates most of both basal and insulin-stimulated glucose uptake. Females showed significantly higher basal and insulin-stimulated glucose transport, higher cytosolic volume, and greater GLUT4 and IRS-1 protein levels than males in both adipose depots. Interestingly, insulin responsiveness was preserved in female subcutaneous adipocytes but deteriorated in subcutaneous male adipocytes during adipose expansion.
SIGNIFICANCE: The improved insulin responsiveness, increased glucose transport, and higher levels of GLUT4 and IRS-1 in adipocytes might protect females from the adverse systemic effects linked to obesity. Insulin responsiveness was preserved in female subcutaneous adipocytes during adipose tissue expansion, which could contribute to the reduced risk of females to develop systemic insulin resistance.

Keywords:  Adipocytes; Depot-differences; GLUT1; GLUT4; Insulin; Obesity; Sex differences

DOI:  https://doi.org/10.1016/j.lfs.2025.123743
Diabetologia. 2025 May 22.

Effect of acute exercise and exercise training on the ability of insulin to clear branched-chain amino acids from plasma in obesity and type 2 diabetes.

Pauline M Møller, Rasmus Kjøbsted, Maria H Petersen, Martin E de Almeida, Andreas J T Pedersen, Jørgen F P Wojtaszewski, Kurt Højlund.

   AIMS/HYPOTHESIS: Insulin resistance in obesity and type 2 diabetes is associated with elevated plasma branched-chain amino acid (BCAA) levels. Here, we examined whether the ability of insulin to clear plasma BCAAs and any influence of acute exercise or exercise training on this response are intact in obesity and type 2 diabetes.
METHODS: In four case-control studies of participants with type 2 diabetes matched to glucose-tolerant individuals with obesity and lean individuals, who underwent hyperinsulinaemic-euglycaemic clamps, we examined the effect of insulin on plasma BCAAs (studies I-IV), with or without prior acute exercise (60 min, 70% V˙O2max ) (study II), and before and after 10 weeks of endurance exercise training (study III) or 8 weeks of high-intensity interval training (study IV).
RESULTS: Insulin sensitivity was reduced in individuals with type 2 diabetes compared with individuals with obesity (study I-IV) and lean individuals (studies I and IV), and in individuals with obesity vs lean individuals (study I) (all p<0.05). Exercise training (studies III and IV) increased insulin sensitivity in all groups (all p<0.01). Plasma BCAAs were elevated in individuals with type 2 diabetes compared with individuals with obesity (studies I, III and IV) and lean individuals (studies I and IV) (all p<0.05). The ability of insulin to reduce plasma BCAAs was significantly attenuated in participants with type 2 diabetes compared with both lean individuals (studies I and IV) and individuals with obesity (studies I, II and IV) (all p<0.05). Acute exercise slightly reduced plasma BCAAs in both individuals with type 2 diabetes and individuals with obesity but did not potentiate insulin's ability to reduce plasma BCAAs (study II). Exercise training had no impact on fasting BCAAs and did not affect insulin's ability to reduce plasma BCAAs in any group (studies III and IV) or rescue the attenuated insulin suppression of plasma BCAAs in participants with type 2 diabetes.
CONCLUSIONS/INTERPRETATION: Our results demonstrate that insulin's ability to suppress plasma BCAAs is impaired in type 2 diabetes but is intact in individuals with obesity. Although acute exercise reduces fasting BCAA levels, neither acute exercise nor exercise training affects insulin's ability to suppress plasma BCAAs in glucose-tolerant individuals with or without obesity or in individuals with type 2 diabetes.

Keywords:  Acute exercise; Branched-chain amino acids; Exercise training; Obesity; Type 2 diabetes

DOI:  https://doi.org/10.1007/s00125-025-06454-y
Diabetes Metab J. 2025 May 22.

Serpina3c Mitigates Adipose Tissue Inflammation by Inhibiting the HIF1α-Mediated Endoplasmic Reticulum Overoxidation in Adipocytes.

Yu Jiang, Jia-Qi Guo, Ya Wu, Peng Zheng, Shao-Fan Wang, Meng-Chen Yang, Gen-Shan Ma, Yu-Yu Yao.

