bims-mimead 2025-10-05 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–10–05
ten papers selected by
Rachel M. Handy, University of Guelph

Defining the vascular niche of human adipose tissue across metabolic states.
Miro1 Mediates Skeletal Muscle Insulin Resistance in Type 2 Diabetes.
Effect of a Low Volume Exercise Intervention on the Plasma Lipidome in People with Normal Glucose, Prediabetes or Type 2 Diabetes: A Randomised Controlled Trial.
Low protein-induced-FGF-21 signaling remodels adipose tissue on reduced markers of senescence during aging.
Genetic Determinants of Fatty Acid Composition in Subcutaneous and Visceral Adipose Tissue.
Glucose-Dependent Insulinotropic Polypeptide and Glucagon After Weight Loss Induced by Diet or Bariatric Surgery.
MTCH2 modulates CPT1 activity to regulate lipid metabolism of adipocytes.
Effects of a GLP-1 Receptor Polymorphism on Responses to Liraglutide.
Diabetic heart shows preferential secretion of inner mitochondrial membrane proteins in the presence of mitochondrial oxidative stress.
Prevention of type 2 diabetes through prediabetes remission without weight loss.

bioRxiv. 2025 Sep 22. pii: 2024.09.22.610444. [Epub ahead of print]

Defining the vascular niche of human adipose tissue across metabolic states.

Ibrahim AlZaim, Mohamed N Hassan, Maja Schröter, Luca Mannino, Katarina Dragicevic, Marie Balle Sjogaard, Joseph Festa, Lolita Dokshokova, Sophie Weinbrenner, Blanca Tardajos Ayllon, Bettina Hansen, Rikke Kongsgaard Rasmussen, Julie N Christensen, Olivia Wagman, Ruby Schipper, Min Cai, Wouter Dheedene, Anja Bille Bohn, Jean Farup, Lin Lin, Samuele Soraggi, Anna Dalsgaard Thorsen, Amanda Bæk, Henrik Holm Thomsen, Maximilian von Heesen, Lena-Christin Conradi, Paul Evans, Carolina E Hagberg, Joerg Heeren, Margo Emont, Evan D Rosen, Aernout Luttun, Anders Etzerodt, Lucas Massier, Mikael Rydén, Niklas Mejhert, Matthias Blüher, Konstantin Khodosevich, Robert A Fenton, Bilal N Sheikh, Niels Jessen, Laura P M H de Rooij, Joanna Kalucka.

Adipose tissue homeostasis depends on a healthy vascular network. Vascular malfunction is a hallmark of obesity 1 , and vascular endothelial dysfunction, in particular, accelerates metabolic diseases, including obesity and diabetes. Single-cell transcriptomics studies have mapped the cellular landscape of human white adipose tissue (WAT) 2-8 . However, the vascular niche remains relatively undefined 9 , especially regarding its heterogeneity, function, and role in metabolic disease. To address this gap, we created a single-cell transcriptome atlas of human subcutaneous adipose tissue (SAT), comprising nearly 70,000 vascular cells from 65 individuals. We characterized seven canonical adipose tissue endothelial cell (AdEC) subtypes and identified a distinct heterogenous population, here referred to as sub-AdECs. Sub-AdECs exhibit gene signatures characteristic of multiple cell types, including mesenchymal, adipocytic, and immune, suggesting they possess diverse properties and identities. Through computational analyses and whole-mount imaging, we validated the occurrence of sub-AdECs and show that these cells likely arise through endothelial-mesenchymal transition (EndMT), the modulation of which limits obesity-associated adipose tissue inflammation and fibrosis. Furthermore, we compared the transcriptomes of vascular cells from individuals living with or without obesity and type 2 diabetes and find metabolic disease-associated inflammatory and fibrotic transcriptomic patterns. The atlas and accompanying analyses establish a solid foundation for investigations into the biology of the adipose tissue vascular niche and its contribution to the pathogenesis of metabolic disease.

DOI: https://doi.org/10.1101/2024.09.22.610444
medRxiv. 2025 Aug 10. pii: 2025.08.06.25333143. [Epub ahead of print]

Miro1 Mediates Skeletal Muscle Insulin Resistance in Type 2 Diabetes.

Elizabeth C Heintz, Wagner S Dantas, Analisa L Taylor, Elizabeth R M Zunica, Kathryn P Belmont, Jacob T Mey, Robbie Beyl, Bolormaa Vandanmagsar, Hailey A Parry, Peter Ajayi, Brian Glancy, Christopher L Axelrod, John P Kirwan.

