American journal of physiology. Endocrinology and metabolism最新文献

{"title":"GDF15 modulates mitochondrial content and differentiation-associated metabolic remodeling in skeletal muscle cells.","authors":"Bianca Cristine Favero-Santos, Carolina Martins Lazaro, Jung Tae Kim, Dimitrius Santiago P S F Guimarães, Ninon M Flores Barrios, Letícia Basso Gomes, Priscila R Raimundo, Francisco Breno S Teofilo, Michelle Gomes da Silva, Thais Amanda Reia, André Gustavo de Oliveira, Marieli Mariano Gonçalves Dias, André Schwambach Vieira, Ana Carolina Migliorini Figueira, Minho Shong, Leonardo R Silveira","doi":"10.1152/ajpendo.00438.2025","DOIUrl":"10.1152/ajpendo.00438.2025","url":null,"abstract":"<p><p>Growth differentiation factor 15 (GDF15) is a distant member of the transforming growth factor-β (TGF-β) superfamily increasingly implicated in metabolic regulation. Evidence points to GDF15 as a myokine that regulates systemic energy homeostasis, yet its role in skeletal muscle remains unclear. Here, we investigated whether GDF15 modulates mitochondrial phenotype during myogenesis using mouse C2C12 myoblasts and complementary models. Bioinformatic analyses of GDF15 interaction networks and gene ontology terms revealed enrichment for pathways related to cell differentiation and metabolic regulation. During myogenic differentiation, <i>Gdf15</i> expression increased at both mRNA and protein levels, with cytoplasmic localization and secretion into the extracellular medium, paralleling enhanced mitochondrial content, mitochondrial DNA copy number, and oxygen consumption. Knockdown of <i>Gdf15</i> reduced mitochondrial markers, increased lactate production, and promoted apoptosis, whereas <i>Gdf15</i> overexpression produced opposite effects. Mechanistically, <i>Gdf15</i> overexpression enhanced peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) transactivation and peroxisome proliferator-activated receptor (PPAR) response element activity, effects that were abolished by silencing PPARδ or estrogen-related receptor alpha (ERRα), suggesting a PGC1α-dependent mechanism. Transcriptomic profiling further supported enrichment of nuclear receptor-related pathways, including PPAR and cAMP response element-binding protein (CREB1) signaling. Finally, exercise training in male C57BL/6 mice elevated GDF15 levels in soleus muscle and improved aerobic performance. Together, these findings demonstrate that GDF15 promotes an oxidative phenotype in skeletal muscle cells through PGC1α-dependent activation of PPAR and ERRα, identifying GDF15 as an autocrine regulator of mitochondrial metabolism and muscle adaptation.<b>NEW & NOTEWORTHY</b> Growth differentiation factor 15 (GDF15) has emerged as a stress-responsive cytokine with systemic metabolic effects, yet its role in skeletal muscle remains poorly defined. Here, we show that GDF15 modulates mitochondrial phenotype and transcriptional programs in myotubes, linking stress signaling to muscle energy regulation. These findings identify skeletal muscle both as a source and a target of GDF15, revealing a novel mechanism by which muscle stress pathways influence whole body metabolic homeostasis.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E363-E378"},"PeriodicalIF":4.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PYY_3-36 potentiates semaglutide-mediated mitochondrial modulation in MASLD.","authors":"Niklas Geiger, Alexander Georg Nickel, Michael Kohlhaas, Jan Michael Federspiel, Jana Gerner, Aisha-Nike Landthaler, Simon Kloock, Thorsten Bischler, Panagiota Arampatzi, Michael Matz, Palina Zytner, Stefan Kircher, Vasco Sequeira, Martin Fassnacht, Andreas Geier, Christoph Maack, Ulrich Dischinger","doi":"10.1152/ajpendo.00036.2026","DOIUrl":"10.1152/ajpendo.00036.2026","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Metabolic dysfunction-associated steatotic liver disease (MASLD) is a frequent comorbidity of obesity. Incretins have emerged as promising therapeutics for MASLD, but their exact mechanisms of action remain unclear. In this study with obese rats, we investigated the cellular effects of the glucagon-like peptide 1 receptor agonist semaglutide and the neuropeptide Y-2 (NPY-2) receptor agonist peptide YY 3-36 (PYY&lt;sub&gt;3-36&lt;/sub&gt;) on hepatic mitochondria with a focus