bims-mimead 2025-09-14 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–09–14
nine papers selected by
Rachel M. Handy, University of Guelph

Combined pharmacological targeting of CD9+ progenitors alleviates obesity-induced adipose tissue fibrosis and metabolic impairment.
Mechanistic Insights Into Postprandial Insulin-Glucagon Interactions and Their Impact on Glucose Flux After Protein-Glucose Coingestion in Humans.
Genetic variance in the murine defensin locus modulates glucose homeostasis.
MRI-Based Genetic Studies Reveal Specific Genetic Variants and Disease Risks Associated With Fat Distribution Across Anatomical Sites.
Genetic subtyping of obesity reveals biological insights into the uncoupling of adiposity from its cardiometabolic comorbidities.
Dietary isoleucine content modulates the metabolic and molecular response to a Western diet in mice.
Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.
Comparative Analysis of Gene and MicroRNA Expression in Subcutaneous Adipose Tissue in Metabolically Healthy and Unhealthy Obesity.
Early adipose tissue wasting in a preclinical model of human lung cancer cachexia.

Cell Rep Med. 2025 Jul 15. pii: S2666-3791(25)00270-8. [Epub ahead of print]6(7): 102197

Combined pharmacological targeting of CD9+ progenitors alleviates obesity-induced adipose tissue fibrosis and metabolic impairment.

Clémentine Rebière, Ana Letícia Silveira, Amanda Oliveira, Christine Rouault, Solia Adriouch, Sébastien Dussaud, Jimon Boniface Abatan, Cindy Rose, Simon Lecoutre, Alexandre Boissonnas, François Lanthiez, Jaqueline Pereira, Gabriela Barbosa Pires Fagundes, Jean Debédat, Fatiha Merabtene, Véronique Pelloux, Jean-Christophe Bichet, Judith Aron-Wisnewsky, Christine Poitou, Laurent Genser, Adaliene Ferreira, Emmanuel L Gautier, Karine Clément, Geneviève Marcelin.

  Fibrosis in visceral white adipose tissue (vWAT) is closely associated with tissue dysfunction and systemic metabolic disturbances in obesity. Identifying pathways amenable to drug intervention to prevent fibrotic changes in vWAT is a critical step in addressing the array of metabolic complications associated with obesity. CD9+ adipose progenitors (Progs) are key drivers of vWAT fibrosis. Here, we explore pharmacological strategies to target these cells and improve metabolic health. Profiling of CD9+ Progs reveals pro-fibrotic pathways that can be targeted by the Food and Drug Administration (FDA)-approved drugs nintedanib and celecoxib. Treatment with this combination blocks the progression of vWAT fibrosis and improves systemic metabolism in obese mice. Within the CD9+ Prog population, both Ly-6C+ Progs and mesothelial cells adopt a pro-fibrotic phenotype during obesity, a shift markedly reduced by the drug treatment. Our data highlight the importance of targeting adipose progenitors to counteract fibrosis and preserve adipose tissue function.

Keywords:  adipose tissue fibrosis; mesothelium; obesity; progenitors; type 2 diabetes

DOI:  https://doi.org/10.1016/j.xcrm.2025.102197
Diabetes. 2025 Sep 10. pii: db250395. [Epub ahead of print]

Mechanistic Insights Into Postprandial Insulin-Glucagon Interactions and Their Impact on Glucose Flux After Protein-Glucose Coingestion in Humans.

Giang M Dao, Chistopher S Shaw, Andrew C Betik, Vicky Kuriel, Clinton R Bruce, Greg M Kowalski.