Imbalanced skeletal muscle mitochondrial dynamics contributed to the onset and progression of type 2 diabetes (T2D) by mechanisms that remained incompletely understood. Here, we examined the role of mitochondrial Rho GTPase 1 (Miro1), an outer mitochondrial membrane enzyme, in the regulation of skeletal muscle insulin action and glucose homeostasis in T2D. Miro1 accumulated in the skeletal muscle of mice and humans with obesity and T2D, a phenomenon driven by impaired insulin-mediated interaction between AKT and Miro1 at the outer mitochondrial membrane. To determine whether Miro1 accumulation was reversible and functionally linked to metabolic improvements, we prospectively evaluated the impact of exercise training on skeletal muscle Miro1 expression, mitochondrial function, and insulin sensitivity in patients with T2D. Patients with T2D (N=24) were randomized to 12 weeks of standard care or exercise training. At baseline and after 12 weeks, we assessed changes in whole-body metabolic and mitochondrial function. Exercise training reduced skeletal muscle Miro1 accumulation (64.3% vs. -53.2% change from baseline; p=0.001) and enhanced mitochondrial oxidative capacity (-37.7% vs. 216.3% change from baseline; p=0.005) and insulin sensitivity (-18.5% vs. 80.0% change from baseline; p=0.007). To further establish a causal role for Miro1 in glucose homeostasis, we generated muscle-specific Miro1 loss- of-function models in mice and cells. Muscle-specific deletion of Miro1 improved insulin action and oxidative capacity in both models. Taken together, these findings supported a key regulatory role for skeletal muscle Miro1 in the pathophysiology of T2D.

DOI: https://doi.org/10.1101/2025.08.06.25333143
Am J Physiol Endocrinol Metab. 2025 Sep 29.

Effect of a Low Volume Exercise Intervention on the Plasma Lipidome in People with Normal Glucose, Prediabetes or Type 2 Diabetes: A Randomised Controlled Trial.

Oana C Marian, Danqing Min, Callum J Baker, Christopher John Hodgkins, James Gerofi, Xiaoyu Wang, Nathan Anthony Johnson, Anthony S Don, Stephen M Twigg.

  High-intensity interval training (HIIT) may improve metabolic outcomes in people with type 2 diabetes (T2D) and prediabetes (PD). This randomised controlled trial assessed plasma lipidomic differences between overweight participants (BMI>25 kg/m2) with normal glucose tolerance (NGT) (n=74), PD (n=60) or newly-diagnosed T2D (n=26), and the effects of a combined HIIT and progressive resistance training (PRT) intervention on circulating lipids. Participants were randomized to either a stretching or HIIT+PRT protocol. Fasted plasma was collected at baseline and after 12-weeks. Plasma lipids, D- and L-serine, and D- and L-alanine, were quantified with liquid chromatography-tandem mass spectrometry. Plasma lipidomics revealed significantly lower levels of sphingomyelin and lysophosphatidylcholine (LPC) and higher diacylglycerol and deoxyceramide species in T2D compared to NGT or PD. The HIIT+PRT intervention significantly reduced circulating deoxyceramides in the T2D group. We investigated the basis for elevated atypical deoxyceramides in T2D, which utilise L-alanine rather than L-serine as biosynthetic substrates. Serine levels were unchanged; however, L-alanine and D-alanine were increased in T2D. Total diacylglycerol, L-alanine and D-alanine positively correlated with fasting glucose, insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), glycated hemoglobin and liver fat, whereas sphingomyelin and LPC inversely correlated with fasting glucose and HOMA-IR. The L-alanine:L-serine ratio positively correlated with deoxyceramide levels, but was unaltered by the HIIT+PRT intervention. This study reveals plasma lipidomic perturbations in T2D, establishing that excess L-alanine may underpin elevated metabolically-adverse deoxyceramide levels in T2D, and demonstrates that a 12-week HIIT+PRT protocol significantly reduces deoxyceramides in individuals with T2D independently of the plasma L-alanine:L-serine ratio.

Keywords:  Deoxyceramides; Diabetes; Exercise; Lipidomics; Prediabetes

DOI:  https://doi.org/10.1152/ajpendo.00171.2025
Geroscience. 2025 Sep 29.

Low protein-induced-FGF-21 signaling remodels adipose tissue on reduced markers of senescence during aging.

Jose G Godoy-Lugo, Khristina E Young, Prerana Vaddi, Yvann Batamack, Jolaiya Aldridge, Sun Ok Fernandez-Kim, Diana C Albarado, Susan J Burke, Jacqueline M Stephens, Christopher D Morrison, Cristal M Hill.

