bims-mimead 2026-05-10 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2026–05–10
eight papers selected by
Rachel M. Handy, University of Guelph

An adipocyte-endothelial framework to identify molecular signatures of metabolic vulnerability in obesity.
Gut microbiota responses to bariatric surgery are associated with metabolic outcomes and type 2 diabetes remission.
Integrated analysis of insulin resistance reveals metabolic remodeling following diet switch-triggered calorie reduction.
Estrogen Mediates Capacity for Hyperplastic Adipose Expansion and Preserves Adipose Progenitor Cell Availability in Subcutaneous Depots of Female Mice.
GPR75 Genetic Manipulations in Mice Reveal Central Mechanism for Weight Loss Independent of Developmental Effects.
No Influence of Menstrual Phase on Substrate Oxidation Following Submaximal Aerobic Exercise in the Fed State.
A Novel Method to Evaluate Insulin Sensitivity by Combining Continuous Glucose Monitoring and Urinary C-Peptide Excretion.
Cytosolic PRDX1 acts as an extramitochondrial sink to set mitochondrial H2O2 levels and enable resilience to chronic mitochondrial oxidative stress.

Res Sq. 2026 Apr 23. pii: rs.3.rs-9485802. [Epub ahead of print]

An adipocyte-endothelial framework to identify molecular signatures of metabolic vulnerability in obesity.

Vaishali Chaurasiya, Luyang Li, Aina Lluch, Ana Fernández-Sánchez, Jukka Harju, Dan Duc Pham, Sanni Perttunen, Salla Keskitalo, Markku Varjosalo, Kirsi H Pietiläinen, P A Nidhina Haridas, José-Maria Moreno-Navarrete, José I Rodríguez-Hermosa, Encarna Piedrafita-Serra, Asha Kar, Päivi Pajukanta, Markku Laakso, Ville Männistö, Jussi Pihlajamäki, Minna U Kaikkonen, Gema Frühbeck, Oriol A Rangel-Zúñiga, Francisco José Tinahones, Carlos Dieguez, Ralph Burkhardt, Marcus Höring, Gerhard Liebisch, Johanna Pörschke, María Gómez-Serrano, Johannes Graumann, Witold Szymanski, José-Manuel Fernández-Real, You Zhou, Vesa Olkkonen, Francisco Ortega.

Obesity-related metabolic disease is linked to impaired adipose tissue function, but the underlying molecular programs are difficult to assign to specific adipose-resident cell types, to mechanistically connect to inflammation, and to distinguish from alterations that normalize with weight loss. We integrated here a layered design combining untargeted proteomics and lipidomics to define obesity-associated, cell-type-resolved molecular phenotypes across isolated adipocytes and adipose microvascular endothelial cells, explore whether an obesity-like inflammatory milieu reproduces adipose-resident cell dysfunction, and identify molecular features that show evidence of recovery after surgery-induced weight loss. As expected, adipocytes from people with obesity show suppression of mitochondrial energy metabolism together with impaired lipid plasticity, as reflected by triglyceride remodelling. By mimicking an obesity-like inflammatory milieu with macrophage-conditioned media, we reproduced most of these changes in adipocyte cultures. Endothelial cells exhibited yet another, opposite trajectory in obesity, with reduced cell-cycle signalling and increased mitochondrial activation, which were recapitulated in vitro when these cells were exposed, respectively, to the secretions of inflamed macrophages and adipocytes. Bulk adipose tissue proteomes and lipidomes showed evidence of metabolic improvement after weight loss, with broad restoration of mitochondrial and substrate-handling pathways and reciprocal triglyceride remodelling. Alongside the inflammation-responsive adipocyte mitochondrial and lipid-handling dysfunction, our cell-type-informed framework probes macrophage and adipocyte-to-endothelial activation in obesity and delineates cross-context cellular programs that recover with weight loss. Additionally, we identified the elements that exhibit the strongest association with dyslipidaemia, hypertriglyceridemia and hyperglycaemia in individuals with obesity, confirming molecular signatures relevant to metabolic obesity in two cross-sectional samples. Vaishali Chaurasiya, Luyang Li, Aina Lluch participated equally.

DOI: https://doi.org/10.21203/rs.3.rs-9485802/v1
Nat Metab. 2026 May 07.

Gut microbiota responses to bariatric surgery are associated with metabolic outcomes and type 2 diabetes remission.