Despite stimulating glucagon secretion, the mechanisms by which protein ingestion lowers glucose excursions remain unclear. We investigated this using the triple stable isotope glucose tracer technique to measure postprandial glucose fluxes. Eleven healthy adults completed three trials, ingesting 25 g glucose (25G; 100 kcal), 50 g glucose (50G; 200 kcal), or 25 g glucose plus 25 g whey protein (25WG; 200 kcal). Glucose excursions were lowest for 25WG. Glucagon increased approximately threefold with 25WG but was suppressed with 25G and 50G. Insulin and glucose-dependent insulinotropic polypeptide (GIP) were higher for 25WG versus 25G, whereas glucagon-like peptide 1 (GLP-1) was similar. Compared with 50G, 25WG produced a greater GIP but similar GLP-1 response, with a trend toward higher early-phase insulin. Endogenous glucose production (EGP) was less suppressed with 25WG (∼50%) versus 25G (∼70%) or 50G (∼80%). Compared with 25G, 25WG did not enhance glucose disposal (Rd) but reduced early-phase (30-60 min) glucose absorption. These findings confirm that protein-glucose coingestion robustly stimulates glucagon while enhancing GIP and insulin, leading to lower postprandial glucose excursions. Despite greater insulin secretion, the net glycemic benefit seems to stem from reduced early glucose absorption rather than increased Rd. This provides novel insights into the mechanisms by which protein improves postprandial glucose handling despite interfering with EGP suppression.
ARTICLE HIGHLIGHTS: Despite stimulating glucagon secretion, the addition of protein to carbohydrate typically lowers postprandial glucose excursions. The mechanisms underlying this phenomenon are incompletely understood. In healthy young adults, using the triple stable isotope glucose tracer technique, we investigated how whey protein and glucose coingestion modulates postprandial glucose fluxes. Despite stimulating glucagon secretion and impairing suppression of endogenous glucose production, whey protein-glucose coingestion significantly reduced glycemic excursions. Although whey protein-glucose coingestion strongly enhanced the insulin and glucose-dependent insulinotropic polypeptide (but not glucagon-like peptide 1) responses, whole-body glucose uptake was not enhanced; rather, the net glycemic benefit seemed to stem from reduced early-phase glucose absorption.

DOI: https://doi.org/10.2337/db25-0395
EMBO J. 2025 Sep 09.

Genetic variance in the murine defensin locus modulates glucose homeostasis.

Stewart W C Masson, Rebecca C Simpson, Harry B Cutler, Patrick W Carlos, Oana C Marian, Belinda Yau, Meg Potter, Søren Madsen, Kristen C Cooke, Niamh R Craw, Oliver K Fuller, Dylan J Harney, Mark Larance, Gregory J Cooney, Grant Morahan, Erin R Shanahan, Melkam A Kebede, Christopher Hodgkins, Richard J Payne, Jacqueline Stöckli, David E James.

  Insulin resistance is a heritable risk factor for many chronic diseases; however, the genetic drivers remain elusive. In seeking these, we performed genetic mapping of insulin sensitivity in 670 chow-fed Diversity Outbred in Australia (DOz) mice and identified a genome-wide significant locus (QTL) on chromosome 8 encompassing 17 defensin genes. By taking a systems genetics approach, we identified alpha-defensin 26 (Defa26) as the causal gene in this region. To validate these findings, we synthesized Defa26 and performed diet supplementation experiments in two mouse strains with distinct endogenous Defa26 expression levels. In the strain with relatively lower endogenous expression (C57BL/6J) supplementation improved insulin sensitivity and reduced gut permeability, while in the strain with higher endogenous expression (A/J) it caused hypoinsulinemia, glucose intolerance and muscle wasting. Based on gut microbiome and plasma bile acid profiling this appeared to be the result of disrupted microbial bile acid metabolism. These data illustrate the danger of single strain over-reliance and provide the first evidence of a link between host-genetics and insulin sensitivity which is mediated by the microbiome.

Keywords:  Bile Acids; Defensin; Diversity Outbred; Insulin Sensitivity; Microbiome

DOI:  https://doi.org/10.1038/s44318-025-00555-5
J Obes. 2025 ;2025 7792701

MRI-Based Genetic Studies Reveal Specific Genetic Variants and Disease Risks Associated With Fat Distribution Across Anatomical Sites.

Altayeb Ahmed, Madeleine Cule, Afreen Naz, Marjola Thanaj, Elena P Sorokin, Chiemela S Odoemelam, Brandon Whitcher, Naveed Sattar, Jimmy D Bell, E Louise Thomas, Hanieh Yaghootkar.