on mitochondrial oxygen consumption and reactive oxygen species (ROS) emission. Following an 8-wk feeding period with a high-fat/fructose diet and Nω-nitro-l-arginine methyl ester (l-NAME), male Wistar rats were randomized into the following treatment groups for further 8 wk: semaglutide (Sema, &lt;i&gt;n&lt;/i&gt; = 10), PYY&lt;sub&gt;3-36&lt;/sub&gt; (&lt;i&gt;n&lt;/i&gt; = 7), semaglutide + PYY&lt;sub&gt;3-36&lt;/sub&gt; (&lt;i&gt;n&lt;/i&gt; = 10), food restriction (FR; &lt;i&gt;n&lt;/i&gt; = 4), and saline control (&lt;i&gt;n&lt;/i&gt; = 17). Mitochondrial respiration and peroxide emission were examined using an Oroboros O2K-respirometer. Hematoxylin and eosin, Oil Red, and Sirius Red stainings were analyzed for fibrosis, inflammation, and lipid storage. Hepatic inflammation and histological MASLD score were significantly mitigated by semaglutide and PYY&lt;sub&gt;3-36&lt;/sub&gt; with additive effects in the combination group. Ribonucleic acid-sequencing revealed downregulation of pathways responsible for oxidative phosphorylation and beta-oxidation. Oxidative phosphorylation (OxPhos)-related genes were significantly reduced in Sema + PYY&lt;sub&gt;3-36&lt;/sub&gt;, consistent with mitochondrial respirometry. Hepatic medium-chain acyl-CoA dehydrogenase and proliferator-activated receptor gamma coactivator-1-alpha expression, key regulators of beta-oxidation, was significantly reduced by PYY&lt;sub&gt;3-36&lt;/sub&gt;. Superior effects occurred in the semaglutide + PYY&lt;sub&gt;3-36&lt;/sub&gt; group with a decline in mitochondrial respiration, decreased mitochondrial H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; production and reduced hepatocellular stress, whereas FR and weight loss had no significant impact on mitochondrial respiration or OxPhos-regulating genes. This study highlights the favorable effects of semaglutide and PYY&lt;sub&gt;3-36&lt;/sub&gt; mitigating mitochondrial dysfunction in MASLD, providing insight into their possible molecular mechanisms.&lt;b&gt;NEW & NOTEWORTHY&lt;/b&gt; This study provides a mechanistic framework for investigating glucagon-like peptide 1 receptor (GLP-1R) and neuropeptide Y-2 receptor (NPY-2R) agonism as therapeutic strategies for MASLD. Semaglutide and PYY&lt;sub&gt;3-36&lt;/sub&gt; restored mitochondrial function, reduced oxidative stress, and limited hepatocellular injury, revealing complementary pathways governing steatosis and metabolic resilience. A weight loss-matched food restriction group showed no improvement in mitochondrial respiration, indicating that benefits extend beyond weight loss. These findings support pathway targeted therapeutic selection and underscore the translational potential of dual agon","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E397-E413"},"PeriodicalIF":4.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148617995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nr4a3 deficiency disrupts MEK1-ERK1/2-Drp1 signaling, driving adiposity and glucose intolerance in male mice.","authors":"Peter N Ellsworth, Kate E Whalen, Jared D Carter, Jacob A Herring, Kavan H Hess, Kristopher L Wieland, Drake C Watkins, Jeremy Y Saito, Erik D Marchant, Nathan D Marchant, Nathan D Walker, Garritt L Page, Yang Cao, Qin Yang, Benjamin T Bikman, Jeffery S Tessem","doi":"10.1152/ajpendo.00322.2025","DOIUrl":"10.1152/ajpendo.00322.2025","url":null,"abstract":"<p><p>Obesity is strongly associated with elevated blood glucose levels, glucose intolerance, insulin resistance, and type 2 diabetes. The Nr4a family of orphan nuclear receptors is essential for proliferation, cell survival, mitochondrial function, and fuel utilization in a tissue-dependent manner. Nr4a3 overexpression has been shown to decrease blood glucose levels and improve glucose tolerance. Here, we present the effects of full body Nr4a3 deletion in mice fed a standard chow diet. We demonstrate that male and female <i>Nr4a3</i> knockout mice fed a standard chow diet have elevated nonfasting blood glucose and impaired glucose tolerance. Male <i>Nr4a3</i> knockout mice have increased body weight, without changes in body length, food intake, movement, or energy expenditure. Interestingly, male, but not female, <i>Nr4a3</i> knockout mice have increased weight of all adipose depots with increased adipocyte cell size. Furthermore, male Nr4a3 mice have impaired adipose mitochondrial respiration, with normal liver and soleus respiration. Finally, we show a significant decrease in Drp1 mRNA, Drp1 protein, and phosphorylated DRP1 levels. These data suggest that Nr4a3 loss impairs expression of the key mitochondrial fission gene Drp1, resulting in impaired adipose mitochondrial respiration and ultimately increasing adipocyte size, adipose depot mass, and body mass. These data demonstrate that Nr4a3 is critical for proper adipocyte function.