bims-mimead 2025-08-03 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–08–03
eight papers selected by
Rachel M. Handy, University of Guelph

HOOK1 gene expression and DNA methylation in obesity and related cardiometabolic traits.
Tissue-Specific Effects of Dietary Protein on Cellular Senescence Are Mediated by Branched-Chain Amino Acids.
Resistance training volume dictates distinct redox molecular signature in white adipose tissue: a high-sensitivity proteomics study.
Bioenergetic profiles and respiratory control in mitochondrial physiology: Precision analysis of oxidative phosphorylation.
Vital Role of Visceral Adipose Tissue in Maintaining Cognitive Functions.
Gut substrate trap of D-lactate from microbiota improves blood glucose and fatty liver disease in obese mice.
Glucose-activated JMJD1A drives visceral adipogenesis via α-ketoglutarate-dependent chromatin remodeling.
Redox proteomics workflow to unveil extracellular targets of oxidation in vascular endothelial cells.

Obes Facts. 2025 Jul 25. 1-24

HOOK1 gene expression and DNA methylation in obesity and related cardiometabolic traits.

Stina Ingrid Alice Svensson, Sadia Saeed, Anne Hoffmann, Adhideb Ghosh, Christian Wolfrum, Mai Britt Dahl, Akin Cayir, Torunn Rønningen, Baoyan Bai, Tom Mala, Jon Adalstein Kristinsson, Peter Kovacs, Matthias Blüher, Tone Gretland Valderhaug, Yvonne Böttcher.

BACKGROUND: Accumulation of fat in omental visceral adipose tissue is strongly linked to metabolic diseases. Our recent findings show a distinct and more accessible chromatin landscape of the visceral depot compared to its subcutaneous counterpart. Based on integrated analysis of chromatin accessibility and transcriptomics, we identified previously unrecognized genes linked with obesity. Here, we performed in-depth analyses of one of the candidates, HOOK1, and tested for depot-specific gene expression, correlation with clinical traits and regulatory mechanisms including DNA methylation.
METHODS: We utilised intra-individually paired adipose tissue samples of human omental visceral (OVAT) and subcutaneous adipose tissue (SAT) from our in-house cohort (N=78). Gene expression was measured using RT-qPCR and pyrosequencing was used to determine DNA methylation levels. Data were analysed for differential gene expression and DNA methylation differences between SAT and OVAT, along with correlation analyses with clinical variables related to obesity. Results were validated in adipose tissue samples from 1,618 donors of the Leipzig Obesity Biobank.
RESULTS: We observed consistently higher HOOK1 gene expression in OVAT compared to SAT and successfully confirmed this effect direction in several validation cohorts. We further identified that HOOK1 gene expression correlated with BMI and hip circumference. We discovered a relationship between DNA methylation of the HOOK1 promoter with clinical variables important for liver function.
CONCLUSIONS: Our data show that HOOK1 gene expression is adipose tissue depot-specific. We observed that gene expression and DNA methylation are correlated to clinical variables of obesity, suggesting that HOOK1 may play a role in obesity and its sequelae.

DOI: https://doi.org/10.1159/000547603
Aging Cell. 2025 Jul 28. e70176

Tissue-Specific Effects of Dietary Protein on Cellular Senescence Are Mediated by Branched-Chain Amino Acids.

Mariah F Calubag, Ismail Ademi, Isaac D Grunow, Lucia E Breuer, Reji Babygirija, Penelope Lialios, Sandra M Le, Michelle M Sonsalla, Julia A Illiano, Bailey A Knopf, Fan Xiao, Dennis Minton, Adam R Konopka, David A Harris, Dudley W Lamming.

Dietary protein is a key regulator of healthy aging in both mice and humans. In mice, reducing dietary levels of the branched-chain amino acids (BCAAs) recapitulates many of the benefits of a low protein diet; BCAA-restricted diets extend lifespan, reduce frailty, and improve metabolic health, while BCAA supplementation shortens lifespan, promotes obesity, and impairs glycemic control. Recently, high protein diets have been shown to promote cellular senescence, a hallmark of aging implicated in many age-related diseases, in the liver of mice. Here, we test the hypothesis that the effects of high protein diets on metabolic health and on cellular senescence are mediated by BCAAs. We find that reducing dietary levels of BCAAs protects male mice from the negative metabolic consequences of both normal and high protein diets. Further, we identify tissue-specific effects of BCAAs on cellular senescence, with restriction of all three BCAAs-but not individual BCAAs-protecting from hepatic cellular senescence while potentiating cellular senescence in white adipose tissue. We also find that these effects are sex-specific. We find that the effects of BCAAs on hepatic cellular senescence are cell-autonomous, with lower levels of BCAAs protecting cultured cells from antimycin-A induced senescence. Our results demonstrate a direct effect of a specific dietary component on a hallmark of aging and suggest that cellular senescence may be highly susceptible to dietary interventions.

