bims-mimead 2025-08-17 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–08–17
eleven papers selected by
Rachel M. Handy, University of Guelph

MRP4 deficiency drives lipid metabolism dysregulation and adipose tissue inflammation through cAMP-CREB-CRTC2 activation.
Adipose-Derived Extracellular Vesicles and Intercellular Crosstalk With Skeletal Muscle: Implications for Sarcopenic Obesity and Metabolic Dysregulation.
Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging.
Alterations of the skeletal muscle nuclear proteome after acute exercise reveals a post-transcriptional influence.
ROS-dependent localization of glycolytic enzymes to mitochondria.
The insulin signalling network.
Pharmacological but Not Physiological Levels of GDF15 and FGF21 Regulate Body Weight and Glycemic Control in Obese Mice.
Chamber oxygen concentration impacts mitochondrial function and hydrogen peroxide appearance in permeabilized human skeletal muscle fibers.
Longitudinal adipose tissue single cell transcriptomics reveals genes and variants regulating weight loss after bariatric surgery.
Dynamic Lipidomic Remodeling and Clinical Correlations after Sleeve Gastrectomy in Obese Subjects.
A comparison of adiponectin-deficient mice reveals the fundamental role of intracellular adiponectin.

Life Sci. 2025 Aug 13. pii: S0024-3205(25)00530-2. [Epub ahead of print] 123895

MRP4 deficiency drives lipid metabolism dysregulation and adipose tissue inflammation through cAMP-CREB-CRTC2 activation.

Ankit P Laddha, Hangyu Wu, Jaeeun Lee, Ji-Young Lee, Neha Mishra, José E Manautou.

  Multidrug resistance-associated protein 4 (MRP4/ABCC4), a plasma membrane transporter, plays a critical role in the efflux of endogenous metabolites and xenobiotics. Recent studies have also implicated MRP4 in adipogenesis and fatty acid metabolism. Our previous work using MRP4 knockout (MRP4-/-) mice demonstrated a strong association between MRP4 deficiency and the development of obesity and diabetes. However, the underlying mechanisms through which MRP4 regulates adipose tissue function remain unclear.
AIM: To investigate the role of MRP4 in adipose tissue dysfunction and metabolic regulation under high-fat, high-sucrose (HFHS) diet conditions.
MATERIALS AND METHODS: MRP4 knockout (MRP4-/-) and wild-type (WT) mice were fed either a regular chow or HFHS diet for 24 weeks. Body weight, plasma glucose, cholesterol, insulin secretion, glucose tolerance, and insulin sensitivity were assessed. Body composition, physical activity, and energy expenditure were measured. Epididymal adipose tissue (EA) was analyzed for gene expression (adipogenic, lipogenic, fibrotic, and inflammatory markers), histology, cAMP levels, and protein expression of phosphorylated CREB (P-CREB) and CRTC2.
KEY FINDINGS: MRP4-/- mice showed greater body weight gain than WT controls, even on a chow diet. Under HFHS conditions, they exhibited exacerbated metabolic dysfunction, including elevated glucose and cholesterol levels, increased adiposity, adipocyte hypertrophy, and altered leptin levels. These mice also showed impaired insulin secretion, reduced glucose tolerance, and decreased insulin sensitivity. Body composition analysis revealed higher fat mass, lower lean mass, and increased water retention. MRP4-/- mice displayed reduced physical activity, altered energy expenditure, and upregulation of adipogenic, fibrotic, and inflammatory genes in EA. Histological analysis confirmed inflammation and fibrosis. Elevated cAMP levels, along with increased P-CREB and CRTC2 expression, indicated activation of the cAMP-CREB-CRTC2 signaling pathway.
SIGNIFICANCE: MRP4 deficiency promotes adipose tissue inflammation, fibrosis, and metabolic dysfunction through activation of the cAMP-CREB-CRTC2 signaling axis. These findings reveal a novel regulatory role for MRP4 in maintaining adipose tissue homeostasis and protecting against diet-induced metabolic disease.

