bims-mimead 2026-03-01 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2026–03–01
nine papers selected by
Rachel M. Handy, University of Guelph

Male obesity causes adipose mitochondrial dysfunction in F1 mouse progeny via a let-7-DICER axis.
MEDAG functions as an A-kinase-anchoring protein in adipocytes.
Weight Loss by Diet Versus Metabolic Surgery Increases Circulating NT-proANP in Obese Individuals.
Fatty acids promote uncoupled respiration via ATP/ADP carriers in white adipocytes.
Estradiol enhances influenza vaccine responses through B cell metabolic reprogramming in female mice.
Visceral, not abdominal subcutaneous, fat cell size associates with metabolic dysfunction-associated liver disease in severe obesity.
Menstrual cycle influences skeletal muscle oxygenation during high-intensity interval training: a work to rest evaluation.
Circulating Asprosin Levels and Body Weight Changes in Postmenopausal Women: Findings from the Women's Health Initiative.
Adipose Tissue-Derived Small Extracellular Vesicles in Plasma Reveal Molecular Circuitries Underlying Glucose Intolerance.

Nat Commun. 2026 Feb 24.

Male obesity causes adipose mitochondrial dysfunction in F1 mouse progeny via a let-7-DICER axis.

Chien Huang, Joo-Hyun Park, Ali Altıntaş, Natasa Stanic, Kristine Kyle de Leon, Signe Isacson, Panagiotis Kalogeropoulos, Hande Topel, Tobias Madsen, Sebastian Zanner, Phillip Mm Ruppert, Rocio Valdebenito, Jesper Havelund, Bjørk Ditlev Marcher Larsen, Yen-Ting Chien, Wen-Chi Huang, Yovita Permata Budi, Yi-Fan Jiang, Andréa Livia Rocha, Niedson Correia Lima-Junior, Karolina Szczepanowska, Jan-Wilm Lackmann, Aleksandra Trifunovic, Eva Kildall Hejbøl, Sönke Detlefsen, Ida Engberg Jepsen, Stefanie Hansborg Kolstrup, Ricardo Laguna-Barraza, Javier Martin-Gonzalez, Konstantin Khodosevich, Nils J Færgeman, Marcelo A Mori, Marc R Friedländer, Anita Öst, Romain Barrès, Jan-Wilhelm Kornfeld.

Male obesity negative affects gametic function and offspring metabolism. We here describe that (F0) obesity and weight loss in male mice reversibly alter metabolism and impair adipose mitochondrial function. These metabolic aberrations are transmitted to male offsprings (F1), which display reduced mitochondrial gene expression. Mechanistically, we identify microRNAs let-7d/e as epigenetic mediators induced in obese F0 sperm and in F0/F1 adipose tissue, where they silence the miRNA processor DICER1 and impair mitochondrial activity. Microinjecting let-7d/e into lean zygotes phenocopies the paternal obesity phenotype, inducing glucose intolerance and mitochondrial gene suppression in sired offspring. Single-cell RNA sequencing of blastomeres reveals that let-7d/e impair oxidative metabolism in early embryos. Furthermore, lifestyle-induced weight loss in males with obesity downregulates human HSA-LET-7D/E in semen, indicating a conserved role for let-7 in transmission of metabolic health. These findings demonstrate that microRNA let-7 in sperm reprograms offspring metabolism by modulating mitochondrial function during early development.

DOI: https://doi.org/10.1038/s41467-026-69686-5
Mol Cell. 2026 Feb 25. pii: S1097-2765(26)00096-1. [Epub ahead of print]

MEDAG functions as an A-kinase-anchoring protein in adipocytes.

Fen Long, Adhideb Ghosh, Tianyu Xu, Lianggong Ding, Chunyan Wu, Radhika Khandelwal, Falko Noé, Wenfei Sun, Hua Dong, Tongtong Wang, Anne Hoffmann, Vincent Gardeux, Bart Deplancke, Laith Abu-Nawwas, Patrik Stefanicka, Lukas Varga, Jonatan R Ruiz, Matthias Blüher, Miroslav Balaz, Anand Kumar Sharma, Christian Wolfrum.