  Objective: To investigate the genetic determinants of fat distribution across anatomical sites and their implications for health outcomes. Methods: We analyzed neck-to-knee MRI data from the UK Biobank (n = 37,589) to measure fat at various locations and used Mendelian randomization to assess effects on 26 obesity-related diseases and 94 biomarkers from FinnGen and other consortia. Result: We identified genetic loci associated with 10 fat depots: abdominal subcutaneous adipose tissue (n = 2 loci), thigh subcutaneous adipose tissue (25), thigh intermuscular adipose tissue (15), visceral adipose tissue (7), liver proton density fat fraction (PDFF) (8), pancreas PDFF (11), paraspinal adipose tissue (9), pelvic bone marrow fat (28), thigh bone marrow fat (27), and vertebrae bone marrow fat (5). Genetically higher abdominal subcutaneous adipose tissue was associated with an adverse metabolic profile and higher risks of Type 2 diabetes, and cardiovascular outcomes. Conversely, higher thigh subcutaneous adipose tissue was associated with a favorable profile and lower risks of Type 2 diabetes and cardiovascular outcomes. Higher visceral adipose tissue was associated with gallstones; higher liver PDFF was associated with elevated tyrosine levels, higher Type 2 diabetes risk, and fatty liver disease; pancreas PDFF was associated with thrombotic events; and thigh bone marrow fat was associated with osteoporosis. Conclusion: These results further suggest a unique contribution of fat deposition in different anatomical locations to disease risk, emphasizing the potential, beyond weight loss per se, for future research into depot-specific therapeutic strategies.

Keywords:  MRI scan; Type 2 diabetes; bone marrow fat; cardiovascular diseases; ectopic fat; liver fat; pancreas fat; subcutaneous fat; visceral fat

DOI:  https://doi.org/10.1155/jobe/7792701
Nat Med. 2025 Sep 12.

Genetic subtyping of obesity reveals biological insights into the uncoupling of adiposity from its cardiometabolic comorbidities.

Nathalie Chami, Zhe Wang, Victor Svenstrup, Virginia Diez Obrero, Daiane Hemerich, Yi Huang, Hesam Dashti, Eleonora Manitta, Michael H Preuss, Kari E North, Louise Aas Holm, Cilius E Fonvig, Jens-Christian Holm, Torben Hansen, Camilla Scheele, Alexander Rauch, Roelof A J Smit, Melina Claussnitzer, Ruth J F Loos.

Obesity is a heterogeneous condition not adequately captured by a single adiposity trait. We conducted a multi-trait genome-wide association analysis using individual-level data from 452,768 UK Biobank participants to study obesity in relation to cardiometabolic health. We defined continuous 'uncoupling phenotypes', ranging from high adiposity with healthy cardiometabolic profiles to low adiposity with unhealthy ones. We identified 266 variants across 205 genomic loci where adiposity-increasing alleles were simultaneously associated with lower cardiometabolic risk. A genetic risk score (GRSuncoupling) aggregating these variants was associated with a lower risk of cardiometabolic disorders, including dyslipidemia and ischemic heart disease, despite higher obesity risk; unlike an adiposity score based on body fat percentage-associated variants (GRSBFP). The 266 variants formed eight genetic subtypes of obesity, each with distinct risk profiles and pathway signatures. Proteomic analyses revealed signatures separating adiposity- and health-driven effects. Our findings reveal new mechanisms that uncouple obesity from cardiometabolic comorbidities and lay a foundation for genetically informed subtyping of obesity to support precision medicine.

DOI: https://doi.org/10.1038/s41591-025-03931-0
Mol Metab. 2025 Sep 10. pii: S2212-8778(25)00155-3. [Epub ahead of print] 102248

Dietary isoleucine content modulates the metabolic and molecular response to a Western diet in mice.

Michaela E Trautman, Cara L Green, Michael R MacArthur, Krittisak Chaiyakul, Yasmine H Alam, Chung-Yang Yeh, Reji Babygirija, Isabella James, Michael Gilpin, Esther Zelenovskiy, Madelyn Green, Ryan N Marshall, Alexander Raskin, Michelle M Sonsalla, Victoria Flores, Judith A Simcox, Irene M Ong, Kristen C Malecki, Cholsoon Jang, Dudley W Lamming.