Keywords:  Adiposity; Fibrosis; Glucose tolerance; MRP4; cAMP

DOI:  https://doi.org/10.1016/j.lfs.2025.123895
Obes Rev. 2025 Aug 13. e70005

Adipose-Derived Extracellular Vesicles and Intercellular Crosstalk With Skeletal Muscle: Implications for Sarcopenic Obesity and Metabolic Dysregulation.

Michael Macleod, Joshua Price, Elpida Tsonou, David J Baker, Kostas Tsintzas, Simon W Jones.

  Sarcopenic obesity, characterized by the concurrent presence of excess adiposity and diminished skeletal muscle mass and function, is closely linked to frailty, chronic inflammation, and insulin resistance. The increasing prevalence of sarcopenic obesity is driven by the global aging population, widespread adoption of sedentary lifestyles, and the ongoing obesity epidemic. Existing research describes a role for dysregulated crosstalk between adipose tissue and skeletal muscle tissue in driving sarcopenic obesity pathology, with recent evidence implying that extracellular vesicles (EVs, nano- to micro-scale, lipid bilayer membrane-delimited particles) have a significant role in facilitating intercellular communication to mediate critical tissue crosstalk. Given the significance of dysregulated tissue crosstalk in sarcopenic obesity pathology and the dysregulation of metabolism, the potential involvement of EVs has garnered considerable attention because of their scope as pharmacological targets and drug delivery vehicles, potentially leading to innovative therapeutic approaches. This review begins with an exploration of EV biology and the challenges associated with the standardization and execution of EV research. It then examines the impact of sarcopenic obesity risk factors on circulating and adipose-derived EV profiles. Current understanding of the role of specific EV cargo, including microRNAs, proteins, and lipids, in mediating crosstalk between adipose tissue and skeletal muscle is critically evaluated. Finally, the potential of EV-based therapeutics for treating sarcopenic obesity is discussed, along with recommendations for future research directions.

Keywords:  adipose tissue; crosstalk; extracellular vesicles; obesity; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1111/obr.70005
bioRxiv. 2025 Aug 06. pii: 2025.08.04.668533. [Epub ahead of print]

Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging.

Manish Mishra, Hee-Hoon Kim, Yun-Hee Youm, Elsie Gonzalez-Hurtado, Konstantin Zaitsev, Tamara Dlugos, Irina Shchukina, Christy Gliniak, Eric Ravussin, Subhasis Mohanty, Albert C Shaw, Philipp E Scherer, Maxim N Artyomov, Vishwa Deep Dixit.

Caloric restriction (CR) extends lifespan, yet the convergent immunometabolic mechanism of healthspan remains unclear. Using longitudinal plasma proteomics analyses in humans achieving 14% CR for 2 years, we identified that inhibition of the complement pathway is linked to lower inflammaging. The protein C3a (and its cleaved form) was significantly lowered by CR, thus reducing inflammation emanating from three canonical complement pathways. Interestingly, circulating C3a levels are increased during aging in mice, with visceral adipose tissue macrophages as the predominant source. In macrophages, C3a signaling via ERK elevated inflammatory cytokine production, suggesting the existence of an autocrine loop that promotes inflammaging. Notably, long-lived FGF21-overexpressing mice and PLA2G7-deficient mice exhibited lower C3a in aging. Specific small molecule-mediated systemic C3 inhibition reduced inflammaging, improved metabolic homeostasis, and enhanced healthspan of aged mice. Collectively, our findings reveal that complement C3 deactivation is a metabolically regulated inflammaging checkpoint that can be harnessed to extend healthspan.

DOI: https://doi.org/10.1101/2025.08.04.668533
Am J Physiol Cell Physiol. 2025 Aug 11.

Alterations of the skeletal muscle nuclear proteome after acute exercise reveals a post-transcriptional influence.

Ryan A Martin, Xiping Zhang, Mark R Viggars, James A Sanford, Zane W Taylor, Joshua R Hansen, Geremy C Clair, Collin M Douglas, Stuart James Hesketh, Joshua N Adkins, Karyn A Esser.