  Induction of catabolic adipocyte activity independent of mitochondrial uncoupling to induce energy expenditure has received increasing attention. In this study, we identified mesenteric estrogen-dependent adipogenesis gene (MEDAG), a poorly studied gene, as a promising therapeutic target for enhancing energy expenditure in adipocytes. We demonstrated that adipose MEDAG expression positively correlates with obesity and metabolic dysfunction in humans. Consistently, adipocyte-specific ablation of Medag in mice leads to increased energy expenditure, offering protection from diet-induced obesity. Mechanistically, we show that MEDAG functions as an A-kinase-anchoring protein (AKAP), which can directly regulate protein kinase A (PKA) activity through a negative feedback loop, involving direct interaction with PKA leading to MEDAG phosphorylation and consequent feedback fine-tuning of PKA activity. Specifically, the direct interaction of MEDAG with the PKA-RIIβ subunit regulates the stability of PKA-RIIβ to prevent PKA hyperactivation. These findings position MEDAG as a target for adipose energy expenditure and uncover its AKAP activity.

Keywords:  AKAP; MEDAG; PKA; cAMP-PKA signaling; catabolic adipocytes; energy expenditure; glucose uptake and utilization; lipolysis; metabolic diseases; obesity

DOI:  https://doi.org/10.1016/j.molcel.2026.02.001
J Clin Med. 2026 Feb 14. pii: 1515. [Epub ahead of print]15(4):

Weight Loss by Diet Versus Metabolic Surgery Increases Circulating NT-proANP in Obese Individuals.

Andreas Schmid, Maria Koukou, Thomas Karrasch, Andreas Schäffler.

  Background: Natriuretic peptides are endocrine factors that regulate various physiological processes via natriuretic peptide receptors (NPRs). Regulation of the atrial natriuretic peptide ANP during weight loss remains widely unknown. The present study investigated serum quantities of the circulating ANP precursor NT-proANP in obesity and during therapy-induced weight loss. Methods: The study enrolled 284 severely obese individuals. A total of 163 patients underwent metabolic surgery (either Roux-en-Y gastric bypass or vertical sleeve gastrectomy) and 121 patients participated in a non-invasive obesity therapy applying low-calorie formula diet. Anthropometric and physiological data were assessed, and blood serum was prepared at study baseline and at follow-up visits (3 and 12 months after start of intervention). Subcutaneous and visceral adipose tissue specimen were obtained from metabolic surgery patients. Circulating NT-proANP levels were determined by ELISA and gene expression levels of the receptor NPRA in adipose tissue were quantified by real-time RT-PCR. Results: Comparative analysis revealed significantly higher NPRA expression in visceral than in subcutaneous adipose tissue. NT-proANP levels significantly increased during weight loss over 12 months upon diet and metabolic surgery. NT-proANP serum concentrations were positively correlated with fibroblast growth factors 19 and 21 quantities at study baseline and considerably increased during weight loss in both cohorts after 12 months. We conclude that weight loss is a positive regulator of circulating NT-proANP quantities, regardless of the applied therapy.

Keywords:  NPRA; NT-proANP; Roux-en-Y gastric bypass (RYGB); adipose tissue; low-calorie formula diet (LCD); obesity

DOI:  https://doi.org/10.3390/jcm15041515
Nat Metab. 2026 Feb 23.

Fatty acids promote uncoupled respiration via ATP/ADP carriers in white adipocytes.

Maryam Ahmadian, A Melisa Aksu, Preetveer Dhillon, Zane J Zerbel, Yosip Kelemen, Oluwafemi Gbayisomore, Nicolás Gómez-Banoy, Serena J Chen, Shannon M Reilly.

