bims-mimead 2026-08-23 papers

Endocrinology. 2026 Aug 18. pii: bqag093. [Epub ahead of print]

Hepatocyte ERα Mediates Estrogen-induced Augmentation of Hepatic Mitochondrial Respiration Following Ovariectomy.

Edziu Franczak, Benjamin A Kugler, Sebastian F Salathe, Julie A Allen, Colin S McCoin, Edward Matthew Morris, John P Thyfault.

Liver-specific ERα knockout (LERKO) mice with normal ovarian function are not susceptible to steatosis and maintain mitochondrial function. Here, we tested whether loss of hepatic ERα blunts estrogen modulation of hepatic mitochondrial respiratory capacity and mitochondrial proteome following ovariectomy (OVX). Sham or OVX surgery was performed in middle-aged female mice (36-40 weeks), followed by AAV injection to generate Control (Con; GFP) or LERKO mice (Cre). All mice were placed on a high-fat diet (HFD) for 10 weeks following surgery. Half of the OVX mice received 17-beta estradiol (E2) replacement (OVX + E2) for the last 4 weeks. OVX mice had greater body mass and adiposity, which was reversed by E2 replacement in both Con and LERKO mice. E2 replacement reduced steatosis in both Con and LERKO OVX mice, but the LERKO OVX mice maintained greater hepatic triglycerides. E2 replacement promoted greater basal and ADP-stimulated (State 3) mitochondrial respiration in Con OVX but not in LERKO OVX mice. Changes in mitochondrial respiration could not be attributed to altered responses to changes in energy demand (GATP) or to alterations in mitochondrial H2O2 production. Conversely, maximal coupled branched-chain amino acid-supported respiration was universally suppressed by E2 replacement. Proteomics analysis revealed E2-mediated reductions in hepatic mitochondrial energy transduction in both Con and LERKO mice. In conclusion, post-ovariectomy estrogen treatment reduces steatosis in the absence of hepatic ERα; however, steatosis remains higher, and mitochondrial deficits persist despite similar proteomic changes, suggesting ERα is required for optimal response to estrogen in modulating hepatic mitochondrial respiration.

Keywords: Estrogen Replacement; Female; Mitochondria; Steatosis

DOI: https://doi.org/10.1210/endocr/bqag093

Nat Metab. 2026 Aug 21.

Multi-organ proteomic atlas of obesity regression in male mice.

Felix Boel, Ellen Gammelmark Klinggaard, Vyacheslav Akimov, Daniel Hansen, M L Uthpala, Babukrishna Maniyadath, Flora Reincke Fuglsang, Marc Pielies Avellí, Simon Rasmussen, Kim Ravnskjær, Susanne Mandrup, Blagoy Blagoev.

Obesity drives systemic metabolic dysfunction, yet how the body adapts and recovers at a system-wide level remains unclear. Here we generate a multi-organ proteomic atlas of diet-induced obesity and its regression in male mice. Using a standardized, semi-automated sample preparation workflow, we quantify 12,936 unique proteins across 15 organs and four timepoints. We find proteomic changes to be highly tissue-dependent, with a small number of proteins displaying shared changes across multiple tissues. While proteomes of most tissues revert to lean levels after weight loss, white adipose tissue retains strong phagocytic and inflammatory responses, and the brain, kidney, bone, thymus and spleen display delayed obesity-induced alterations. We map the adipose tissue-specific immune regulators using ligand-target inference and show reduced expression of proteasomal subunits in brown adipose tissue, resulting in stalled ubiquitin turnover. Finally, we make all datasets open access and create an interactive webtool to facilitate further community-driven discovery.

DOI: https://doi.org/10.1038/s42255-026-01599-5

Diabetes. 2026 Aug 18. pii: db260239. [Epub ahead of print]

Comparing the Independent Effects of Weight Loss or Exercise Training on Skeletal Muscle Lipid Localization and Insulin Sensitivity in Humans.

Simona Zarini, Karin Zemski Berry, Amanda Garfield, Emily Macias, Purevsuren Jambal, Sophia Bowen, Melanie G Cree, Janet K Snell-Bergeon, Chris Johnson, P Darrell Neufer, Ian Tamburini, Marcus Seldin, Bryan C Bergman.

