bims-mimead 2025-11-09 papers

Issue of 2025–11–09
six papers selected by
Rachel M. Handy, University of Guelph

Front Endocrinol (Lausanne). 2025 ;16 1682231

Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan.

The aged population, expected to double by 2050, makes up a large proportion of people living with metabolic disease. Obesity rates in the elderly are rapidly increasing, with estimates that nearly 40% of men and women over the age of 60 are classified as obese. White adipose tissue (WAT) is a highly metabolically active organ that undergoes significant changes during both obesity and aging, and metabolic dysfunction in WAT is a major cause for elevated diabetes risk. A marked difference in fat distribution is often reported between men and women. Many studies suggest that pre-menopausal women are protected from the accumulation of visceral adiposity due to gonadal estrogen, which exerts cardiometabolic benefits. Men with obesity harbor a disproportionately higher volume of intra-abdominal fat than premenopausal age-matched women with obesity, an effect that is negated by menopause as women begin to gain intra-abdominal fat. Post-menopausal women are at increased risk of developing diabetes, which can be mitigated by estrogen replacement therapy, suggesting an important role for sex steroids in diabetes risk. In addition to being highly responsive to gonadal estrogens, WAT has the capacity to convert androgens into estrogens, which may similarly impact WAT distribution and metabolism. Estrogens, comprised primarily of estrone (E1) and estradiol (E2) within WAT, are biosynthesized from circulating androgens androstenedione (A4) and testosterone (T) by aromatase (CYP19A1), which is highly expressed in human and mouse adipose tissue. In post-menopausal women, WAT becomes the predominant source of estrogen production, with age-associated increases in WAT aromatase expression that are mirrored by obesity. In contrast to ovarian estrogen production, in which E2 is the predominant estrogen type, E1 tends to be the predominant estrogen post-menopause. To date, little is known about WAT-derived estrogens and their impact on metabolic health, but emerging evidence suggests that increased E1 levels may contribute to metabolic dysfunction in aging. This review will introduce known sex differences in adipose metabolism associated with aging, obesity, and diabetes, and discuss the impact of WAT-derived sex hormones on local and systemic metabolism.

Keywords: adipocyte; aromatase; estradiol; estrone; menopause; obesity; sex hormones; sex steroids

DOI: https://doi.org/10.3389/fendo.2025.1682231

Prog Biomed Eng (Bristol). 2025 Nov 07.

Tissue Engineered Models of Adipose Tissue Dysfunction to Investigate Obesity-Related Comorbidities.

Lara Ece Celebi, Frank Ketchum, Dila Naz Bozkaya, Pinar Zorlutuna.

Emerging evidence suggests that adipose tissue is not just a fat depot but a metabolically active organ that plays a central role in connecting obesity with its comorbidities. Understanding the complex interactions between adipocytes and neighboring cell types in obesity requires models that accurately replicate adipocyte behavior within their natural environment. Three-dimensional (3D) adipocyte cultures mimic the native tissue microenvironment by incorporating the spatial architecture as well as cell-cell and cell-extracellular matrix (ECM) interactions present in vivo, offering improved platforms for (patho)physiological adipose tissue modeling. 3D models of adipose tissue dysfunction enable the study of complex cellular crosstalk, such as adipocyte cancer cell interactions in breast, colorectal, bone, and pancreatic cancers; epicardial and pericardial adipocyte-myocardial cell dynamics in obesity-related cardiac dysfunction; and adipocyte-hepatocyte interactions in the development of non-alcoholic fatty liver disease, among other critical pathophysiological processes. In this review, we first discuss 3D models of adipose tissue and current strategies for mimicking the obesogenic microenvironment, including dietary stimulation of hyperlipidemia and hyperglycemia, as well as the incorporation of oxygen gradients, proinflammatory cytokines, and immune cells. Secondly, we examine 3D co-culture platforms that incorporate disease-associated/dysfunctional adipocytes with various cell types, such as cancer cells, cardiac cells, hepatocytes, immune cells, endothelial cells, and fibroblasts, to model intercellular and interorgan crosstalk in obesity. Lastly, we provide insights into enhancing the physiological relevance of dysfunctional adipose tissue models and their co-culture systems while discussing future directions in tissue engineering aimed at improving clinical translation and reducing obesity related complications and mortality.