   Background: Visceral white adipose tissue (vWAT) inflammation is a critical pathology of obesity-caused heart damage and is closely associated with adipocyte endoplasmic reticulum (ER) dysfunction. Serine (or cysteine) peptidase inhibitor, clade A, member 3C (Serpina3c) has been identified as an adipokine with anti-vWAT inflammatory effects. However, it remains unclear whether Serpina3c deficiency promotion of vWAT inflammation involves adipocyte ER dysfunction and whether it further contributes to heart damage in obesity.
Methods: Wild type and Serpina3c knockout (Serpina3c-/-) mice were fed a high-fat diet (HFD) for 12 weeks. An adeno-associated virus (AAV) was injected locally into epididymal white adipose tissue (eWAT) of Serpina3c-/- mice to induce eWAT-adipocyte- specific overexpression of Serpina3c (AAV-Serpina3c) or knockdown of hypoxia-inducible factor 1α (AAV-shHIF1α). In vitro experiments were performed in 3T3-L1 adipocytes.
Results: Serpina3c-/- mice exhibited more severe eWAT, serum and heart inflammation after HFD feeding. Consistently, these adverse phenotypes were mitigated in AAV-Serpina3c and AAV-shHIF1α mice. Mechanistically, ER oxidoreductase 1α (Ero1α) and protein disulfide isomerase (PDI) family members PDIA3 and PDIA4 were found to be target genes of HIF1α. In the obese mice, Serpina3c deficiency caused adipocyte more hypertrophy, and activated HIF1α-Ero1α/PDI mediated ER overoxidation and ER stress in eWAT. Subsequently, this led to increased adipocyte apoptosis and chemokine production and decreased adiponectin expression, which promoted macrophage infiltration and M1 polarization in eWAT, thus exacerbating eWAT inflammation and ultimately facilitating serum and distal heart inflammation.
Conclusion: These findings indicate that Serpina3c is a significant regulator of adipocyte ER redox homeostasis, thus highlighting Serpina3c as a potential therapeutic target for obesity-related eWAT inflammation and heart damage.

Keywords:  Adipose tissue; Endoplasmic reticulum; Infammation; Obesity; Serpins

DOI:  https://doi.org/10.4093/dmj.2024.0441
Stem Cell Rev Rep. 2025 May 23.

Low Intensity Pulsed Ultrasounds Modulate Adipose Stem Cells Differentiation.

Tamara Fernández-Marcelo, Alba Calero, Beatriz de Lucas, María Garrido, Raúl L Arregui, Paulina Sury, Elena Quintana, Laura M Pérez, Elisa Fernández-Millán, Beatriz G Gálvez.

  LIPUS, low intensity pulsed ultrasounds, are considered a safe and non-invasive tool that have been used extensively in medicine for chronic diseases. We evaluated the effects produced by LIPUS on the physiological behaviour of mouse and human adipose stem cells (ASCs) as well as on adipose tissue explants. LIPUS stimulation for one minute did not affect mouse or human ASC proliferation or apoptosis, with no evident changes in morphology or cell growth. Further, RNA-seq analysis revealed more than 200 genes differentially expressed after ultrasound stimulation of mouse and human ASCs. Among them, the changes in gene expression mainly belong to the canonical pathways of stemness, energy metabolism or chemokine signalling. On the other hand, the migration ability of mouse and human ASCs was partially affected by the ultrasound protocol, slightly increasing their capacity to migrate, while maintaining their stemness properties. Major affection was detected on the adipocyte differentiation capacity. Indeed, LIPUS-treated ASCs were unable to differentiate into mature adipocytes and their inflammatory secretion profile was reduced in both mouse and human ASCs. These effects were confirmed on an ex vivo model of adipose tissue explants, demonstrating that LIPUS also provoked an anti-inflammatory profile in the adipose tissue while reducing adipocytes differentiation and lipids content. Overall, the strong adipogenesis blockade, the reduction of their secretion profile and the RNA-seq analysis suggest that LIPUS-treated ASCs may be prevented from differentiating into mature adipocytes and from exacerbating inflammation, thus limiting their contribution to obesity.

Keywords:  Adiponectin; Adipose-derived stem cells; Inflammation; Low-intensity pulsed ultrasound; Obesity

DOI:  https://doi.org/10.1007/s12015-025-10896-7
Cell Rep. 2025 May 22. pii: S2211-1247(25)00503-0. [Epub ahead of print]44(6): 115732

Exploring adipose tissue-derived extracellular vesicles in inter-organ crosstalk: Implications for metabolic regulation and adipose tissue function.

Soazig Le Lay, Philipp E Scherer.