  Exercise is firmly established as a key contributor to overall well-being and is frequently employed as a therapeutic approach to mitigate various health conditions. One pivotal aspect of the impact of exercise lies in the systemic transcriptional response, which underpins its beneficial adaptations. While extensive research has been devoted to understanding the transcriptional response to exercise, our knowledge of the protein constituents of nuclear processes accompanying gene expression in skeletal muscle remains largely elusive. We hypothesize that alterations in the nuclear proteome following exercise hold vital clues for comprehending exercise-induced transcriptional regulation and related nuclear functions. We first detail the successful isolation of skeletal muscle nuclei from C57BL/6 mice encapsulating 2,030 proteins linked to nuclear processes such as transcription, RNA processing, chromatin modifications, and nuclear transport. We then used this approach to isolate muscle nuclei in sedentary, immediately post-, 1-hour, and 4-hours after a 30-minute treadmill running session, to gain insight into the nuclear proteome after exercise. We found 54 proteins linked to mRNA splicing and nucleocytoplasmic transport, many of which were substantially reduced immediately post-exercise followed by a rapid increase 1- and 4-hours post-exercise. Super resolution microscopy experiments highlight localization changes in mRNA processing proteins post-exercise, further suggesting changes in nuclear transport dynamics. Our data provides important insight into changes in the nuclear proteome following exercise. In particular it highlights proteins contributing to mRNA processing and splicing in addition to transcriptional processes with exercise offering broader changes in mechanisms modulating the molecular response to acute exercise.

Keywords:  Exercise; Muscle; Nuclear Proteome; Nuclei; Proteome

DOI:  https://doi.org/10.1152/ajpcell.00575.2024
Redox Biol. 2025 Aug 12. pii: S2213-2317(25)00325-8. [Epub ahead of print]86 103812

ROS-dependent localization of glycolytic enzymes to mitochondria.

Pau B Esparza-Moltó, Arvind V Goswami, Süleyman Bozkurt, Christian Münch, Laura E Newman, Alexandra G Moyzis, Gladys R Rojas, Deann Guan, Jeffrey R Jones, Fred H Gage, Gerald S Shadel.

  Mitochondrial reactive oxygen species (mtROS) regulate cellular signaling pathways, but also cause oxidative stress when de-regulated during aging and pathological conditions such as neurodegenerative diseases. The dynamic redistribution of proteins between cellular compartments is a common mechanism to control their stability and biological activities. By targeting the BirA∗ biotin ligase to the outer mitochondrial membrane in HEK293 cells, we identified proteins whose labeling increased or decreased in response to treatment with menadione, consistent with a dynamic change in their mitochondrial localization in response to increased mtROS production. These proteins represent potential candidates for future studies of mitochondrial oxidative stress signaling. A subset of glycolytic enzymes was found in this screen and confirmed, by mitochondrial fractionation and imaging, to increase localization to mitochondria in response to menadione, despite no change in their overall abundance. Submitochondrial fractionation studies are consistent with import of a pool of these enzymes to the mitochondrial intermembrane space. Localization of glycolytic enzymes to mitochondria was also increased in cells grown under hypoxia or that express a mitochondria-targeted d-amino-acid oxidase (conditions that induce increased mtROS production), and inhibited basally under normal growth conditions by the mitochondrial antioxidant MnTBAP. Finally, primary Alzheimer's disease fibroblasts also had glycolytic enzymes associated with mitochondria that was reduced by antioxidants, consistent with increased mtROS altering their relative distribution between the cytoplasm and mitochondria. We speculate that the increased mitochondrial localization of glycolytic enzymes is an adaptive response to mtROS that alters glucose flux toward the antioxidant pentose phosphate pathway, creates distinct regulatory pools of mitochondrial metabolites or new metabolic circuits, and/or provides cytoprotection or other adaptive responses via moonlighting functions unrelated to their enzymatic activity.

