American journal of physiology. Endocrinology and metabolism最新文献

{"title":"Glutamine metabolism shapes the phenotypic adaptation of uterine dendritic cells in response to early allogeneic pregnancy.","authors":"Songchen Cai, Agnes Wieczorek, Christopher Urbschat, Maria Emilia Solano, Yong Zeng, Petra Clara Arck, Lianghui Diao, Kristin Thiele","doi":"10.1152/ajpendo.00520.2025","DOIUrl":"10.1152/ajpendo.00520.2025","url":null,"abstract":"<p><p>The impact of metabolic reprogramming on immune cell functions is increasingly recognized. However, it remains largely unexplored in terms of immune cell adaptation during reproduction. Dendritic cells (DC) are crucial for establishing and maintaining pregnancy by orchestrating maternal immune adaptation essential for embryo implantation and decidualization. Here, we characterized the phenotypic and metabolic characteristics of DCs during early pregnancy in an allogeneic mouse model and in response to the specific deletion of hormonal receptors on DCs. The frequency of uterine CD11c⁺ DCs on <i>gestational day 7.5</i> remained equal to that of nonpregnant mice. However, we observed a functional shift from conventional DC 1 (cDC1) to cDC2 in pregnant mice. In parallel, a metabolic switch in uterine DCs was identified by upregulation of genes representing fatty acid synthesis (fatty acid synthase and acetyl-CoA carboxylase), fatty acid oxidation (carnitine palmitoyltransferase Ia), and glutamine-related metabolic pathways (<i>Got2</i>). The cell-specific deletion of the glucocorticoid receptor in DCs reduced their major histocompatibility complex II expression, accompanied by a reduction in <i>Got2</i> expression. Glutamine deprivation in vitro dramatically reduced the absolute number of cultured bone marrow cells and the frequency of cDC1s while simultaneously increasing the frequency of cDC2s. Collectively, these findings establish glutamine metabolism as a key driver of DC adaptation during early pregnancy, revealing novel metabolic-immunological cross talk at the maternal-fetal interface.<b>NEW & NOTEWORTHY</b> The present study provides novel insights into the spatiotemporal features of dendritic cells concerning phenotypic and metabolic adaptation in the uterus, the uterus-draining lymph nodes, and peripheral blood mononuclear cells during early pregnancy. It further underscores the fundamental role of glutamine metabolism in regulating uterine dendritic cells to facilitate fetal tolerance, embryo implantation, and promote decidualization.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E154-E164"},"PeriodicalIF":4.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148256975","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":"Gut microbiota-generated trimethylamine <i>N</i>-oxide from dietary choline and glucose homeostasis in humans.","authors":"Eleni Laskaridou, Cortney N Steele, Glen R Reid, Janet T Rinehart, Elaina L Marinik, Kristen R Howard, Brenda M Davy, Michael G Sweet, Andrew P Neilson, Kevin P Davy","doi":"10.1152/ajpendo.00160.2026","DOIUrl":"10.1152/ajpendo.00160.2026","url":null,"abstract":"<p><p>The causal relationship between gut microbiota-generated trimethylamine <i>N</i>-oxide (TMAO) and type 2 diabetes remains unclear. We tested the hypothesis that gut microbiota-generated increases in plasma TMAO concentrations will impair insulin sensitivity and glucose tolerance in healthy, sedentary humans. To address this, we performed two studies utilizing a randomized double-blind, placebo-controlled, crossover design. Eligible participants (age of 35 ± 16 yr for the acute study and 46 ± 14 yr for the short-term study) consumed a 1,000 mg/day dose of choline bitartrate and placebo (maltodextrin) the night before each testing session (for the acute study, <i>n</i> = 20, 8 women) or for 4 wk (for the short-term study, <i>n</i> = 23, 13 women). An oral glucose tolerance test was performed the day after the acute study and before and after the short-term study. Insulin sensitivity was calculated using the Matsuda index. Plasma TMAO was increased (both <i>P</i> < 0.05) 400% and 110% following acute and 4 wk of daily ingestion of 1,000 mg of choline bitartrate, respectively. There were no statistically significant differences in insulin sensitivity (Matsuda index) or insulin resistance (HOMA-IR) between the interventions in both the acute study and short-term study. In addition, there were no significant differences between conditions in fasting glucose, 2-h glucose, area under the curve, and incremental area under the curve in the acute and short-term study. Taken together, the results of the present study suggest that the relationship between TMAO and glucose homeostasis may not be causal in nature.<b>NEW & NOTEWORTHY</b> Trimethylamine <i>N</i>-oxide (TMAO), a gut microbiota-derived metabolite, has been linked to impaired glucose homeostasis and type 2 diabetes, but causality is unclear. In two randomized, double-blind, placebo-controlled studies, acute and short-term dietary choline increased TMAO without affecting insulin sensitivity, glucose tolerance, or fasting glucose and insulin. These findings do not support a causal role for TMAO, though longer-term studies are needed.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E148-E153"},"PeriodicalIF":4.