Energy stored in adipocytes as triglycerides is mobilized via lipolysis, releasing fatty acids and glycerol into the circulation. Re-esterification of fatty acids that remain within the adipose tissue is the primary driver of adipocyte ATP consumption. Paradoxically, re-esterification suppresses respiration in lipolytic adipocytes. We previously found that STAT3 drives respiration by inhibiting re-esterification via GPAT3. Here we show that free fatty acids drive uncoupled respiration in complex with the ATP/ADP carriers. The impacts of lipolysis and re-esterification on uncoupled respiration correspond with fatty acids, not fatty acyl-CoAs or beta-oxidation. Under standard housing conditions, brown adipocyte uncoupling via uncoupling protein 1 is the dominant thermogenic pathway. However, in obese thermoneutral-adapted mice, uncoupled respiration in white adipocytes contributes to thermogenesis and cold tolerance, independent of brown adipose tissue or muscle activity. Our results suggest that uncoupled respiration in white adipocytes contributes to whole-body energy expenditure and could be a promising target for obesity treatment.

DOI: https://doi.org/10.1038/s42255-026-01467-2
mBio. 2026 Feb 26. e0396525

Estradiol enhances influenza vaccine responses through B cell metabolic reprogramming in female mice.

Laura A St Clair, Emily G Watters, Anna Yin, Jennifer A Liu, Sabal Chaulagain, Elizabeth A Thompson, Sabra L Klein.

  Reproductive-aged females mount stronger antibody responses to influenza vaccination than males, with the sex difference waning in older age. Estradiol has been implicated as a driver, but the mechanisms mediating how estradiol affects B cell function remain elusive. Adult (3 months) and aged (17 months) male and female mice were vaccinated and boosted with inactivated influenza vaccine. Metabolomics analysis of splenic B cells revealed that adult female B cells were enriched in lipid metabolic pathways, whereas B cells from males were enriched in central carbon-associated pathways following vaccination. B cells from vaccinated adult females exhibited greater expression of mTOR and related proteins than those from males, a difference diminished in aged mice. In adult females, estradiol depletion reduced, and replacement increased, mTOR activity in B cells, particularly in germinal center B cells and plasmablasts in lymphoid tissues, and plasma cells in bone marrow. In males, neither testosterone depletion nor repletion altered B cell metabolism. These findings are consistent with evidence that estradiol enhances mTOR activation via estrogen receptor α (ERα) signaling, suggesting coordinated regulation between estrogen and mTOR signaling in B cells. Inhibition of mTOR with rapamycin impaired vaccine-induced antibody responses and protection in adult females. In aged females, supplementation with estradiol or treatment with a selective ERα agonist increased mTOR signaling and enhanced antibody responses compared with mock-treated aged females. These data identify estrogen signaling as a regulator of B cell metabolism that supports greater expansion and function of antibody-secreting cells following vaccination in females compared with males.
IMPORTANCE: Vaccine-induced immunity differs between the sexes, with adult females mounting stronger antibody responses to influenza vaccination than age-matched males. We show that estradiol in females regulates B cell metabolism to promote the maturation and metabolic activation of antibody-secreting B cells, thereby enhancing humoral immunity and protection following vaccination. mTOR signaling in B cells was greater in adult females than males after vaccination, which was diminished with aging or depletion of estradiol. Therapeutic treatment of aged females with either estradiol or a selective estrogen receptor α modulator increased mTOR signaling and improved vaccine-induced antibody responses, thereby eliminating the effects of aging on influenza immunity. Harnessing estrogen-signaling mechanisms to improve responses to influenza vaccines could be a novel therapeutic strategy to improve public health.

Keywords:  aging; estrogen; immunometabolomics; influenza; neutralizing antibodies; sex difference

DOI:  https://doi.org/10.1128/mbio.03965-25
Obes Facts. 2026 Feb 25. 1-25

Visceral, not abdominal subcutaneous, fat cell size associates with metabolic dysfunction-associated liver disease in severe obesity.

Eve-Julie Tremblay, Laurent Biertho, Stéfane Lebel, Christian Y Couture, Ina Maltais-Payette, Giada Ostinelli, Marie-Frédérique Gauthier, Fannie Lajeunesse-Trempe, Pascale Mauriège, André Tchernof.