  Cellular senescence and metabolic impairment occur during aging, with adipose tissue decline playing a key role in this process. Furthermore, the detriments of aging on adipose tissue function are further exacerbated by obesity. Dietary protein restriction (DPR), without reducing calorie intake, protects against age-related metabolic decline and extends lifespan through the metabolic hormone FGF21. Here, we demonstrate that protein restriction significantly decreases pro-oncogenic and senescence-related markers in adipose tissue, including SASP, Cdkn1a Cdkn1a, and SA-βgal staining. Additionally, mice fed a low-protein diet during diet-induced obesity demonstrated significant decreases in tumorigenic and cell cycle markers compared with mice fed a control protein and high-fat diet, suggesting that a low-protein diet decreases the burden of cellular senescence on adipose tissue in aged mice and aged obese mice. Conversely, mice lacking FGF21 failed to exhibit the benefits of protein restriction on markers of senescence in white and brown adipose tissue. These data demonstrate that protein restriction exerts distinct beneficial effects on white and brown adipose tissue remodeling on senescence and other markers associated with improvements in lifespan and particularly health span. Given the negative impact of cellular senescence on adipose tissue, protein restriction offers a potential dietary intervention to prevent the detriments of cellular senescence on adipose tissue function during obesity and aging.

Keywords:  Adipose Tissue; Amino acid; Dietary protein; Dietary restriction; FGF21; Lifespan; Metabolic health; Senescence

DOI:  https://doi.org/10.1007/s11357-025-01853-w
Obesity (Silver Spring). 2025 Sep 29.

Genetic Determinants of Fatty Acid Composition in Subcutaneous and Visceral Adipose Tissue.

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

   OBJECTIVE: Fatty acids in adipose tissue are key structural and metabolic regulators of cardiometabolic health, but the genetic architecture governing depot-specific composition in subcutaneous (SAT) and visceral adipose tissue (VAT) is not well defined.
METHODS: We used MRI-derived estimates of fatty acid composition in SAT and VAT from 33,583 UK Biobank participants to perform genome-wide association studies. Functional annotation, fine mapping, colocalization, and expression QTL analyses were conducted to prioritize likely causal variants and explore mechanisms.
RESULTS: We identified six loci associated with adipose tissue fatty acid composition, including both shared (PKD2L1, INSIG1) and depot-specific associations (LEKR1 and KLF14 for SAT; CDCA2 for VAT). The strongest association, rs603424-G (near PKD2L1), was linked to higher monounsaturated and polyunsaturated fatty acids, lower saturated fatty acids, and increased SCD1 expression in SAT and VAT, suggesting a role in desaturation and lipid remodeling. Several loci were linked to cardiometabolic outcomes including type 2 diabetes, hypertension, and cholelithiasis, with functional evidence supporting gene-diet interactions at the PKD2L1 locus.
CONCLUSIONS: Our findings uncover genetic determinants of human adipose tissue fatty acid composition, highlight depot-specific regulation, and point to SCD1 as a potential metabolic regulator. These results deepen understanding of lipid metabolism and its links to cardiometabolic risk.

Keywords:   SCD1 ; MRI scan; cardiometabolic disease; fatty acids; visceral adipose tissue

DOI:  https://doi.org/10.1002/oby.70045
Obesity (Silver Spring). 2025 Sep 29.

Glucose-Dependent Insulinotropic Polypeptide and Glucagon After Weight Loss Induced by Diet or Bariatric Surgery.

Amanda Finn, Yenni Cedillo, Marthe Aukan, Barbara Gower, Catia Martins.

   OBJECTIVE: This study compared the effects of a very low-energy diet (VLED), alone or combined with sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB), on glucose-dependent insulinotropic polypeptide (GIP) and glucagon concentrations, hormones likely to play a role in weight loss maintenance.
METHODS: Participants with severe obesity underwent 10 weeks of VLED alone (n = 15) or combined with SG (n = 15) or RYGB (n = 14). Plasma concentrations of glucagon and GIP (fasting and the first 60 min of a meal), insulin sensitivity, respiratory quotient, and resting energy expenditure (REE) were measured at pre- and post-intervention. Differences in hormone concentrations between groups at follow-up and associations between hormones and metabolic outcomes were evaluated.
RESULTS: Fasting glucagon concentrations were higher, while postprandial GIP concentrations were lower, after RYGB compared to SG. An increase in postprandial glucagon was associated with a decrease in Matsuda index in the RYGB group and with an increase in REE in all groups. An increase in fasting GIP was correlated with an increase in HOMA-IR.
CONCLUSIONS: RYGB was associated with lower postprandial GIP and greater glucagon concentrations compared with other groups. These hormonal changes are likely to impact REE, as well as insulin sensitivity, potentially modulating the likelihood of weight loss maintenance.
TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04051190.