  The amino acid composition of the diet has recently emerged as a critical regulator of metabolic health. Consumption of the branched-chain amino acid isoleucine is positively correlated with body mass index in humans, and reducing dietary levels of isoleucine rapidly improves the metabolic health of diet-induced obese male C57BL/6J mice. However, there are some reports that dietary supplementation with extra BCAAs has health benefits. Further, the interactions between sex, genetic background, and dietary isoleucine levels in response to a Western Diet (WD) remain incompletely understood. Here, we find that although the magnitude of the effect varies by sex and strain, reducing dietary levels of isoleucine protects C57BL/6J and DBA/2J mice of both sexes from the deleterious metabolic effects of a WD, while increasing dietary levels of isoleucine impairs aspects of metabolic health. Despite broadly positive responses across all sexes and strains to reduced isoleucine, the molecular response of each sex and strain is highly distinctive. Using a multi-omics approach, we identify a core sex- and strain- independent molecular response to dietary isoleucine, and identify mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype. Intriguingly, the metabolic effects of reduced isoleucine in mice are not associated with FGF21 - and we find that in humans, plasma FGF21 levels are likewise not associated with dietary levels of isoleucine. Finally, an analysis of human NHANES data shows that isoleucine content varies widely across foods, and that individuals with higher Healthy Eating Index scores tend to consume lower amounts of isoleucine. Our results suggest that the dietary level of isoleucine is a potential mediator of the metabolic and molecular response to a WD, and imply that reducing dietary isoleucine may represent a theoretically translatable strategy to protect from the negative metabolic consequences of a WD.

Keywords:  Branched-chain amino acids; Isoleucine; adiposity; insulin resistance; metabolic health; western diet

DOI:  https://doi.org/10.1016/j.molmet.2025.102248
Autophagy. 2025 Sep 13.

Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.

Antonis Roussos, Katerina Kitopoulou, Fivos Borbolis, Christina Ploumi, Despoina D Gianniou, Zhiquan Li, Haijun He, Eleni Tsakiri, Helena Borland, Ioannis K Kostakis, Martina Samiotaki, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.

  Mitochondrial dysfunction and impaired mitophagy are hallmarks of aging and age-related pathologies. Disrupted inter-organellar communication among mitochondria, endoplasmic reticulum (ER), and lysosomes, further contributes to cellular dysfunction. While mitophagy has emerged as a promising target for neuroprotection and geroprotection, its potential to restore age-associated defects in organellar crosstalk remains unclear. Here, we show that mitophagy deficiency deregulates the morphology and homeostasis of mitochondria, ER and lysosomes, mirroring age-related alterations. In contrast, urolithin A (UA), a gut-derived metabolite and potent mitophagy inducer, restores inter-organellar communication via calcium signaling, thereby, promoting mitophagy, healthspan and longevity. Our multi-omic analyses reveal that UA reorganizes ER, mitochondrial and lysosomal networks, linking inter-organellar dynamics to mitochondrial quality control. In C. elegans, UA induces calcium release from the ER, enhances lysosomal activity, and drives DRP-1/DNM1L/DRP1-mediated mitochondrial fission, culminating in efficient mitophagy. Calcium chelation abolishes UA-induced mitophagy, blocking its beneficial impact on muscle function and lifespan, underscoring the critical role of calcium signaling in UA's geroprotective effects. Furthermore, UA-induced calcium elevation activates mitochondrial biogenesis via UNC-43/CAMK2D and SKN-1/NFE2L2/Nrf2 pathways, which are both essential for healthspan and lifespan extension. Similarly, in mammalian cells, UA increases intracellular calcium, enhances mitophagy and mitochondrial metabolism, and mitigates stress-induced senescence in a calcium-dependent manner. Our findings uncover a conserved mechanism by which UA-induced mitophagy restores inter-organellar communication, supporting cellular homeostasis and organismal health.