INTRODUCTION: Adipocyte hypertrophy is an important marker of adipose tissue dysfunction which significantly correlates with cardiometabolic risk factors. Fat cell size increases with adiposity and then plateaus at body mass index (BMI) values higher than 30 kg/m2. It is unknown whether fat cell size still associates with markers of dysmetabolism in severe obesity. Our objectives were to examine the associations between adipocyte diameter and markers of cardiometabolic health in a large sample of participants with severe obesity while adjusting for age, BMI and waist circumference.
METHODS: Biopsy samples of liver as well as abdominal subcutaneous and omental adipose tissues were obtained from 337 bariatric surgery patients. Evaluation of histological liver characteristics (steatosis, steatohepatitis, portal and lobular inflammation, hepatocellular ballooning and hepatic fibrosis) was performed by specialized pathologists. Adipocyte diameters were measured automatically using microscopy imaging. Lipid-lipoprotein profile, glucose-insulin homeostasis and adipokine levels were measured from blood samples.
RESULTS: Omental fat cell size was significantly larger with the presence of metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, liver fibrosis and lobular inflammation, as well as the presence and severity of portal inflammation. When stratified by gender, omental adipocytes were larger in women with liver injury, but not in men.
CONCLUSION: In participants with severe obesity, associations between adipocyte hypertrophy and cardiometabolic risk factors are mostly seen in the omental fat compartment, and especially in women.

DOI: https://doi.org/10.1159/000550650
Appl Physiol Nutr Metab. 2026 Feb 26.

Menstrual cycle influences skeletal muscle oxygenation during high-intensity interval training: a work to rest evaluation.

Paul A Baker, Alex Ladan, Kelly Joniak, Sam R Moore, Morgan Britton, Elena Cantu, Nathaniel Jenkins, Abbie E Smith-Ryan.

INTRODUCTION: The menstrual cycle (MC), characterized by hormonal fluctuations, may impact skeletal muscle oxygenation (SMO) during high-intensity interval training (HIIT). SMO measured around HIIT in eumenorrheic (EUM) or hormonal contraceptive (HC) users can inform exercise and recovery practices.
METHODS: Females who were EUM (no hormonal contraceptive n=21; copper intrauterine device n=5) or using HC (oral n=5; hormonal intrauterine n=6) completed two HIIT protocols (HIIT1:1: 10×60s work/60s rest; HIIT2:1: 20×20s work/10s rest) during both low-hormone (LHP) and high-hormone phases (HHP) of the MC, in randomized order. SMO (tissue saturation index [TSI] and total hemoglobin [THb] were measured at rest, during HIIT, and during 15-minute recovery using near-infrared spectroscopy. Data were analyzed as repeated measures ANOVA.
RESULTS: During HIIT1:1, TSI desaturation was greater in LHP (-8.30±3.30%) compared to HHP (-6.77±4.55%; MC phase p<0.001). During HIIT2:1, TSI desaturation was greater in HHP (-6.98±3.54%) compared to LHP (-6.71±3.61%; MC phase p<0.001). During HIIT2:1, TSI resaturation was greater in LHP (-5.05±3.31%) compared to HHP (-5.33±3.31%; MC phase p=0.004). During recovery from HIIT1:1, THb was greater in LHP (16.25±6.32 µM) compared to HHP (15.91±6.46 µM; MC phase p=0.039). During HIIT2:1 recovery, THb was higher in HHP (15.92±5.47 µM) compared to LHP (14.08±5.05 µM; MC phase p=0.039). During HIIT2:1, HC demonstrated greater TSI desaturation and resaturation in HHP compared to LHP (p<0.001).
CONCLUSION: These data suggest MC influences SMO during HIIT, with HHP favoring longer work/rest intervals (HIIT1:1), while recovery remains unaffected; HC demonstrated greater SMO fluctuations during HIIT2:1 in HHP.

DOI: https://doi.org/10.1139/apnm-2025-0397
J Nutr. 2026 Feb 25. pii: S0022-3166(26)00090-8. [Epub ahead of print] 101441

Circulating Asprosin Levels and Body Weight Changes in Postmenopausal Women: Findings from the Women's Health Initiative.

Stella Ng, Bo Yang, Jie Li, Elizabeth S Silva, JoAnn E Manson, Lawrence S Phillips, Alexander P Reiner, Atul R Chopra, Simin Liu.