DOI: https://doi.org/10.1111/acel.70176
Am J Physiol Endocrinol Metab. 2025 Aug 01.

Resistance training volume dictates distinct redox molecular signature in white adipose tissue: a high-sensitivity proteomics study.

Ivo Vieira de Sousa Neto, Isabelle Souza Luz, Adelino Sanchez Ramos da Silva, Wendy Assis Silveira, Muhammad Tahir, Fabiane Hiratsuka Veiga de Souza, Paulo Eduardo Narcizo de Souza, Ramires Alsamir Tibana, Bernardo Petriz, Thiago Dos Santos Rosa, Jonato Prestes, Arkadiusz Nawrocki, Martin Røssel Larsen, Wagner Fontes, Rita de Cassia Marqueti.

  Although white adipose tissue (WAT) serves as a dynamic storage organ that regulates overall metabolism, the molecular impacts of resistance training (RT) on WAT are still not fully understood. Considering that training variables influence RT outcomes, understanding the relationship between exercise volume and WAT remodeling is crucial for elucidating adaptive mechanisms. The hypothesis posits that a higher volume of RT, specifically 8 weeks of climbing a vertical ladder for 8 sets (RT-8), will lead to more significant positive adaptations in WAT remodeling than a lower volume of 4 sets (RT-4). The investigation combined histological, molecular (proteomic), and biochemical analyses (EPR, zymography and ELISA) with bioinformatics tools. By high-throughput mass spectrometry-based proteomics, we quantified 4434 proteins in WAT of male rats and revealed that the RT-8 group displayed increased protein abundance associated with lipid transport, fatty acid unsaturation, and lipolysis compared to RT-4. Additionally, compared to sedentary controls, RT-8 showed enhanced antioxidant capacity through phase II antioxidant enzymes (thioredoxins, peroxiredoxins, glutathione transferases, and ferritin). In contrast, the RT-4 group did not significantly alter the redox proteome, but selectively upregulated first-line antioxidant defense via the α-Klotho/SOD/catalase axis. RT-4 was also associated with a reduction in ROS production (superoxide ion and hydrogen peroxide), matrix metalloproteinase-2 (MMP-2) activity and adipocyte cross-sectional area to a similar extent as RT-8, without disrupting redox balance, ubiquitin ligase complex activity, or inflammatory pathways. Our findings contribute to the growing body of literature suggesting that RT volume is a key determinant of the WAT proteomic signature, with training volume eliciting distinct molecular adaptations.

Keywords:  adipose tissue; proteome; redox state; resistance training; training variables

DOI:  https://doi.org/10.1152/ajpendo.00231.2025
Exp Physiol. 2025 Aug 01.

Bioenergetic profiles and respiratory control in mitochondrial physiology: Precision analysis of oxidative phosphorylation.

Alba Timón-Gómez, Carolina Doerrier, Zuzana Sumbalová, Luiz F Garcia-Souza, Eleonora Baglivo, Luiza H D Cardoso, Erich Gnaiger.

  Oxidative phosphorylation (OXPHOS) is fundamental to mitochondrial function. Respirometry with living cells provides limited information compared to precision OXPHOS analysis with mitochondrial preparations, including isolated mitochondria, tissue homogenates, permeabilized tissues, and permeabilized cells. We studied mouse mitochondria from brain, a glucose-dependent tissue, and from heart, which relies highly on fatty acid oxidation (FAO). HEK 293T cells were analysed as a widely used experimental model. Human peripheral blood mononuclear cells (PBMCs) and platelets were obtained from non-invasive liquid biopsies, considering their potential as mitochondrial biomarkers. Twenty respiratory states were interrogated applying two substrate-uncoupler-inhibitor titration (SUIT) reference protocols in parallel. Convergent electron transfer (ET) into the coenzyme Q junction increased OXPHOS and ET capacities compared to separately stimulated pathways. In mouse heart and human PBMCs, OXPHOS capacities were identical to ET capacities in every pathway state. While this equivalence applied to the NADH-linked pathway in platelets, ET capacity exceeded OXPHOS capacity supported by NADH-linked substrates plus succinate. Surprisingly, mouse brain exhibited the highest excess ET capacity in the NADH-linked pathway. In contrast, ET capacity of different batches of HEK 293T cells varied at constant OXPHOS capacity. Precision OXPHOS analysis enables attribution of respiratory performance to nutrient-specific pathways. In studies ranging from exercise physiology to mitochondrial diseases, metabolic adjustments must be distinguished from functional defects. Bioenergetic profiles obtained by precision OXPHOS analysis gain perspective in the context of comparative mitochondrial physiology.