  Intercellular and inter-organ communication systems are vital for tissue homeostasis and disease development, utilizing soluble bioactive molecules for signaling. The field of extracellular vesicle (EV) biology has rapidly expanded in recent decades, highlighting EVs as effective bioactive nanovectors for cell-to-cell communication in various physiological and pathological contexts. Numerous studies indicate that adipocyte-derived EVs are crucial components of the adipose secretome, playing a key role in autocrine and paracrine interactions within adipose tissue, as well as in endocrine signaling. This review aims to present an updated perspective on EVs as mediators of communication between adipose tissue and other organs, while also examining their therapeutic potential in the light of recent advancements in EV biology research.

Keywords:  CP: Metabolism; CP: Molecular biology; EVs; MASH; adipocyte; adipose tissue; diabetes; exosomes; extracellular vesicles; insulin resistance; liver; microvesicles; obesity

DOI:  https://doi.org/10.1016/j.celrep.2025.115732
Nature. 2025 May 21.

Unravelling cysteine-deficiency-associated rapid weight loss.

Alan Varghese, Ivan Gusarov, Begoña Gamallo-Lana, Daria Dolgonos, Yatin Mankan, Ilya Shamovsky, Mydia Phan, Rebecca Jones, Maria Gomez-Jenkins, Eileen White, Rui Wang, Drew R Jones, Thales Papagiannakopoulos, Michael E Pacold, Adam C Mar, Dan R Littman, Evgeny Nudler.

Around 40% of the US population and 1 in 6 individuals worldwide have obesity, with the incidence surging globally1,2. Various dietary interventions, including carbohydrate, fat and, more recently, amino acid restriction, have been explored to combat this epidemic3-6. Here we investigated the impact of removing individual amino acids on the weight profiles of mice. We show that conditional cysteine restriction resulted in the most substantial weight loss when compared to essential amino acid restriction, amounting to 30% within 1 week, which was readily reversed. We found that cysteine deficiency activated the integrated stress response and oxidative stress response, which amplify each other, leading to the induction of GDF15 and FGF21, partly explaining the phenotype7-9. Notably, we observed lower levels of tissue coenzyme A (CoA), which has been considered to be extremely stable10, resulting in reduced mitochondrial functionality and metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective tricarboxylic acid cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen-rich compounds and amino acids. In summary, our investigation reveals that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism and stress signalling compared with other amino acid restrictions. These findings suggest strategies for addressing a range of metabolic diseases and the growing obesity crisis.

DOI: https://doi.org/10.1038/s41586-025-08996-y
Cell Rep. 2025 May 15. pii: S2211-1247(25)00481-4. [Epub ahead of print]44(5): 115710

De novo serine biosynthesis is protective in mitochondrial disease.

Christopher B Jackson, Anastasiia Marmyleva, Geoffray Monteuuis, Ryan Awadhpersad, Takayuki Mito, Nicola Zamboni, Takashi Tatsuta, Amy E Vincent, Liya Wang, Nahid A Khan, Thomas Langer, Christopher J Carroll, Anu Suomalainen.

  The importance of serine as a metabolic regulator is well known for tumors and is also gaining attention in degenerative diseases. Recent data indicate that de novo serine biosynthesis is an integral component of the metabolic response to mitochondrial disease, but the roles of the response have remained unknown. Here, we report that glucose-driven de novo serine biosynthesis maintains metabolic homeostasis in energetic stress. Pharmacological inhibition of the rate-limiting enzyme, phosphoglycerate dehydrogenase (PHGDH), aggravated mitochondrial muscle disease, suppressed oxidative phosphorylation and mitochondrial translation, altered whole-cell lipid profiles, and enhanced the mitochondrial integrated stress response (ISRmt) in vivo in skeletal muscle and in cultured cells. Our evidence indicates that de novo serine biosynthesis is essential to maintain mitochondrial respiration, redox balance, and cellular lipid homeostasis in skeletal muscle with mitochondrial dysfunction. Our evidence implies that interventions activating de novo serine synthesis may protect against mitochondrial failure in skeletal muscle.

Keywords:  CP: Metabolism; de novo serine synthesis; mitochondrial disease; mitochondrial integrated stress response; mitochondrial translation; tissue specificity; treatment

DOI:  https://doi.org/10.1016/j.celrep.2025.115710
Circ Res. 2025 May 23. 136(11): 1407-1432

Skeletal Muscle as a Mediator of Interorgan Crosstalk During Exercise: Implications for Aging and Obesity.