<b>NEW & NOTEWORTHY</b> This study reveals that full-body <i>Nr4a3</i> deletion in mice leads to elevated blood glucose, impaired glucose tolerance, and increased adiposity, particularly in males. Notably, male <i>Nr4a3</i> knockout mice exhibited enlarged adipocytes and impaired mitochondrial respiration in adipose tissue, which is linked to reduced expression of the mitochondrial fission gene DRP1. These findings highlight Nr4a3's critical role in regulating glucose metabolism and adipose tissue function, with implications for understanding obesity and type 2 diabetes.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E379-E396"},"PeriodicalIF":4.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13528230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nitrate and resveratrol supplementation selectively enhances hepatic adaptations to aerobic exercise in high-fat fed male mice.","authors":"Rachel M Handy, Geneviève J DesOrmeaux, Sandra Guga, Katarzyna Hodun-Bielska, Anna E Kupraty, Sara M Frangos, Fasih A Rahman, Adrian Chabowski, Henver S Brunetta, Graham P Holloway","doi":"10.1152/ajpendo.00529.2025","DOIUrl":"10.1152/ajpendo.00529.2025","url":null,"abstract":"<p><p>Aerobic exercise training (AET) and numerous dietary interventions, including nitrate and resveratrol supplementation, display overlapping mechanisms affecting mitochondrial bioenergetics and metabolism in diverse tissues. However, it remains unclear if a combination of these interventions results in additive benefits for the prevention of obesity-related comorbidities. To investigate this, C57Bl/6N mice consumed a high-fat diet and remained sedentary (HFD) or performed AET for 6 wk in the absence (HFD + AET) or presence of nitrate + resveratrol supplementation (HFD + AET + NR). As expected, AET attenuated body weight gain, reduced adipocyte cross-sectional area and markers of cellular stress/inflammation within white adipose tissue, and increased mitochondrial respiratory capacity and decreased lipid content within skeletal muscle independent of supplementation. Although AET alone was sufficient to improve glucose tolerance, the addition of +NR provided modest liver-specific enhancements, including increased mitochondrial respiratory capacity, reduced reactive lipid accumulation, and a unique proteomic signature associated with altered amino acid metabolism, corresponding to further reductions in systemic fasting blood glucose levels. These data suggest that although AET remains a primary lifestyle intervention to drive metabolic improvements during high-fat feeding, targeted dietary supplementation may provide tissue-specific enhancements, particularly within the liver, that complement exercise adaptations.<b>NEW & NOTEWORTHY</b> Dietary supplementation may alter the adaptive response to aerobic exercise training (AET). We investigated whether combined dietary nitrate + resveratrol supplementation could complement adaptations to AET in a high-lipid environment. AET attenuates various metabolic impairments associated with high-fat feeding, whereas nitrate + resveratrol supplementation provides modest, liver-specific enhancements. Although AET serves as the primary therapeutic intervention for high-fat diet-induced cardiometabolic disease, targeted dietary supplementation may provide complementary tissue-specific benefits.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E209-E220"},"PeriodicalIF":4.