Keywords:  Alzheimer's disease; Glycolytic enzymes; Mitochondria; Proximity labeling; Reactive oxygen species; Stress signaling

DOI:  https://doi.org/10.1016/j.redox.2025.103812
Nat Metab. 2025 Aug 11.

The insulin signalling network.

James G Burchfield, Alexis Diaz-Vegas, David E James.

Insulin signalling is a central regulator of metabolism, orchestrating nutrient homeostasis and coordinating carbohydrate, protein and lipid metabolism. This network operates through dynamic, tightly regulated protein phosphorylation events involving key kinases such as AKT, shaping cellular responses with remarkable precision. Advances in phosphoproteomics have expanded our understanding of insulin signalling, revealing its intricate regulation and links to disease, particularly cardiometabolic disease. Major insights, such as the mechanisms of AKT activation and the influence of genetic and environmental factors, have emerged from studying this network. In this Review, we examine the architecture of insulin signalling, focusing on its precise temporal regulation. We highlight AKT's central role in insulin action and its vast substrate repertoire, which governs diverse cellular functions. Additionally, we explore feedback and crosstalk mechanisms, such as insulin receptor substrate protein signalling, which integrates inputs through phosphorylation at hundreds of distinct sites. Crucially, phosphoproteomics has uncovered complexities in insulin-resistant states, where network rewiring is characterized by disrupted phosphorylation and the emergence of novel sites that are absent in healthy cells. These insights redefine insulin signalling and its dysfunction, highlighting new therapeutic opportunities.

DOI: https://doi.org/10.1038/s42255-025-01349-z
FASEB J. 2025 Aug 15. 39(15): e70918

Pharmacological but Not Physiological Levels of GDF15 and FGF21 Regulate Body Weight and Glycemic Control in Obese Mice.

Sarah Engelbeen, Julie Mie Jacobsen, Luisa Deisen, Elisa Parsche, Alberte Buch-Ramussen, Christoffer Clemmensen, Rune Ehrenreich Kuhre, Kornelia Johann, Maximilian Kleinert.

  GDF15 and FGF21 are stress-induced hormone-like factors with putative roles in the regulation of energy homeostasis. Since their plasma levels increase with obesity, it has been proposed that GDF15 and FGF21 jointly impose a cap on weight gain during diet-induced obesity. To test this hypothesis, we generated single Gdf15 knockout (KO) and Fgf21 KO, and double Gdf15/Fgf21 KO mice. Depletion of both GDF15 and FGF21 had minimal effects on the gain of body weight, fat, and fat-free mass in male or female mice fed either chow diet or high-fat, high-sucrose diet. Similarly, glucose tolerance, fasting glucose, and plasma insulin levels were largely unaffected by the combined absence of GDF15 and FGF21. Thus, combined deletion of endogenous Gdf15 and Fgf21 exerted a limited influence on body weight gain or glycaemic control. By contrast, pharmacological dosing of obese male mice with long-acting recombinant GDF15 or FGF21 produced meaningful weight loss on their own (8%-10%), and GDF15 + FGF21 co-administration yielded an impressive, additive weight reduction of 25%. Combinatorial treatment also improved glucose tolerance, lowered fasting insulin levels, and reduced hepatic fat content. In conclusion, while endogenous GDF15 and FGF21 appear largely nonessential for the regulation of weight gain and glycemia, pharmacological co-treatment with GDF15 and FGF21 elicits robust weight-loss benefits.

Keywords:  FGF21; GDF15; diet‐induced obesity; energy homeostasis regulation; gene knockout mice; glucose tolerance; pharmacological weight‐loss therapy

DOI:  https://doi.org/10.1096/fj.202501350R
Biochim Biophys Acta Bioenerg. 2025 Aug 11. pii: S0005-2728(25)00034-9. [Epub ahead of print]1866(4): 149568

Chamber oxygen concentration impacts mitochondrial function and hydrogen peroxide appearance in permeabilized human skeletal muscle fibers.