Keywords:  OXPHOS; coupling control; electron transfer system (ETS); high‐resolution respirometry (HRR); pathway control; substrate‐uncoupler‐inhibitor‐titration (SUIT) protocol

DOI:  https://doi.org/10.1113/EP092792
Int J Mol Sci. 2025 Jul 09. pii: 6597. [Epub ahead of print]26(14):

Vital Role of Visceral Adipose Tissue in Maintaining Cognitive Functions.

Rina Shirafuji, Yoko Amagase, Ai Goto, Yoshinori Takei.

  The aging process involves a decline in certain cognitive abilities. Cognitive aging progresses more quickly with obesity and more slowly with exercise and fasting. All of these conditions have strong impacts on white adipose tissue, which suggests that this tissue may play a pivotal role in the progression of cognitive aging. Brain-derived neurotrophic factor (BDNF), a neurotrophin indispensable for maintaining brain functions, becomes insufficient with age. Obesity also decreases the BDNF level in the hippocampus. This deficiency not only results in cognitive impairment but increases susceptibility to obesity. Both exercise and fasting increase the BDNF level in the hippocampus. Our study demonstrates that the chemokine ligand CX3CL1 in white adipose tissue is involved in the regulation of the BDNF level in the hippocampus. Aging reduces CX3CL1 expression, interfering with the mechanisms. Other studies have suggested that obesity increases adipose CX3CL1 expression; however, CX3CL1 augmented under obese condition may not contribute to the promotion of the BDNF level in the hippocampus. This suggests that the malfunction of the adipose CX3CL1-mediated mechanism could be involved in the downregulation of the hippocampus BDNF level under obese conditions. Studies have also suggested that the adipose CX3CL1-mediated mechanism appears to be involved in the exercise-induced promotion of BDNF expression in the hippocampus. Its involvement in the fasting-induced BDNF promotion is still unknown. Therefore, aging, obesity, and exercise appear to affect white adipose tissue to regulate the hippocampus BDNF level. While further studies are required to elucidate the precise role of the adipose CX3CL1-mediated regulation of BDNF expression, studies on white adipose tissue may provide new therapeutic targets for preventing age-associated cognitive decline.

Keywords:  BDNF; aging; cognitive function; exercise; fasting; hippocampus; obesity; visceral adipose tissue

DOI:  https://doi.org/10.3390/ijms26146597
Cell Metab. 2025 Jul 23. pii: S1550-4131(25)00328-6. [Epub ahead of print]

Gut substrate trap of D-lactate from microbiota improves blood glucose and fatty liver disease in obese mice.

Han Fang, Fernando F Anhê, Dana Kukje Zada, Nicole G Barra, Rodrigo Rodrigues E-Lacerda, Breanne T McAlpin, Ryan Wylie, Line Berthiaume, Étienne Audet-Walsh, Conor O'Dwyer, Peyman Ghorbani, Morgan D Fullerton, Claudia Gagnon, André Tchernof, André Marette, Jonathan D Schertzer.

  L-lactate participates in metabolism, including the Cori cycle, but less is known about D-lactate. We found that circulating D-lactate was higher in humans and mice with obesity. D-lactate increased hepatic glycogen, triglycerides, and blood glucose more than equimolar L-lactate in mice. Stable isotope analyses showed that D-lactate is metabolized in mice and in hepatocytes to pyruvate, TCA intermediates, lipids, and glucose. The gut microbiota is the main source of blood D-lactate. Colonization of mice with a bacterial strain that produced D-lactate elevated blood glucose more than an L-lactate producer. Oral delivery of a biocompatible polymer that traps gut D-lactate, forcing fecal excretion, lowered blood glucose and insulin resistance in obese mice in a polymer length- and dose-dependent manner. This D-lactate trap lowered hepatic inflammation and fibrosis in mice with metabolic dysfunction-associated fatty liver disease (MAFLD)/metabolic dysfunction-associated steatohepatitis (MASH). Therefore, microbial-derived D-lactate contributes to host glucose and lipid metabolism and can be trapped to improve metabolic disease during obesity.

Keywords:  diabetes; fibrosis; gut; inflammation; liver; metabolic dysfunction-associated steatotic liver disease; microbiome; obesity; polymer; postbiotics

DOI:  https://doi.org/10.1016/j.cmet.2025.07.001
Cell Rep. 2025 Jul 26. pii: S2211-1247(25)00831-9. [Epub ahead of print]44(8): 116060

Glucose-activated JMJD1A drives visceral adipogenesis via α-ketoglutarate-dependent chromatin remodeling.