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low oxygen availability induces a metabolic shift toward enhanced glucose utilization in nonlipid-loaded and lipid-loaded HepG2 cells.","authors":"Geng Li, Ludwig J Dubois, Rianne Biemans, Gijs H Goossens, Ruth C R Meex","doi":"10.1152/ajpendo.00095.2026","DOIUrl":"10.1152/ajpendo.00095.2026","url":null,"abstract":"<p><p>Liver function is impaired in metabolic dysfunction-associated fatty liver disease. Previous studies have demonstrated that oxygen availability in the tissue microenvironment affects adipose tissue and skeletal muscle function, but its hepatic effects remain unclear. This study aimed to investigate the impact of oxygen levels on metabolic pathways in HepG2 cells. Nonlipid-loaded and lipid-loaded HepG2 cells were exposed to different physiological O₂ levels (5% and 10%) or standard laboratory conditions (21% O₂) for 24 h. Thereafter, we determined lipid content, gene expression of metabolic markers, glycogen content, and glucose release. Furthermore, mitochondrial respiration and glycolytic activity were assessed by measuring the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), respectively. Exposure to 5% O₂ increased the expression of the gluconeogenic gene glucose-6-phosphatase catalytic subunit 1 (<i>G6PC1</i>) in both nonlipid-loaded and steatotic HepG2 cells compared with 21% O₂ (<i>P</i> < 0.001). Furthermore, 5% O₂ decreased the expression of lipogenic genes [sterol regulatory element binding transcription factor 1 (<i>SREBF1</i>), acetyl-CoA carboxylase beta (<i>ACACB</i>), and fatty acid synthase (<i>FASN</i>)] in nonlipid-loaded and/or steatotic cells (all <i>P</i> < 0.05), whereas genes involved in fatty acid oxidation [peroxisome proliferator-activated receptor gamma coactivator 1-alpha (<i>PPARGC1A</i>), <i>P</i> < 0.001 and peroxisome proliferator-activated receptor alpha (<i>PPARA</i>), <i>P</i> = 0.038] were downregulated in steatotic cells. Low oxygen exposure increased glycogen content in nonlipid-loaded and steatotic cells (both <i>P</i> < 0.001) and reduced glucose release (<i>P</i> < 0.05). Finally, low oxygen exposure reduced OCR (<i>P</i> < 0.05) and increased glycolysis (<i>P</i> < 0.001) in both nonlipid-loaded and steatotic cells compared with 21%. In conclusion, our findings demonstrate that reduced oxygen availability in the microenvironment has marked effects on metabolic pathways in nonlipid-loaded and steatotic hepatocytes, inducing a metabolic shift to enhanced reliance on glucose as an energy source.<b>NEW & NOTEWORTHY</b> Oxygen availability in the tissue microenvironment affects adipose tissue and skeletal muscle function, but the effects of oxygen levels on hepatic metabolism are unclear. Low oxygen exposure altered expression of genes involved in glucose and lipid metabolism, increased glycogen content, decreased glucose release and oxygen consumption, and increased glycolytic rate compared with exposure to 21% O₂ in both nonlipid-loaded and steatotic HepG2 cells, indicative of a shift to enhanced reliance on glucose as an energy source.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E198-E207"},"PeriodicalIF":4.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential impact of cancer- and chemotherapy-induced cachexia: a comparative analysis in a preclinical model of colorectal cancer by biological sex.","authors":"Ana Regina Cabrera, Eleanor R Schrems, Ruqaiza Muhyudin, Francielly Morena, Stavroula Tsitkanou, Ronald G Jones, Kaitlyn Parker, Morghan Relich, Kevin A Murach, Timothy J Muldoon, Tyrone A Washington, Nicholas P Greene","doi":"10.1152/ajpendo.00131.2026","DOIUrl":"10.1152/ajpendo.00131.2026","url":null,"abstract":"<p><p>Cancer cachexia is a wasting condition characterized by muscle loss and reduced quality of life in cancer patients. Although biological sex differences in the progression of cancer cachexia have been increasingly recognized, their role during chemotherapy-treated cancer cachexia remains largely unexplored. We evaluated such potential differences in male and female mice implanted subcutaneously with Colon-26 (C26) allografts. Our novel approach to disentangle the effects of chemotherapy consisted of administering two cycles of 75% of the maximum tolerated dose of 5-fluorouracil, cisplatin, or paclitaxel in the presence and absence of cancer (<i>n</i> = 6-11/condition). Muscles and organs were collected 25 days after tumor implant, and protein turnover markers, gene expression through RNA sequencing, and mitochondrial function were evaluated in gastrocnemius. A two-way