Keywords: 3D cell culture models; adipocyte hypertrophy; adipose tissue dysfunction; in vitro disease model; obesity

DOI: https://doi.org/10.1088/2516-1091/ae1cfe

FASEB J. 2025 Nov 15. 39(21): e71163

Endocrine, Metabolic, and Skeletal Muscle Proteomic Responses During Energy Deficit With Concomitant Aerobic Exercise in Humans.

Yusuke Nishimura, Carl Langan-Evans, Harry L Taylor, Wee L Foo, James P Morton, Sam Shepherd, Juliette A Strauss, Jatin G Burniston, José L Areta.

Energy deficit is a potent physiological stressor that has shaped human evolution and can improve lifespan and healthspan in a wide range of species. Preserving locomotive capacity was likely essential for survival during the human hunter-gatherer period but surprisingly little is known about the molecular effects of energy deficit on human skeletal muscle, which is a key tissue for locomotion and metabolic health. Here we show that after a 5-day 78% reduction in energy availability with concomitant aerobic exercise in healthy men there was a profound modulation of skeletal muscle phenotype alongside increases in fat oxidation at rest and during exercise and a 2.1 ± 0.8 kg loss of fat free mass and 0.8 ± 0.6 kg of fat mass. We used stable isotope (D2O) labelling and peptide mass spectrometry to investigate the abundance and turnover rates of individual proteins. Abundance (1469 proteins) and synthesis rate (736 proteins) data discovered a shift toward a more oxidative phenotype and reorganization of cytoskeleton and extracellular matrix structure during energy deficit. Mitochondrial components: TCA, electron transport chain and beta-oxidation, were prominently represented amongst proteins that increased in abundance and synthesis rate, as well as proteins related to mitochondrial proteostasis, remodeling and quality-control such as BDH1 and LONP1. Changes in muscle metabolic pathways occurred alongside a reduction in extracellular matrix proteins, which may counteract the age-related muscle fibrosis. Our results suggest that muscle metabolic pathways are not only preserved but positively affected during periods of concomitant low energy availability and exercise.

Keywords: aerobic exercise; dietary restriction; fibrosis; human evolution; lifespan; mitochondria; proteome; skeletal muscle; weight loss

DOI: https://doi.org/10.1096/fj.202502384RR

NPJ Metab Health Dis. 2025 Nov 07. 3(1): 44

AQP7 deficiency drives adipose tissue remodeling and disrupts homeostasis.

Ines Pd Costa, Guglielmo Schiano, Juan Manuel Sacnun, Rebecca Herzog, Alastair Kerr, Ingrid Dahlman, Christine Delporte, Klaus Kratochwill, Olivier Devuyst.

The aquaporin-7 (AQP7) channel mediates glycerol release from adipocytes. Genetic variants decreasing AQP7 expression are associated with adiposity and metabolic complications in humans. Using human data, mouse models, and cellular systems, we investigated how AQP7 influences adipose tissue maturation and homeostasis. Negative correlations between methylation on the AQP7 locus, expression of AQP7 in the adipose tissue and BMI were observed in humans. Mice lacking Aqp7 had increased body weight and visceral fat accumulation, due to adipocyte hypertrophy and chronic inflammation, impairing transport across the peritoneal membrane. These changes were further intensified by a high-glucose diet. Mechanistically, AQP7 deficiency disrupted the expression of genes related to adipogenesis and adipocyte function, resulting in a shift toward fibrosis and inflammation, while secreted factors from AQP7-null adipocytes promoted fibroblast activation. These findings establish AQP7 as a key regulator of adipose tissue homeostasis, metabolic dysregulation, and inflammation/fibrosis, exacerbated by glucose-induced obesity.

DOI: https://doi.org/10.1038/s44324-025-00085-y

J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70114

Anabolic Effects of Salbutamol Are Lost Upon Immobilization.