Bradley A Ruple, Soung Hun Park, Jesse C Craig, Matthew T Lewis, Joel D Trinity, Russell S Richardson, Ryan M Broxterman.

  Skeletal muscle mitochondrial respiration is commonly assessed ex vivo using permeabilized fibers in media with high oxygen (O2) concentrations to ensure that O2 availability does not limit respiration. However, high O2 concentrations also increase the production of reactive O2 species that can negatively affect respiration. In this study, we tested the hypotheses that permeabilized fiber mitochondria in a high, compared to low, O2 concentration would (i) not be different at maximal state 3 respiration rate (Vmax), (ii) have lower submaximal respiration rates at submaximal O2 concentrations, and (iii) have greater total cumulative hydrogen peroxide (H2O2) appearance. We continuously monitored mitochondrial state 3 respiration and H2O2 appearance rates using high-resolution respirometry in permeabilized skeletal muscle fibers (12 untrained participants; 22 ± 4 yrs) with either control (~127 mmHg; CON) or high (~327 mmHg; HIGH) partial pressures of O2 (PO2). Vmax was not different between conditions (HIGH: 80.7 ± 16.7 vs. CON: 82.3 ± 18.7 pmol/s/mg, p = 0.695). The PO2 at 80 % Vmax (P80) was greater in HIGH (73.9 ± 25.5 vs. 28.0 ± 7.1 mmHg, p < 0.001) and respiration rates at 5-60 mmHg PO2 were lower for HIGH than CON (all p < 0.001). Additionally, the total cumulative H2O2 appearance was greater in HIGH than CON (n = 11; 51.5 ± 23.2 vs. 18.3 ± 10.3 pmol/mg, p < 0.001), and this difference was directly correlated with the difference in P80 (r = 0.655, p = 0.029). The current findings support that a high O2 concentration, by itself, does not appear to affect Vmax in the permeabilized skeletal muscle fiber preparation, but the corollary increase in H2O2 exposure may diminish mitochondrial state 3 respiratory function.

Keywords:  Maximal respiration; Oxygen availability; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.bbabio.2025.149568
medRxiv. 2025 Jul 14. pii: 2025.07.11.25331390. [Epub ahead of print]

Longitudinal adipose tissue single cell transcriptomics reveals genes and variants regulating weight loss after bariatric surgery.

Seung Hyuk T Lee, Asha Kar, Sini Heinonen, Marcus Alvarez, Sandhya Rajkumar, Kristina M Garske, Kyla Z Gelev, Birgitta W van der Kolk, Ulla Säiläkivi, Tuure Saarinen, Dorota Kaminska, Ville Männistö, Markku Laakso, Jussi Pihlajamäki, Anne Juuti, Brunilda Balliu, Kirsi H Pietiläinen, Päivi Pajukanta.

Ability to lose weight during different obesity treatments shows substantial variability between individuals and is likely under genetic control; however, the underlying predictive variants and weight loss genes remain unknown. Here we profiled longitudinal, single cell level adipose transcriptomes of individuals undergoing bariatric surgery to elucidate genes and their regulatory variants contributing to interindividual variability in weight loss outcomes. We identified wide-spread cellular and subcellular transcriptional changes to weight loss with most profound responses in adipocyte subtypes. By clustering the weight loss genes based on their cell-type level co-expression profiles, we uncovered functionally distinct subsets of genes reflecting altered adipocyte expression of central adipocyte function enriched genes. Next, we discovered that body mass index (BMI) polygenic risk score (PRS) built using the cis regulatory variants in these 45 adipocyte weight loss genes significantly predict the magnitude of the achieved weight loss and are strongly enriched for variance explained in the change of BMI. Taken together, this longitudinal single nucleus adipose data establishes gene signatures for weight loss and discovers genetic regulators underlying the interindividual variability of weight loss.

DOI: https://doi.org/10.1101/2025.07.11.25331390
Diabetes Metab J. 2025 Aug 14.

Dynamic Lipidomic Remodeling and Clinical Correlations after Sleeve Gastrectomy in Obese Subjects.