factorial analysis was conducted to assess main effects and interactions across groups (<i>P</i> < 0.05). We demonstrate that chemotherapy exhibited preserved fat mass in males and maintained body weight in females. Chemotherapy elicited negative impacts on muscle in both sexes, even with a reduced or absent tumor burden. In males, protein synthesis was lower in the presence of cancer and chemotherapy without corresponding differences in atrogenes. Cluster analysis revealed largest differences in muscle transcriptome between cancer control and C26-paclitaxel in male mice, highlighting altered regulation of ubiquitin-mediated proteolysis. These findings point to divergent mechanisms during protein processing in endoplasmic reticulum regulation in muscle atrophy associated with cancer in the presence of chemotherapy. Our results highlight distinct mechanisms underlying cancer cachexia alone versus the addition of chemotherapy and further indicate that responses to chemotherapy differ between biological sexes.<b>NEW & NOTEWORTHY</b> Our study highlights critical differences in the mechanisms mediating muscle loss between cancer and chemotherapy-treated cancer, particularly those by which proteins are degraded and processed. Our data point to biological sex differences in the responsiveness to chemotherapy agents as well as the wasting response. Major differences were observed between sexes, specifically fat mass preservation in male mice and the preservation of body weight in female mice, both despite significant reduction in muscle mass.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E221-E236"},"PeriodicalIF":4.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13439732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148443900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypothalamic-pituitary-gonadal axis programming and disrupted ovarian-endocrine function in female offspring of the preeclamptic-like BPH/5 mouse.","authors":"Victoria N Bailey, Kendall R Ball, Kalynn E Grandberry, Linda A Nduwimana, Bryce M Borne, Viviane C L Gomes","doi":"10.1152/ajpendo.00543.2025","DOIUrl":"10.1152/ajpendo.00543.2025","url":null,"abstract":"<p><p>Children born after preeclampsia, the leading hypertensive disorder of pregnancy, are predisposed to long-term cardiometabolic and reproductive disorders that are likely associated with prenatal exposure to a dysregulated maternal endocrine milieu. We have previously described abnormal pubertal development and hyperandrogenism in female offspring from the preeclamptic-like blood pressure high subline 5 (BPH/5) mouse, recapitulating patterns observed in adolescents born after preeclampsia. Herein, our objective was to elucidate BPH/5 offspring hypothalamic-pituitary-gonadal (HPG) axis programming and the associated hormonal profile of late-gestation BPH/5 dams. Reproductive and metabolic phenotypes of BPH/5 and blood pressure normal subline 3 (BPN/3) offspring were assessed from birth to adulthood, including anogenital distance, pubertal onset, ovarian function, and adiposity. Maternal late-gestation circulating hormones and placental steroidogenic enzymes were also investigated. Anogenital distance, indicative of prenatal androgen exposure, was longer in BPH/5 male and female offspring. BPH/5 female offspring exhibited precocious pubertal onset and, during adulthood, abnormal estrous cycles, increased visceral adiposity, increased serum anti-Mullerian hormone (AMH), and ovarian morphology consistent with a polycystic ovary syndrome (PCOS)-like phenotype. Serum testosterone did not differ between late-gestation BPH/5 and BPN/3 dams. Conversely, serum AMH concentrations were threefold higher in late-gestation BPH/5 dams, a maternal endocrine disruption previously linked to abnormal female fetus HPG axis programming and PCOS-like offspring phenotype. In conclusion, BPH/5 offspring recapitulate the aberrant reproductive phenotype seen in children born after preeclampsia and major PCOS-like characteristics. Furthermore, maternal AMH excess was identified in late-gestation BPH/5 females, highlighting this as a valuable model of the interplay between PCOS and preeclampsia.