BACKGROUND: Periods of muscle disuse occur during hospitalization, illness or the recovery from (sports) injury and lead to a rapid loss of muscle mass and the development of insulin resistance. Salbutamol is a fast-acting β2-adrenoreceptor agonist that may improve muscle protein synthesis and insulin sensitivity during experimental muscle disuse and thereby attenuate or preserve muscle mass; however, this has not yet been tested as a standalone intervention.
METHODS: Effects of salbutamol treatment on muscle metabolism were studied in a randomized controlled trial using a human forearm immobilization model (n = 20). Before and after immobilization for 2 days, we measured whole-body glucose disposal, forearm glucose uptake and amino acid kinetics during fasting and hyperinsulinaemic-hyperaminoacidaemic-euglycemic clamp conditions using forearm balance and L-[ring-2H5]-phenylalanine infusion. Underlying mechanistic effects were studied as well using a complementary murine hindleg immobilization model (2 weeks) using tracer approaches (i.e., deuterated water and 14C-labelled phenylalanine) and molecular analyses (e.g., RNA-seq and western blot).
RESULTS: In humans, salbutamol enhanced insulin-stimulated glucose disposal on the whole-body level (+21%, p = 0.010) but was unable to ameliorate the immobilization-induced decrease in forearm glucose uptake. Salbutamol decreased the efflux of amino acids from the immobilized forearm, indicating increased muscle protein synthesis and/or inhibition of breakdown. However, this did not affect the immobilization-induced impairment of amino acid net balance in both postabsorptive (-250%) and clamp conditions (-261%, both p = 0.031). In agreement, in mice, salbutamol increased cumulative muscle protein synthesis (+0.87%, p < 0.001) but did not result in a net gain of muscle mass upon immobilization due to an accompanying increase in muscle protein turnover (+13%, p < 0.001). Molecular analyses revealed immobilization inhibited salbutamol's effects on the muscle transcriptome, specifically the muscle contraction pathway (-2.1 normalized enrichment score, p < 0.001).
CONCLUSIONS: Salbutamol increases muscle mass and glucose uptake, although these effects are limited to active but not inactive muscles. This demonstrates that the mechanism of action and efficacy of β2-adrenoreceptor signalling are hampered upon immobilization, which offers potential for a combined treatment intervention of reintroducing muscle contraction and salbutamol administration to improve muscle mass and clinical outcomes during episodes of physical inactivity.

Keywords: Type 2 diabetes; anabolic resistance; cAMP; insulin resistance; muscle disuse atrophy; sarcopenia; β2‐adrenoreceptor

DOI: https://doi.org/10.1002/jcsm.70114

J Natl Med Assoc. 2025 Nov 04. pii: S0027-9684(25)00331-1. [Epub ahead of print]

A biochemical study of estrogen receptor beta and oxidative stress in females with ovarian cancer.

Ali M A Al-Kufaishi, Noor J T Al-Musawi.

OBJECTIVES: The study includes the interpretation of hormonal disturbances resulting from the activation of Beta estrogen receptors, which leads to increased oxidative stress and its relationship to the development1and spread of ovarian1cancer in perimenopause women compared to healthy women.
METHODS: Blood samples were collected from (12) perimenopause women with ovarian cancer immediately after diagnosis to be compared with (45) healthy women. Estrogen receptor beta and some hormones were assessed using ELISA and miniVIDAS, while spectrophotometric methods were used to evaluate variables associated with oxidative stress.
RESULTS: The results show a significant increase in the values of estrogen receptors beta for women with ovarian cancer (48.4±3.18) ng/mL compared to healthy women (36.20±2.44) ng/mL. Also, a significant increase was remark in the values of each estrogen, progesterone, DHEA-s, testosterone, AMH, and total oxidant status. In contrast, a significant1decrease in the concentrations of total antioxidant capacity. The results also show a positive1correlation between1the values of total oxidants and the hormones studied, compared to the negative correlation with total antioxidants.
CONCLUSION: The significant increase in the values of beta-estrogen receptors as well as the estrogen hormone that may be derived from adipose tissue in women with ovarian cancer in the perimenopause stage has multiple effects, for example, causing disturbances in some hormones such as progesterone, DHEA-s, testosterone, and AMH. These hormonal disturbances resulting from granulosa cell tumors (GCTs) play a role in increasing the metabolic rate and thus increasing the oxidative stress of the cells.

Keywords: Hormonal disorders; Ovarian cancer; Oxidative stress; Perimenopause; β-estrogen receptors

DOI: https://doi.org/10.1016/j.jnma.2025.10.004