Keywords:  Calcium; ER; cellular senescence; geroprotection; lysosome; mitochondria

DOI:  https://doi.org/10.1080/15548627.2025.2561073
Int J Mol Sci. 2025 Aug 24. pii: 8212. [Epub ahead of print]26(17):

Comparative Analysis of Gene and MicroRNA Expression in Subcutaneous Adipose Tissue in Metabolically Healthy and Unhealthy Obesity.

Natalia O Markina, Georgy A Matveev, Ksenia A Zasypkina, Natalia V Khromova, Alina Yu Babenko, Evgeny V Shlyakhto.

  Metabolically healthy (MHO) and unhealthy obesity (MUO) exhibit distinct molecular genetic mechanisms underlying metabolic disorders. Studying gene and microRNA expression in subcutaneous adipose tissue (SAT) may reveal key pathogenetic differences between these phenotypes. We compared the expression of genes (ADIPOQ, HIF1A, CCL2) and microRNAs (miR-142-3p, miR-155, miR-378) in SAT between MHO and MUO patients and assessed their association with metabolic parameters. The study included 39 obese patients (19 MHO, 20 MUO) and 10 healthy controls. SAT biopsies were analyzed using real-time PCR. Correlations with clinical and metabolic markers were evaluated. Obese patients showed decreased ADIPOQ (p = 0.039) and miR-142 (p = 0.008) expression and increased CCL2 (p = 0.004), miR-155 (p = 0.017), and miR-378 (p = 0.04) expression compared to the controls. MUO patients exhibited higher HIF1A expression (p = 0.03) and strong correlations between CCL2 and dyslipidemia (total cholesterol, triglycerides)/dysglycemia (fasting glucose) (r = 0.45, p = 0.03; r = 0.52, p = 0.01; r = 0.63, p = 0.001, respectively). miR-142 negatively correlated with fibrosis markers, while miR-378 was linked to insulin resistance. The differential gene and microRNA expression highlights the role of inflammation, hypoxia, and fibrosis in MUO pathogenesis. miR-142-3p, miR-155, and miR-378 may serve as potential biomarkers for metabolic risk stratification and therapeutic targets.

Keywords:  adipose tissue hypoxia; insulin resistance; metabolically healthy obesity; microRNA; subcutaneous adipose tissue

DOI:  https://doi.org/10.3390/ijms26178212
Cell Rep. 2025 Sep 09. pii: S2211-1247(25)01049-6. [Epub ahead of print]44(9): 116278

Early adipose tissue wasting in a preclinical model of human lung cancer cachexia.

Deena B Snoke, Jos L van der Velden, Emma R Bellafleur, Jacob S Dearborn, Sean M Lenahan, Alexandra E Beal, Reem Aboushousha, Skyler C J Heininger, Jennifer L Ather, Madeleine M Mank, Hailey Sarausky, Daniel Stephenson, Julie A Reisz, Angelo D'Alessandro, Devdoot Majumdar, Thomas P Ahern, Kaiwen Xu, Kim L Sandler, Bennett A Landman, Yvonne M W Janssen-Heininger, Matthew E Poynter, David J Seward, Michael J Toth.

  Cancer cachexia (CC), a syndrome of skeletal muscle and adipose wasting, reduces responsiveness to therapies and increases mortality. There are no approved treatments for CC, which may relate to discordance between preclinical models and human CC. To address the need for clinically relevant models of lung CC, we generated inducible, lung epithelial cell-specific KrasG12D/+ (G12D) mice. G12D mice develop CC over a protracted time course and phenocopy tissue and tumor, cellular, mutational, transcriptomic, and metabolic characteristics of human lung CC. G12D mice demonstrate early loss of adipose, a phenotype that was apparent across numerous models of CC and translates to patients with lung cancer. Tumor-released factors promote adipocyte lipolysis, a driver of adipose wasting in CC, and adipose wasting was inversely related to tumor burden. Thus, G12D mice model key features of human lung CC and highlight a role for early tumor metabolic reprogramming of adipose tissue in CC.

Keywords:  CP: Cancer; CP: Metabolism; inflammation; lipolysis; lung neoplasms; organoids; skeletal muscle

DOI:  https://doi.org/10.1016/j.celrep.2025.116278