Gakyung Lee, Yeong Chan Lee, Minkuk Park, Seong Min Kim, Ji-Hyeon Park, Dae Ho Lee.

   Background: Sleeve gastrectomy (SG) is an effective and the most commonly performed surgical intervention for obesity. However, detailed studies on the underlying mechanisms, particularly those involving lipid metabolism, remain limited. This study aimed to identify novel pathways associated with the metabolic efficacy of SG by assessing alterations in the serum lipidomic profiles of obese subjects following surgery.
Methods: A prospective study of 50 obese participants undergoing laparoscopic SG was conducted at a tertiary medical center. Serum samples were collected before surgery and 6 months after SG. Lipidomic profiling was performed alongside comprehensive follow-up assessments. Statistical analyses explored lipidomic alterations and their correlations with changes in clinical parameters (Clinical trial registration No. KCT0003527 and KCT0009704).
Results: Participants experienced a 25% reduction in body weight 6 months after SG, with a marked reduction (>70%) in hepatic steatosis and insulin resistance, and a 2-fold increase in plasma oxyntomodulin levels. Lipidomic analysis revealed significant molecular shifts in lipid subclasses based on the fatty acyl composition of lipid species, showing a trend toward higher unsaturation and longer carbon chain lengths, as well as metabolic regulation in specific lipid pathways. Key findings included characteristic shifts within triacylglycerols and glycerophospholipids, which were significantly associated with changes in oxyntomodulin levels. Enhanced phosphatidylcholine-to-lysophosphatidylcholine conversion and upregulated ether lipid levels correlated with liver stiffness measures. Metabolic remodeling of sphingolipids-characterized by a decrease in ceramide/sphingomyelin levels and upregulation of the hexosylceramide pathway-emerged as an additional lipidomic signature after SG.
Conclusion: These findings highlight the complex lipidomic remodeling underlying the metabolic efficacy and therapeutic potential of SG.

Keywords:  Bariatric surgery; Gastrectomy; Lipid metabolism; Lipidomics; Obesity

DOI:  https://doi.org/10.4093/dmj.2025.0120
bioRxiv. 2025 Jul 14. pii: 2025.07.12.664095. [Epub ahead of print]

A comparison of adiponectin-deficient mice reveals the fundamental role of intracellular adiponectin.

Toshiharu Onodera, Dae-Seok Kim, May-Yun Wang, Megan Virostek, Shiuhwei Chen, Zachary A Kipp, Evelyn A Bates, Yan Li, Clair Crewe, Chao Li, Xue-Nan Sun, Qianbin Zhang, Mengle Shao, Jihoon Shin, Christine M Kusminski, Ruth Gordillo, Rana K Gupta, Terry D Hinds, Iichiro Shimomura, Philipp E Scherer.

Adiponectin is an important adipokine with insulin-sensitizing, anti-inflammatory, and anti-fibrotic properties. The physiological roles of adiponectin have been studied using global adiponectin knockout (KO) mice. However, the reported phenotypes of adiponectin KO mice vary based on the mouse lines generated by different strategies and investigators. We performed a head-to-head comparison of the adiponectin KO mice that were generated in Dallas, Houston and Osaka. RNAseq revealed that the expression of the bioactive domain of adiponectin - the globular domain - was preserved in the Houston and Osaka KO mice. A complete adiponectin KO model, such as the Dallas KO mouse, exhibits a lower body weight, the highest adipocyte mitochondrial function and displays a susceptibility to DNA damage-mediated lung fibrosis. The reconstitution of globular adiponectin into the Dallas KO mice prompted an increase in body weight and a partial recapitulation of the Osaka KO model transcriptome signature. The intracellular globular adiponectin form is important, as we found that globular adiponectin enhances PPARγ activity by modulating the coregulators interacting with PPARγ. Overall, the residual expression of globular adiponectin regulates adipose tissue metabolism by altering PPARγ activity, highlighting an important novel role of intracellular adiponectin.

DOI: https://doi.org/10.1101/2025.07.12.664095