Chenxu Yang, Makoto Arai, Eko Fuji Ariyanto, Ji Zhang, Debby Mirani Lubis, Ryo Ito, Shiyu Xie, Mio Nitta, Fuka Kawashima, Tomofumi Ishitsuka, Chaoran Yang, Tomohiro Suzuki, Tetsuro Komatsu, Hina Sagae, Hitomi Jin, Hiroki Takahashi, Eri Kobayashi, Yuchen Wei, Bohao Liu, Hyunmi Choi, Youichiro Wada, Toshiya Tanaka, Tsuyoshi Osawa, Hiroshi Kimura, Tatsuhiko Kodama, Hiroyuki Aburatani, Makoto Tachibana, Yoichi Shinkai, Takeshi Inagaki, Tomoyoshi Soga, Timothy F Osborne, Takeshi Yoneshiro, Yoshihiro Matsumura, Juro Sakai.

  Adipose tissue remodels via hypertrophy or hyperplasia in response to nutrient status, but the mechanisms governing these expansion modes remain unclear. Here, we identify a nutrient-sensitive epigenetic circuit linking glucose metabolism to chromatin remodeling during adipogenesis. Upon glucose stimulation, α-ketoglutarate (α-KG) accumulates in the nucleus and activates the histone demethylase JMJD1A to remove repressive histone H3 lysine 9 dimethylation (H3K9me2) marks at glycolytic and adipogenic gene loci, including Pparg. JMJD1A is recruited to pre-marked promoter chromatin via nuclear factor IC (NFIC), enabling carbohydrate-responsive element-binding protein (ChREBP) binding and transcriptional activation. This feedforward mechanism couples nutrient flux to chromatin accessibility and gene expression. In vivo, JMJD1A is essential for de novo adipogenesis and hyperplastic expansion in visceral fat under nutrient excess. JMJD1A deficiency impairs hyperplasia, exacerbates adipocyte hypertrophy, and induces local inflammation. These findings define a glucose-α-KG-JMJD1A-ChREBP axis regulating depot-specific adipogenesis and uncover a chromatin-based mechanism by which glucose metabolism governs adaptive adipose tissue remodeling.

Keywords:  Adipogenesis; CP: Metabolism; adipose hyperplasia; adipose hypertrophy; glycolysis; histone H3 lysine 9 di-methylation; histone demethylation; obesity; peroxisome proliferator-activated receptor; visceral fat; α-ketoglutarate

DOI:  https://doi.org/10.1016/j.celrep.2025.116060
J Proteomics. 2025 Jul 23. pii: S1874-3919(25)00133-2. [Epub ahead of print]321 105506

Redox proteomics workflow to unveil extracellular targets of oxidation in vascular endothelial cells.

Danielle Fernandes Vileigas, Railmara Pereira da Silva, Bianca Dempsey, Mariana Pereira Massafera, Mikaela Peglow Pinz, Flavia Carla Meotti.

  Redox regulation has emerged as a key process in cellular signaling. The role of extracellular cell surface redox-sensitive proteins in redox regulation and intracellular communication has been supported by secretion of oxidoreductases that modulate thiol-disulfide switches. Despite these advances, redox-sensitive targets on the cell surface remain little explored. We established a comprehensive redox proteomic workflow using plasma membrane impermeable thiol labeling where we identified 1159 cell surface and extracellular proteins susceptible to oxidation. Treatment with diamide or urate hydroperoxide (HOOU) resulted in 377 and 12 differentially abundant redox-modulated proteins compared to control. Such proteins represent chaperones, adhesion molecules, vesicle-associated proteins, channels, receptors, cytoskeleton, and others, which may play a relevant role in several signaling pathway. Eleven oxidoreductases were redox-modulated by diamide, including members of the protein disulfide isomerase (PDI), peroxiredoxin (PRDX), and quiescin sulfhydryl oxidase (QSOX) families, with a particular focus on PDI TMX3 (TMX3), which provides the first evidence of its secretion in endothelial cells. In conclusion, our findings not only revealed potential redox-sensitive targets on the cell surface but also offer a useful tool for future investigations aiming to analyze redox regulation in the extracellular environment across diverse biological contexts. SIGNIFICANCE: Redox signaling at the cell surface is emerging as a crucial regulator of vascular function, emphasizing its role in cardiovascular disease. However, the extracellular redox proteome remains underexplored because of the complexity of the method. We developed a reproducible workflow combining differential thiol labeling and mass spectrometry to systematically map oxidized extracellular proteins in endothelial cells exposed to oxidants. Hundreds of proteins were identified as redox-sensitive targets. Key functional groups included molecular chaperones, adhesion molecules, vesicle-associated proteins, channels, receptors, and cytoskeleton. This work reveals novel insights into extracellular redox regulation, expands the repertoire of known redox-sensitive proteins, and establishes a versatile platform to investigate redox dynamics at cell surface both in vascular biology and other pathophysiological contexts.

Keywords:  Extracellular surface proteins; HUVECs; Oxidation; Proteomics; Redox-modulated proteins

DOI:  https://doi.org/10.1016/j.jprot.2025.105506