Lisa M Olsson, Heidi Borgeraas, Rima M Chakaroun, Dag Hofsø, Jens Kristoffer Hertel, Chinmay Dwibedi, Matthias Mitteregger, Jens Juul Holst, Valentina Tremaroli, Jøran Hjelmesæth, Fredrik Bäckhed.

Bariatric surgeries, such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), improve obesity and type 2 diabetes (T2D). Both surgeries affect the gut microbiota, but their contribution to T2D remission remains unclear. In this subanalysis (RYGB, n = 39; SG, n = 38) of the randomized controlled Oseberg trial ( NCT01778738 ), in which participants underwent either RYGB or SG surgery, we profiled the faecal microbiome of individuals with obesity and T2D before and 12 months after surgery. We show that both surgeries altered the microbiome in the same direction, but with larger changes after RYGB. The SG-associated altered microbiome composition correlated positively with circulating glucagon-like peptide 1 levels, beta-cell function and 5 year T2D remission. Remission was also linked to increased gene richness and metabolic potential for fermentation, methanogenesis and butyrate production. Notably, these associations persisted after accounting for the extent of weight loss. Our findings indicate that surgery-specific microbial adaptations influence metabolic improvements and may help to explain heterogeneity in T2D remission after bariatric surgery.

DOI: https://doi.org/10.1038/s42255-026-01525-9
Sci Adv. 2026 May 08. 12(19): eaed0535

Integrated analysis of insulin resistance reveals metabolic remodeling following diet switch-triggered calorie reduction.

Xiaowen Duan, Lucy M Davis, Satish Patel, Guillaume Bidault, Lu Long, Benjamin Jenkins, Yao Yi, Pushpa Pushpa, Julia R Wesseling, Albert Koulman, Antonio Vidal-Puig, Daniel J Fazakerley, David B Savage.

Insulin resistance (IR) links obesity to metabolic disorders. While weight loss reverses IR, we show that calorie reduction (CR) can do so in obese mice within a day before significant weight loss. In contrast to whole-body IR, individual tissues do not revert to their original chow diet-fed states after CR. In the liver, improved insulin sensitivity correlates with reduced triacylglycerol and diacylglycerol and protein kinase C epsilon activity, alongside substantially decreased de novo lipogenesis and increased ketones. In muscle, insulin-sensitive glucose disposal was restored, whereas obesity-associated adipose tissue changes largely persisted following CR, specifically the reduction in fasting lipolytic activity mediated at least, in part, by lower β-adrenergic receptor 3 expression. This, combined with enhanced oxidative pathways in muscle and liver, resulted in lowered plasma free fatty acid levels and muscle and liver lipids, facilitating insulin-stimulated glucose disposal and thus restored insulin sensitivity.

DOI: https://doi.org/10.1126/sciadv.aed0535
Diabetes. 2026 May 07. pii: db250773. [Epub ahead of print]

Estrogen Mediates Capacity for Hyperplastic Adipose Expansion and Preserves Adipose Progenitor Cell Availability in Subcutaneous Depots of Female Mice.

Taylor B Scheidl, Jessica L Wager, Sophie Z Yonan, Ji Soo Yoon, Elizabeth A Wellberg, Jennifer A Thompson.

ARTICLE HIGHLIGHTS: We undertook this study to elucidate the role of adipose progenitor cells (APCs) in governing sex differences in metabolic disease susceptibility and the heightened risk for metabolic disease in women after menopause. How do sex and estrogen influence APC differentiation capacity in subcutaneous adipose depots, and how does this relate to metabolic function in obesity? Estrogen mediates the recruitment of APCs for hyperplastic expansion of subcutaneous depots, which may contribute to female-specific protection against obesity-induced metabolic disease. Our findings highlight an underrecognized contributor to sex differences in the risk for obesity-associated metabolic disease throughout the life course and implore a revision of the adipose tissue expandability hypothesis in consideration of the influence of sex.

DOI: https://doi.org/10.2337/db25-0773
Mol Metab. 2026 May 06. pii: S2212-8778(26)00065-7. [Epub ahead of print] 102381

GPR75 Genetic Manipulations in Mice Reveal Central Mechanism for Weight Loss Independent of Developmental Effects.

Hua V Lin, Ibragim Gaidarov, Giuseppe Militello, Kevin W Hunt.