Julia A Shero, Maléne E Lindholm, Marco Sandri, Kristin I Stanford.

  Physical exercise is critical for preventing and managing chronic conditions, such as cardiovascular disease, type 2 diabetes, hypertension, and sarcopenia. Regular physical activity significantly reduces cardiovascular and all-cause mortality. Exercise also enhances metabolic health by promoting muscle growth, mitochondrial biogenesis, and improved nutrient storage while preventing age-related muscle dysfunction. Key metabolic benefits include increased glucose uptake, enhanced fat oxidation, and the release of exercise-induced molecules called myokines, which mediate interorgan communication and improve overall metabolic function. These myokines and other exercise-induced signaling molecules hold promise as therapeutic targets for aging and obesity-related conditions.

Keywords:  cardiovascular diseases; epinephrine; hypertension; muscle, skeletal; sarcopenia

DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325614
Cell Cycle. 2025 May 20. 1-13

Succinate reduces biological activity and mitochondrial function of human adipose-derived stem cells.

Bo Wang, Xinxin Wang, Meijin Guo, Huiming Xu.

  Elevated succinate accumulation has been demonstrated to be associated with metabolic and inflammatory disorders. Our previous study revealed that adipose-derived stem cells (ADSC) from obese individuals exhibit high succinate, reduced biological activity, and mitochondrial dysfunction. However, the precise role of succinate in these processes remains unclear. Here, we investigated the effects of excess succinate on cellular biological activity, immunomodulatory capacity, and mitochondrial function of ADSC. We found that elevated succinate levels in ADSC decreased proliferation and differentiation potential, while promoting M1 macrophage polarization. Furthermore, succinate accumulation impaired mitochondrial biogenesis and metabolism, increasing in reactive oxygen species (ROS) production and inflammatory responses. Transcriptome sequencing analysis further confirmed that succinate upregulated inflammatory pathways, suppressed mitochondrial biogenesis and metabolism, and enhanced cellular apoptosis and senescence, accompanied by reduced DNA replication and repair. Overall, these findings imply that succinate accumulation in ADSC triggers inflammatory response and mitochondrial dysfunction, potentially contributing to a decline of cellular biological activity. Targeting succinate may offer therapeutic potential for metabolic disorders.

Keywords:  Succinate; adipose-derived stem cells; mitochondrial dysfunction; reduced biological activity

DOI:  https://doi.org/10.1080/15384101.2025.2508109
Exp Mol Pathol. 2025 May 20. pii: S0014-4800(25)00021-8. [Epub ahead of print]143 104971

Estrogen induces the alternative activation of macrophages through binding to estrogen receptor-alpha.

Amina Belboul, Jason Ashworth, Abdulmannan Fadel, Jessica Mcloughlin, Ayman Mahmoud, Mohamed El Mohtadi.

  Age-related impaired wounds represent a major health burden resulting in considerable morbidity and mortality in the elderly. When injury occurs, monocytes migrate to the damaged site and undergo differentiation into tissue-resident macrophages, which are crucial for wound repair. For proper resolution of the inflammatory response, macrophages differentiate into two distinct phenotypes classified as classically-activatedpro-inflammatory and alternatively-activatedanti-inflammatory macrophages. Pro-inflammatory macrophages are commonly linked with pro-inflammatory events, while anti-inflammatory macrophages are known to be pro-regenerative. The age-related delay in wound repair is often attributed to the age-related decrease in local and systemic estrogen levels in both genders. However, despite its well-documented anti-inflammatory effect in wound healing, the role of estrogen and involvement of Estrogen Receptors (ERs) in macrophage polarization has gained little attention to date. To investigate the impact of estrogen and ERs on the polarization of macrophages, monocyte-derived macrophages were pre-treated with estrogen, ER-alpha agonist/antagonist or ER-beta agonist/antagonist prior to stimulation with LPS/IFN-γ or IL-4/IL-13 to produce pro-inflammatory or anti-inflammatory macrophages. Our findings confirm that estrogen promotes the alternative activation of macrophages via possible ER-α signalling. Selective targeting of ER-α with agents like PPT could potentially lead to the development of novel therapies to treat excessive inflammation in impaired wounds.

Keywords:  Estrogen; Estrogen receptors; Inflammation; Macrophage polarization

DOI:  https://doi.org/10.1016/j.yexmp.2025.104971