<b>NEW & NOTEWORTHY</b> This study explored hypothalamic-pituitary-gonadal (HPG) axis development in offspring from the preeclamptic-like BPH/5 mouse model. Female BPH/5 offspring exhibited precocious pubertal development, elevated AMH, abnormal estrous cycles, abnormal ovarian histomorphology, and increased visceral adiposity. Interestingly, male and female offspring had longer anogenital distance, indicative of prenatal androgen exposure. Late-gestation BPH/5 dams exhibited a threefold higher AMH concentration, elucidating a novel developmental link between preeclampsia, offspring HPG axis programming, and postnatal ovarian and endocrine dysfunction.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E237-E251"},"PeriodicalIF":4.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148443885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemogenetic placental activation and proteomic extracellular vesicle signatures predict functional roles across pregnancy and postpartum.","authors":"Geoffrey A Dunn, Arthur S Feltrin, Rodrigo Orso, Tracy L Bale","doi":"10.1152/ajpendo.00061.2026","DOIUrl":"10.1152/ajpendo.00061.2026","url":null,"abstract":"<p><p>Mechanisms underlying homeostatic regulation of maternal health during pregnancy and the postpartum period are critical yet remain understudied. Extracellular vesicles (EVs) are vital sources of cell-to-cell communication that maintain homeostasis and are at their highest circulating concentration during pregnancy. Recent studies have implicated EVs and their cargo as facilitators in important physiological functions during pregnancy, including glucose and immune regulation, but precise mechanisms are not known. In this study, we aimed to compare changes in EVs and their protein cargo using unbiased proteomic analyses across pregnancy and postpartum periods to assert unique EV functions. As expected, we found significantly higher EV concentrations during pregnancy relative to nonpregnant and postpartum groups. We identified unique EV protein profiles across groups, suggesting EVs were highly responsive to their current environment and performing unique functions. Surprisingly, while postpartum mice had similar EV concentrations as nonpregnant mice, their EVs had the least overlap in protein composition between groups and the greatest number of proteins clustered in a biological function-a significant reduction around cell adhesion processes postpartum. Lastly, to examine a homeostatic role for maternal circulating EVs, we used a novel chemogenetic approach to control dynamic EV secretion and measured changes in maternal glucose regulation. We found that an acute increase in circulating EVs reduced maternal glucose sensitivity, keeping glucose levels elevated longer following a glucose challenge. In summary, these results demonstrate the unique EV protein cargo changes that occur in pregnancy and postpartum and their potential importance in maintenance of maternal health.<b>NEW & NOTEWORTHY</b> Extracellular vesicles in maternal circulation express unique proteomic cargo profiles across pregnancy and postpartum. Chemogenetic activation of the placental secretory pathway releases extracellular vesicles into maternal circulation that influence maternal glucose regulation.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E184-E197"},"PeriodicalIF":4.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13456656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148350265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Obesity-related circulating endothelial extracellular vesicles negatively affect cerebral microvascular cell function.","authors":"Samuel T Ruzzene, Vinicius P Garcia, Auburn R Berry, Madeleine F Stone, Kendra N Wegerson, Emily I Ostrander, Hannah K Fandl, Jared J Greiner, Andrew J Park, Brian L Stauffer, Christopher A DeSouza","doi":"10.1152/ajpendo.00128.2026","DOIUrl":"10.1152/ajpendo.00128.2026","url":null,"abstract":"<p><p>The aim of this study was to determine, in vitro, the effect of endothelial cell-derived extracellular vesicles (EEVs) from adults with obesity on brain microvascular endothelial cell nitric oxide (NO) and endothelin (ET)-1 production as well as tissue-type plasminogen activator (t-PA) release. Circulating EEVs (CD144+ extracellular vesicles) were identified, enumerated, and isolated (flow cytometry) from 24 midlife and older sedentary adults (45-71 