   OBJECTIVE: Human genetic studies have identified GPR75 loss-of-function variants to be strongly protective against obesity, establishing GPR75 as a compelling therapeutic target. However, critical questions remain regarding the translational potential of GPR75 inhibition. These include whether adult-onset inhibition can reverse established obesity and which tissue compartments mediate weight loss. Here, we address these fundamental questions using novel genetic mouse models.
METHODS: We generated whole-body inducible Gpr75 knockout mice to assess the effects of adult-onset Gpr75 deletion. Adult Gpr75flox/flox; R26-CreERT mice were treated with tamoxifen either pre-obesity and then challenged with high-fat diet (HFD) to evaluate protection from weight gain, or post-obesity establishment to evaluate weight loss. The role of brain Gpr75 was determined using neonatal intracerebroventricular injection of adeno-associated viruses carrying artificial microRNAs targeting Gpr75, and weight gain on HFD was evaluated. Both male and female mice were examined.
RESULTS: Adult-onset Gpr75 knockout prevented diet-induced obesity when induced prior to HFD challenge, indicating the body weight phenotype is independent of developmental effects. Strikingly, Gpr75 deletion induced in obese mice produced robust weight loss, demonstrating the potential for therapeutic efficacy. Body composition analysis revealed specific fat mass reduction with complete lean mass preservation in Gpr75 inducible knockout mice. The body weight differences occurred with no change or only modest reductions in food intake. Postnatal brain-targeted Gpr75 knockdown was sufficient to confer significant protection from diet-induced obesity, with efficacy correlating to knockdown efficiency.
CONCLUSIONS: These data provide compelling genetic evidence that Gpr75 inhibition in adulthood can achieve substantial weight loss with selective fat mass reduction and lean mass preservation, operating through a mechanism that extends beyond appetite suppression alone. In addition, Gpr75 action in the postnatal brain plays a critical role in mediating these effects. Our findings de-risk a major translational concern, i.e., the developmental impacts of GPR75 on body weight regulation, and support the exploration of brain-penetrant GPR75 inhibitors as a novel obesity therapeutic strategy.

Keywords:  GPR75; body composition; inducible knockout; knockdown; obesity; weight loss

DOI:  https://doi.org/10.1016/j.molmet.2026.102381
Med Sci Sports Exerc. 2026 Apr 29.

No Influence of Menstrual Phase on Substrate Oxidation Following Submaximal Aerobic Exercise in the Fed State.

Jessica A L Tucker, Derek P D Bornath, Seth F McCarthy, Tom J Hazell.

   INTRODUCTION: Recently the influence of the menstrual cycle and more importantly, fluctuations in key sex hormones across the follicular (FP), ovulation (OP) and luteal (LP) phases have on during exercise substrate oxidation has been questioned. In addition to a significant amount of work not following best practices when determining menstrual phase, the inter- and intra-individual variability in hormonal concentrations across cycles may be affecting our understanding.
PURPOSE: To examine the effect of three hormonally distinct phases of the menstrual cycle (FP, OP, LP) on during and post-exercise substrate oxidation following an acute bout of submaximal aerobic exercise in the fed state while utilizing best practices to determine menstrual phase.
METHODS: Thirteen females (age: 24±4 y, BMI: 24.8±5.4 kg·m -2, V̇O2max: 41.02±5.30 mL·kg·min -1) completed 30 min of submaximal aerobic exercise in the FP, OP, and LP where menstrual phase was tracked using cycle counting, oral body temperature, ovulation strips, and blood sampling. Between-phase differences in respiratory exchange ratio (RER), substrate oxidation, oxygen consumption (V̇O2), overall session O2, and post-exercise metabolism were compared using a series of linear mixed models (LMMs; timepoint x phase).
RESULTS: There were no between-phase differences in V̇O2, overall session O2, post-exercise metabolism, or RER (P>0.119, R 2<0.993). There were also no between-phase differences in fat (P=0.417, R 2=0.920) or carbohydrate oxidation (P=0.235, R 2=0.845) during or post-exercise.
CONCLUSIONS: These findings demonstrate no differences across menstrual phase in during and post-exercise metabolism following an acute bout of submaximal exercise.

Keywords:  ENERGY METABOLISM; ESTRADIOL; FEMALE; LIPID METABOLISM; PROGESTERONE

DOI:  https://doi.org/10.1249/MSS.0000000000004023
Diabetes Obes Metab. 2026 May 04.

A Novel Method to Evaluate Insulin Sensitivity by Combining Continuous Glucose Monitoring and Urinary C-Peptide Excretion.

Guillermo Sanchez-Delgado, Kara L Marlatt, Robbie A Beyl, Joshua R Sparks, Emily W Flanagan, Frank L Greenway, Eric Ravussin.