   BACKGROUND: Weight changes after menopause contribute to cardiometabolic risk, yet hormonal determinants of long-term weight trajectories remain incompletely understood. Asprosin, a fasting-induced adipokine involved in hepatic gluconeogenesis and appetite regulation, has been associated with metabolic disease, though its prospective role in affecting weight change remain unknown.
OBJECTIVE: To examine whether plasma asprosin levels are directly and prospectively associated with changes in body weight and body composition among postmenopausal women.
METHODS: In a case-control study of 4,020 postmenopausal women (1,987 newly occurred/incident diabetes cases and 2,033 matched controls) nested within the Women's Health Initiative (WHI), we prospectively evaluated participants' baseline plasma levels of asprosin in relation to three-year changes in weight, measures of central obesity, and the risk of major weight gain or loss (≥ 7% of baseline weight). Associations were examined overall and stratified by whether they developed diabetes during followup or by baseline BMI. Dual-energy X-ray absorptiometry (DXA)-derived fat and lean mass were available in a subset of participants (n = 178).
RESULTS: In the full cohort (n = 4,020), baseline asprosin was not associated with three-year weight change or changes in central adiposity. However, among matched controls with BMI < 30 kg/m2, participants in the highest asprosin quartile gained 1.61 kg less than those in the lowest quartile (adjusted β (95% CI): -1.61 (-2.69, -0.52), p for trend < 0.01) and had lower odds of major weight gain (adjusted OR (95% CI): 0.57 (0.37, 0.88), p for trend < 0.01) and higher odds of major weight loss (adjusted OR (95% CI): 1.83 (1.10, 3.05), p for trend = 0.02).
CONCLUSIONS: In this prospective study of postmenopausal women followed for three years, baseline asprosin levels were associated with weight change in apparently healthy women without diabetes or obesity.

Keywords:  DXA; body composition; body fat distribution; body mass index; lean mass; obesity; postmenopausal women’s health; type 2 diabetes; waist circumference; weight change

DOI:  https://doi.org/10.1016/j.tjnut.2026.101441
Obesity (Silver Spring). 2026 Feb 22.

Adipose Tissue-Derived Small Extracellular Vesicles in Plasma Reveal Molecular Circuitries Underlying Glucose Intolerance.

Shalini Mishra, Yixin Su, Ashish Kumar, Sangeeta Singh, Brian S Finlin, Fang-Chi Hsu, Jingyun Lee, Cristina M Furdui, Philip A Kern, Swapan K Das, Gagan Deep.

OBJECTIVE: Glucose tolerance (GT) is a major effector for adipose tissue (AT) remodeling in obesity, yet its molecular mechanisms remain incompletely defined. We hypothesized that the biophysical and molecular profiles of AT-derived small extracellular vesicles (sEVAT) change in response to glucose availability and differ by GT status.
METHODS: sEVAT were isolated from plasma of individuals with normal GT (NGT) and impaired GT (IGT) (n = 5/group) at fasting (0 h) and 1 h post glucose challenge during oral glucose tolerance test (OGTT). sEVAT were characterized for size, concentration, surface expression of insulin receptor-α (INSRα), proteome, and insulin signaling-related miRNAs. C2C12 myotubes were treated with sEVAT for 48 h, followed by quantification of 84 insulin signaling-related genes.
RESULT: The size and concentration of sEVAT did not differ between groups. At fasting, INSRα expression on sEVAT was comparable; however, groups exhibited opposite directional changes at 1-h OGTT. LC-MS/MS identified significant proteomic differences between NGT and IGT sEVAT. miR-27a-5p and miR-145a-5p levels in sEVAT also differed significantly by GT status. Notably, treatment with sEVAT (IGT-0 h) significantly downregulated insulin signaling-related genes in myotubes.
CONCLUSIONS: Distinct molecular signatures in sEVAT offer a unique insight into AT dysfunction during IGT and offer novel diagnostic and therapeutic targets.

DOI: https://doi.org/10.1002/oby.70157