yr): 12 normal weight [6 M/6 F; body mass index (BMI) ≥18.5 and ≤25 kg/m²] adults and 12 adults with obesity (6 M/6 F; BMI ≥ 30.0 kg/m²). Human cerebral microvascular endothelial cells (hCMECs) were cultured and treated with EEVs from either normal-weight adults or adults with obesity. Expression of phosphorylated (p)-eNOS (Ser1177) was ∼20% lower (31.5 ± 5.6 vs. 39.1 ± 7.9 AU) and p-eNOS (Thr495) expression ∼40% higher (47.3 ± 13.2 vs. 33.4 ± 10.5 AU) in hCMECs treated with EEVs from obese compared with normal weight adults. As a result, NO production was significantly lower (∼20%) in hCMECs treated with EEVs from adults with obesity (4.9 ± 0.4 vs. 5.9 ± 0.5 µmol/L). Cell expression of Big ET-1 (317.8 ± 51.8 vs. 241.6 ± 65.0 AU) and endothelin-converting enzyme (838.3 ± 160.8 vs. 631.8 ± 126.3 AU) as well as ET-1 production (21.9 ± 1.6 vs. 18.0 ± 3.9 pg/mL) were significantly higher in hCMECs treated with EEVs from adults with obesity. t-PA release in response to thrombin was significantly lower in hCMECs treated with EEVs from obese (from 49.3 ± 6.6 to 52.3 ± 8.2 pg/mL) compared with normal weight (from 52.3 ± 8.8 to 62.0 ± 8.1 pg/mL) adults. Circulating EEVs are a potential mediator of obesity-related cerebrovascular dysfunction and stroke risk.<b>NEW & NOTEWORTHY</b> Despite an improved understanding of many of the pathological consequences associated with human obesity, factors that initiate, promote, and accelerate cerebrovascular events are not completely understood. This study provides novel data demonstrating that circulating EEVs from adults with obesity adversely affect eNOS activity, reducing nitric oxide bioavailability, enhancing ET-1 production, and impairing t-PA release in brain microvascular endothelial cells in vitro. These changes in endothelial cell phenotype have been linked with cerebrovascular dysfunction and ischemic stroke risk.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E165-E173"},"PeriodicalIF":4.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel insights into the role of Annexin A2 signaling pathway in female reproductive system diseases: from mechanisms to advanced therapies.","authors":"Yirong Ding, Yue Chen, Yu Pan, Ruiqi Fu, Wenjie Wang, Xiwen Wang, Yu Liu, Suya Bao, Ying Chen, Hengwei Liu","doi":"10.1152/ajpendo.00462.2025","DOIUrl":"10.1152/ajpendo.00462.2025","url":null,"abstract":"<p><p>Annexin A2 (ANXA2) is a calcium-dependent protein with high affinity for phospholipids, and its multifunctional nature has drawn increasing attention in the onset and progression of various disorders of the female reproductive system (FRS). Beyond its canonical roles in endocytosis, cytoskeletal dynamics, angiogenesis, and extracellular matrix (ECM) remodeling, ANXA2 signaling integrates phosphorylation events, interactions with S100A10, and fibrinolytic activity to shape reproductive biology. Emerging evidence demonstrates that aberrant ANXA2 expression is implicated in gynecological cancers, endometriosis, adenomyosis, infertility, and pregnancy-related complications, where it modulates processes such as epithelial-mesenchymal transition (EMT), trophoblast invasion, vascular integrity, and immune homeostasis. Elevated ANXA2 levels have been correlated with tumor aggressiveness, recurrence risk, chemoresistance, and poor prognosis, whereas circulating ANXA2 and exosome-derived ANXA2 show promise as minimally invasive biomarkers for benign reproductive system disorders. Despite these advances, the precise molecular mechanisms and context-specific functions of ANXA2 remain incompletely understood, and significant gaps persist regarding its clinical translation. This review synthesizes current knowledge of ANXA2 signaling in female reproductive diseases, highlights its potential diagnostic and therapeutic value, and identifies key challenges and research priorities. A deeper understanding of ANXA2 biology may not only refine disease stratification and prognosis but also open new avenues for targeted interventions, positioning ANXA2 as a promising node for precision medicine in reproductive health.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E131-E147"},"PeriodicalIF":4.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147669161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}