ARTICLE HIGHLIGHTS: Subcellular accumulation of lipids is linked to insulin resistance, but changes in localization from weight loss or exercise training have not been thoroughly explored. We evaluated the independent effects of two insulin-sensitizing interventions, weight loss and exercise training, on lipid subcellular distribution in fractionated skeletal muscle, muscle mitochondrial function, and gene expression. Exercise training increased cytosolic storage of diacylglycerols and sphingolipids, and weight loss increased cytosolic sphingosine and decreased mitochondrial/endoplasmic reticulum triacylglycerol and diacylglycerol accumulation. Exercise training prevented the negative effects of mitochondrial lipids on mitochondrial function. Changes in specific subcellular lipid storage help explain muscle insulin sensitization following lifestyle interventions.

DOI: https://doi.org/10.2337/db26-0239

FEBS Lett. 2026 Aug 21.

Partial depletion of plasminogen activator inhibitor-1 decreases subcutaneous fat cell hypertrophy and liver cholesterol in high-fat-fed female mice.

Claudia E Ramirez Bustamante, Robert Sharp, Pradip K Saha, Elizabeth S Anaya, Elizabeth L Lieu, Evelyn L de Groot, Pooja Patel, Mi Jeong Heo, Aaron R Cox, Kang Ho Kim, Sean M Hartig.

Higher levels of plasminogen activator inhibitor-1 (PAI-1) circulate in the blood of people with obesity and predict hyperlipidemia and metabolic dysfunction-associated steatotic liver disease in studies predominantly conducted in women. To understand the roles of PAI-1 in women with obesity, we generated inducible whole-body PAI-1-depleted female mice (Pai-1i-KD). After high-fat diet feeding, Pai-1i-KD and littermate controls did not differ in body weight or energy balance. However, Pai-1i-KD females accumulated smaller inguinal WAT adipocytes. Spectral flow cytometry revealed reduced adipocyte progenitors and macrophages in inguinal WAT. Pai-1i-KD mice also exhibited decreased liver cholesterol. These preclinical findings argue that elevated PAI-1 alters subcutaneous adipose tissue biology and contributes to pathogenic phenotypes of obesity.

Keywords: adipose tissue; fibrosis; high‐fat diet; metabolism; obesity; sex differences

DOI: https://doi.org/10.1002/1873-3468.70439

Aging Cell. 2026 Sep;25(9): e70678

Aged Mitochondrial DNA Is Associated With Aberrant Acute Exercise-Induced Redox Responses in Human Skeletal Muscle.

Bradley A Ruple, Nicholas A Carlini, Jason S Kofoed, Helya Rostamkhani, Brady E Hanson, Jesse C Craig, Shelby C Osburn, Allison M Manuel, Paul A Stewart, Jonathan Wanagat, Ryan M Broxterman, Joel D Trinity.

Redox imbalances and mitochondrial dysfunction are key contributors to age-related declines in skeletal muscle and may contribute to impaired exercise responsiveness. Here, we investigated the influence of aging on skeletal muscle redox at rest and in response to acute exercise, examining how mitochondrial quality and quantity relate to skeletal muscle redox status. Skeletal muscle biopsies were obtained from 12 young (22 ± 4 years) and 10 older adults (66 ± 7 years) before and immediately after 60-min of high-intensity knee-extension exercise. We assessed mitochondrial respiration, mitochondrial DNA (mtDNA) copy number and deletion mutation frequency at baseline, while skeletal muscle redox proteomics was performed on pre- and post-exercise biopsies in a subset of participants. Mitochondrial respiration was preserved with age (max respiration, p = 0.123). However, the older adults had a lower mtDNA copy number (p = 0.046) and higher mtDNA deletion frequency (p = 0.001), with widespread remodeling of the skeletal muscle redox proteome, including altered thiol occupancy of proteins involved in metabolism, immune function, and extracellular matrix organization. In response to exercise, young skeletal muscle exhibited predominantly reversible peptide reductions, whereas preferential oxidation of mitochondrial antioxidant proteins, including PRDX3, occurred in older muscle. Both mtDNA deletion frequency and mitochondrial respiration were strongly associated with exercise-induced redox modifications in mitochondrial proteins. These findings suggest that aging alters both the regulation and resolution of exercise-induced redox signaling, with mitochondrial genomic instability and respiration shaping redox responsiveness.

Keywords: aging; exercise; mitochondrial DNA; oxidative stress; redox proteomics

DOI: https://doi.org/10.1111/acel.70678

Diabetes. 2026 Aug 18. pii: db260066. [Epub ahead of print]

Organelle-Specific Lipid Profiles Underlie Metabolic Health in a Nutrition-Dependent Manner.