   AIM: Assessing insulin sensitivity is a central component of clinical research in metabolism. Although considered the gold standard, the euglycemic-hyperinsulinemic clamp evaluates insulin sensitivity under non-physiological conditions and is highly burdensome and costly, thereby prompting the development of alternative methods. The 24-h urinary C-peptide excretion rate adjusted for energy intake is a surrogate marker of insulin sensitivity in non-diabetic adults. We hypothesized that the combination of 24-h continuous glucose monitoring (CGM) and 24-h urinary C-peptide excretion (24 h-glycemia/C-peptide ratio) would be a better predictor of insulin sensitivity than the C-peptide excretion rate adjusted for energy intake or other widely accepted indexes.
METHODS: Thirteen non-diabetic individuals (7 women, 6 men; 52.2 ± 13.8 years; BMI: 26.1 ± 3.7 kg/m2) participated in this cross-sectional study. They completed a 24-h stay in a whole-room indirect calorimeter wearing a CGM sensor (Dexcom G6 Pro) while all produced urine was collected. Insulin sensitivity was assessed by a 2-step hyperinsulinemic-euglycemic clamp [180 min at 10 mU/min/m2 (low-dose) and 120 min at 80 mU/min/m2 (high-dose)].
RESULTS: The 24 h-glycemia/C-peptide ratio was positively associated with the clamp's low-dose glucose infusion rate (GIR: R2 = 0.401, p = 0.020) and tended to be associated with the high-dose GIR (R2 = 0.266, p = 0.086). The associations between GIR and previously accepted markers of insulin sensitivity resulted in R2 ranging from 0.248 to 0.456 for the clamp low dose and R2 ranging from 0.108 to 0.174 for the clamp high dose.
CONCLUSIONS: These results suggest that the 24 h-glycemia/C-peptide ratio is a promising simple, inexpensive, non-invasive, and physiological marker of insulin sensitivity that deserves further investigation.

Keywords:  CGM; C‐peptide; hyperinsulinemic‐euglycemic clamp; insulin resistance; prediabetes

DOI:  https://doi.org/10.1111/dom.70802
Redox Biol. 2026 Apr 30. pii: S2213-2317(26)00193-X. [Epub ahead of print]94 104195

Cytosolic PRDX1 acts as an extramitochondrial sink to set mitochondrial H2O2 levels and enable resilience to chronic mitochondrial oxidative stress.

Lianne Jhc Jacobs, Sebastian Doll, Dietrich Trümbach, Matteo Veronese, Giada Di Pietro, Fatma Isil Yapici, Lidwina Hasberg, Pascal Gentzsch, Sarah Gerlich, Jens Hansen, Silvia von Karstedt, Elena I Rugarli, Marcus Conrad, Armindo Salvador, Jan Riemer.

Hydrogen peroxide (H2O2) plays a dual role as both a signalling molecule and a mediator of oxidative stress. Although mitochondria are major producers of H2O2, the relative contributions of mitochondrial versus cytosolic antioxidant systems to mitochondrial H2O2 homeostasis in intact cells remain poorly defined. Here, we combined compartment-resolved live-cell imaging using HyPer7, inducible mitochondrial H2O2 generation (matrix-targeted d-amino acid oxidase), kinetic modelling, and a targeted CRISPR/Cas9 screen to dissect determinants of mitochondrial H2O2 dynamics in HEK293 cells. Unexpectedly, we found that the cytosolic peroxiredoxin PRDX1 is a dominant regulator of mitochondrial matrix H2O2 levels. Loss of cytosolic PRDXs markedly enhanced matrix Hyper7 signals under both exogenous and mitochondria-intrinsic H2O2 production, exceeding the effects of deleting mitochondrial peroxiredoxins. Modelling and transport experiments indicated a very high permeability of the mitochondrial inner membrane to H2O2 enabling rapid efflux and the establishment of steep concentration gradients. This permits the cytosol to function as a major sink to limit matrix H2O2 accumulation. PRDX1 deficiency sensitized cells to chronic mitochondrial oxidative stress. A targeted CRISPR screen identified the Rab7 GAP TBC1D5, linking mitophagy to cellular survival under these conditions. Consistently, PRDX1/2-deficient cells exhibited elevated mitophagic flux, indicating mitochondrial quality control as a compensatory response. Our study reveals that cytosolic PRDXs critically impact mitochondrial redox homeostasis and provides a systems-level framework for understanding compartmental redox control and stress adaptation.

DOI: https://doi.org/10.1016/j.redox.2026.104195