Keywords:  GIP; bariatric surgery; glucagon; obesity

DOI:  https://doi.org/10.1002/oby.70049
Nat Commun. 2025 Oct 03. 16(1): 8831

MTCH2 modulates CPT1 activity to regulate lipid metabolism of adipocytes.

Chunyan Wu, Tongtong Wang, Adhideb Ghosh, Fen Long, Anand Kumar Sharma, Tina Dahlby, Falko Noé, Ilenia Severi, Georgia Colleluori, Saverio Cinti, Antonio Giordano, Lianggong Ding, Radhika Khandelwal, Sarantos Kostidis, Martin Giera, Lucia Balazova, Vincent Gardeux, Laith Abu-Nawwas, Bart Deplancke, Sabita Chourasia, Sandra Kleiner, Bradford S Hamilton, Juan Manuel Alcántara Alcántara, Jonatan R Ruiz, Matthias Blüher, Anton Pekcec, Miroslav Balaz, Atan Gross, Heike Neubauer, Christian Wolfrum.

Metabolic disorders, including obesity and metabolic-associated steatohepatitis, arise from a chronic energy surplus. Thus, enhancing energy dissipation through increased respiration holds significant therapeutic potential for metabolic disorders. Through a comprehensive analysis of human and murine adipose tissues, along with a functional screen, we identify mitochondrial carrier homolog 2, a mitochondrial outer membrane protein, as a pivotal regulator of mitochondrial metabolism. Intriguingly, its expression in adipose tissue is a strong determinant of obesity in humans. Adipocyte-specific ablation of mitochondrial carrier homolog 2 improves mitochondrial function and whole-body energy expenditure, independent of uncoupling protein 1. Furthermore, mitochondrial carrier homolog 2 regulates mitochondrial influx of free fatty acids by modulating the sensitivity of carnitine palmitoyltransferase 1 to malonyl-CoA through direct physical interaction, leading to enhanced energy expenditure in adipocytes/adipose tissue. Here we show mitochondrial carrier homolog 2 functions as a negative regulator of energy metabolism in adipocytes and represents a potential target for treating obesity and related metabolic disorders.

DOI: https://doi.org/10.1038/s41467-025-63880-7
J Endocrinol. 2025 Oct 03. pii: JOE-25-0174. [Epub ahead of print]

Effects of a GLP-1 Receptor Polymorphism on Responses to Liraglutide.

Mona Mashayekhi, Bilgunay Ilkin Safa, Hui Nian, Jessica K Devin, Jorge L Gamboa, Chang Yu, Rui Chen, Joshua A Beckman, John R Koethe, Heidi J Silver, Kevin Niswender, James M Luther, Nancy J Brown.

  The rs6923761 (Gly168Ser) missense variant in the glucagon-like peptide-1 receptor (GLP-1R) has been associated with favorable anthropometric and metabolic parameters in individuals with obesity but decreased responsiveness to incretin-based therapies. Here we performed a pre-specified analysis of a randomized controlled trial in individuals with obesity and pre-diabetes comparing treatment with the GLP-1R agonist liraglutide, the dipeptidyl peptidase 4 inhibitor sitagliptin or hypocaloric diet, and evaluated the effects of the rs6923761 variant on outcomes. We found significantly greater weight loss to liraglutide with each copy of the variant allele present, indicating a gene dose effect. In addition, individuals with the variant allele exhibited a significant reduction in the pro-thrombotic and pro-inflammatory factor plasminogen activator inhibitor-1 after liraglutide treatment. There was no effect of genotype on fasting glucose after liraglutide treatment, yet individuals with the variant allele exhibited decreased responsiveness to liraglutide and hypocaloric diet in measurements of fasting insulin, C-peptide, glucagon, as well as in HOMA-IR. In conclusion, we found that the GLP-1R rs6923761 variant exerts a dual impact on liraglutide efficacy -- enhancing weight loss while diminishing metabolic benefits. The observed associations could be consistent with constitutive activation of the GLP-1R in the presence of this variant with reduced activation/signaling in response to pharmacologic agents, a pattern that has been observed with the rs10305492 variant in animal models. Future studies are needed to investigate the molecular mechanisms of associations with the rs6923761 variant.