Cassandra Tabasso, Chaitanya K Gavini, Karin Zemski Berry, Hadi Salem, Axel K F Aguettaz, Sylviane Lagarrigue, Bryan C Bergman, Virginie Mansuy-Aubert, Francesca Amati.

ARTICLE HIGHLIGHTS: Skeletal muscle insulin resistance is linked to lipid metabolism, yet whole-tissue analyses obscure how subcellular lipid remodeling contributes to metabolic dysfunction. We investigated whether Western diet induces compartment-specific changes in skeletal muscle lipid classes and fatty acid (FA) composition and how these relate to metabolic health. Western diet disrupts the relationship between lipids and metabolism. Diacylglycerol FA composition reflected dietary supply. Phospholipid remodeling was class and compartment specific. Lipid droplet-localized 1,3-diacylglycerol, phosphatidylethanolamine, and phosphatidylglycerol reflected muscle health. These results highlight subcellular lipid organization as a key determinant of muscle insulin resistance and provide a framework for identifying early lipid signatures relevant to human diabetes research.

DOI: https://doi.org/10.2337/db26-0066

BMJ Open. 2026 Aug 20. 16(8): e122003

Women in healthy transition deep phenotyping cohort study protocol (KiSO-DP): a within-participant multidisciplinary longitudinal cohort study across the menopausal transition.

Andrea Tamariz-Ellemann, Ann-Sofie Kleis-Olsen, Amalie Bach Andersen, Laura Bachmann Thomsen, Marcos Paulo Rocha, Jonathan Fønss Frydenholm, Jakob Solgaard Jensen, Ellen Christine Leth Loekkegaard, Ylva Hellsten, Maria Hybholt, Lasse Gliemann.

BACKGROUND: Cardiovascular disease risk accelerates in women after the menopausal transition, coinciding with the cessation of endogenous oestrogen production. The accompanying decline in vascular function is considered a key driver of this shift. However, longitudinal studies investigating the impact and time course of changes in cardiovascular and skeletal muscle function during the menopausal transition and in the subsequent years are warranted.
OBJECTIVES: The Women in Healthy Transition (KiSO) Deep Phenotyping (DP) study is a multidisciplinary prospective longitudinal cohort study with the objective to determine cardiovascular changes from the late reproductive stage through 20 years of postmenopause. The primary outcome is quantification of endothelium-dependent vascular function. Secondary outcomes include evaluating endothelium-independent vascular function, conduit artery endothelial function, mitochondrial function, circulating skeletal muscle vascular markers and sociological factors. The overall aim is to provide deep mechanistic, longitudinal insight into menopause-related vascular ageing to inform future cardiovascular disease prevention strategies in women.
METHODS: 200 healthy women will be examined at the late reproductive stage and at 1, 3, 5, 10 and 20 years postmenopause. At each test round vascular function is evaluated using invasive intra-arterial infusion protocols, including acetylcholine and epoprostenol infusions, as well as flow-mediated dilation. Additional measures include arterial blood pressure, arterial compliance, echocardiography, cardiorespiratory fitness, whole-blood rheology, dual-energy X-ray absorptiometry-derived body composition, circulating reproductive and cardiometabolic biomarkers, skeletal muscle biopsies for assessment of mitochondrial capacity and proteins related to skeletal muscle and cardiometabolic health. Menopausal staging is determined using Stages of Reproductive Aging Workshop (STRAW)+10 criteria supported by follicle-stimulating hormone, anti-Müllerian hormone concentrations and antral follicle count.
ETHICS AND DISSEMINATION: The study is conducted in accordance with the Declaration of Helsinki and has been approved by the regional ethics committee: Ethics Committee of Copenhagen (H-22025286) and is registered with ClinicalTrial.gov (NCT05647876). Findings from the study will be disseminated through publications in peer-reviewed scientific journals, presentations at national and international conferences and through PhD theses. The results are expected to provide novel insights into the development of vascular and skeletal muscle function across the menopausal transition and may contribute to future strategies for prevention of cardiovascular disease in women.
TRIAL REGISTRATION NUMBER: NCT05647876.

Keywords: Aging; Physiology; Vascular medicine

DOI: https://doi.org/10.1136/bmjopen-2026-122003