Keywords:  GLP-1 receptor; PAI-1; liraglutide; rs6923761; weight loss

DOI:  https://doi.org/10.1530/JOE-25-0174
Am J Physiol Endocrinol Metab. 2025 Oct 03.

Diabetic heart shows preferential secretion of inner mitochondrial membrane proteins in the presence of mitochondrial oxidative stress.

Paula M Miotto, Jacqueline Bayliss, Gio Fidelito, James R Bell, Lea M D Delbridge, Matthew J Watt, Magdalene K Montgomery.

  Heart disease, including diabetic cardiomyopathy, is a leading cause of mortality in patients with type 2 diabetes (T2D). Defects in heart function are accompanied by marked changes in cardiac metabolism, including dysregulation of lipid and glucose metabolism, mitochondrial dysfunction, and oxidative stress. In addition to these metabolic defects, the heart is an important endocrine organ. However, while T2D has been shown to impact the secretome of liver, skeletal muscle and adipose tissue (among others), little is known about the secretome of the heart, and the influence of T2D on cardiac protein secretion. Using precision-cut heart slices from mice with insulin resistance (20-weeks of high-fat feeding) and T2D (db/db mice) compared to their respective controls, we performed mass spectrometry proteomics analysis of cardiac protein secretion as well as proteins contained within extracellular vesicles (EV). We reveal striking remodelling of cardiac protein secretion in T2D but not diet-induced insulin resistance. Specifically, we show a marked increase in the secretion of inner mitochondrial membrane (IMM) proteins in T2D, which was accompanied by a disproportional accumulation of outer mitochondrial membrane proteins within the heart. This was associated with increased mitochondrial oxidative stress, selective oxidative damage to IMM proteins, and reduced markers of LC3-mediated mitophagy in the db/db heart, highlighting secretion of mitochondrial components as a potential alternative pathway for mitochondrial quality control. Altogether, this study provides an in-depth proteomics analysis showing remodelling of cardiac protein secretion in T2D and provides insights into a possible link between mitochondrial oxidative stress and the release of mitochondrial components.

Keywords:  cardiokine; diabetic heart; endocrine; mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.1152/ajpendo.00073.2025
Nat Med. 2025 Sep 29.

Prevention of type 2 diabetes through prediabetes remission without weight loss.

Arvid Sandforth, Elsa Vazquez Arreola, Robert L Hanson, Nicolai J Wewer Albrechtsen, Jens Juul Holst, Robert Ahrends, Cristina Coman, Felicia Gerst, Estela Lorza-Gil, Yurong Cheng, Leontine Sandforth, Sarah Katzenstein, Marlene Ganslmeier, Jochen Seissler, Hans Hauner, Nikolaos Perakakis, Robert Wagner, Jürgen Machann, Fritz Schick, Andreas Peter, Rainer Lehmann, Cora Weigert, Jennifer Maurer, Hubert Preissl, Martin Heni, Julia Szendrödi, Stefan Kopf, Michele Solimena, Peter Schwarz, Matthias Blüher, Hans-Ulrich Häring, Martin Hrabé de Angelis, Annette Schürmann, Stefan Kabisch, Knut Mai, Andreas F H Pfeiffer, Stefan Bornstein, Michael Stumvoll, Michael Roden, Norbert Stefan, Andreas Fritsche, Andreas L Birkenfeld, Reiner Jumpertz von Schwartzenberg.

Clinical practice guidelines recommend defined weight loss goals for the prevention of type 2 diabetes (T2D) in those individuals with increased risk, such as prediabetes. However, achieving prediabetes remission, that is, reaching normal glucose regulation according to American Diabetes Association criteria, is more efficient in preventing T2D than solely reaching weight loss goals. Here we present a post hoc analysis of the large, multicenter, randomized, controlled Prediabetes Lifestyle Intervention Study (PLIS), demonstrating that prediabetes remission is achievable without weight loss or even weight gain, and that it also protects against incident T2D. The underlying mechanisms include improved insulin sensitivity, β-cell function and increments in β-cell-GLP-1 sensitivity. Weight gain was similar in those achieving prediabetes remission (responders) compared with nonresponders; however, adipose tissue was differentially redistributed in responders and nonresponders when compared against each other-while nonresponders increased visceral adipose tissue mass, responders increased adipose tissue in subcutaneous depots. The findings were reproduced in the US Diabetes Prevention Program. These data uncover essential pathways for prediabetes remission without weight loss and emphasize the need to include glycemic targets in current clinical practice guidelines to improve T2D prevention.

DOI: https://doi.org/10.1038/s41591-025-03944-9