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13398441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275710","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":"Branched-chain and glucogenic amino acids predict brown fat recruitment and metabolic clearance in adults with overweight or obesity.","authors":"Lijuan Sun, Hui Jen Goh, Xinyan Bi, Priya Govindharajulu, Mya Thway Tint, Karen Mei-Ling Tan, Hong Pan, Bright Starling Emerald, Melvin Khee-Shing Leow","doi":"10.1152/ajpendo.00078.2026","DOIUrl":"10.1152/ajpendo.00078.2026","url":null,"abstract":"<p><p>The relationship between circulating amino acids (AAs), particularly branched-chain amino acids (BCAAs), and brown adipose tissue (BAT) recruitment and their subsequent fate during thermogenesis remains poorly defined. We investigated the longitudinal changes and predictive role of serum AAs metabolism in 25 participants with overweight or obesity following a 12-wk BAT-activating intervention (curcumin supplementation and/or cold exposure). Participants were stratified into BAT responders (<i>n</i> = 8) and nonresponders (<i>n</i> = 17) via fusion 18-fluorine fluorodeoxyglucose positron emission tomography-magnetic resonance (¹⁸F-FDG PET/MR) imaging. BAT responders exhibited a significant systemic clearance of several AAs, including phenylalanine, glutamine, asparagine, and glycine, whereas nonresponders showed a significant increase in valine and total BCAAs. Multiple linear regression analysis identified baseline levels of total BCAAs (β = 0.81, <i>P</i> = 0.007) and glucogenic AAs (β = 0.65, <i>P</i> < 0.001) as independent positive predictors of BAT activity. Furthermore, the magnitude of BAT activation was inversely associated with the longitudinal change in these AAs, suggesting that activated BAT serves as a significant site for systemic AA clearance. We conclude that circulating branched-chain and glucogenic AAs are closely associated with the capacity for BAT recruitment and activation. The resulting enhanced metabolic demand transforms the activated BAT into an effective site for systemic AA clearance and improved metabolic homeostasis.<b>NEW & NOTEWORTHY</b> Elevated circulating branched-chain amino acids (BCAAs) are established biomarkers of metabolic dysfunction, but the regulatory role of human brown adipose tissue (BAT) remains unclear. We demonstrate that high baseline BCAA and glucogenic amino acid levels independently predict the capacity of BAT recruitment. Furthermore, successful BAT activation is associated with the systemic clearance of these metabolites. These findings suggest that BAT serves as a key regulator of amino acid homeostasis and represents a potential therapeutic target for addressing metabolic disorders in adults.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E174-E183"},"PeriodicalIF":4.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337382","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":"Pioglitazone increases adiponectin and attenuates the appearance of diet-induced insulin resistance in high-fat-fed beagles.","authors":"Guillaume Kraft, Ashley Tovar, Kalisha Yankey, Melanie Scott, Jessica L Graves, Ben Farmer, Matthew Peloquin, Alan D Cherrington","doi":"10.1152/ajpendo.00515.2025","DOIUrl":"10.1152/ajpendo.00515.2025","url":null,"abstract":"<p><p>This study investigated the efficacy of thiazolidinediones in mitigating diet-induced obesity and associated glucose intolerance in canines in vivo. We used a multitechnique approach and compared the results related to <i>1</i>) fasting metabolites, hormones, and lipides; <i>2</i>) oral glucose tolerance test (OGTT), and <i>3</i>) hyperinsulinemic euglycemic (HIEG) clamps in 24 healthy dogs that were then fed a high-fat diet and assigned to a placebo group (<i>n</i> = 8) or received a daily dose of pioglitazone group (<i>n</i> = 16) for 56 days. The animals were studied before and after treatment, acting as their own controls, and we used a principal component analysis to combine the results obtained for the three different techniques. Both groups experienced weight gain, with 12% and 14% increases in the placebo and pioglitazone groups, respectively. The fasting level of free fatty acids was increased in both placebo (+17.5%) and pioglitazone groups (+7.7%), as were the insulin levels (+27% and 35%, respectively, in placebo and pioglitazone), but fasting glucose levels were reduced slightly in both (-2.7 and -2.9 mg/dL, respectively). Pioglitazone increased fasting adiponectin levels by 54% between <i>day -1</i> and <i>day 56</i>. OGTTs revealed a significantly better glucose tolerance in the pioglitazone treatment group compared with the placebo group, as the level of insulin secreted during the OGTT was normalized. HIEG clamps demonstrated that, in the placebo group, glucose infusion rate and glucose utilization decreased in response to the diet, but this effect was prevented by pioglitazone. In conclusion, these findings show that pioglitazone is beneficial in preventing the consequences of dietary metabolic stress and overfeeding in canines.<b>NEW & NOTEWORTHY</b> This study validates the efficacy of the thiazolidinediones (TZD) drug pioglitazone in a fat-fed canine model. Using a novel principal component analysis integrating multimodal data (fasting metabolites, OGTT, and clamp results), we demonstrate that pioglitazone effectively reverses diet-induced glucose intolerance and significantly improves insulin sensitivity. Mechanistically, this improvement is driven by adiponectin action. These findings provide strong evidence supporting TZD use as a prophylactic tool for mitigating metabolic syndrome.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E35-E48"},"PeriodicalIF":4.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147985911","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":"The effect of ghrelin on insulin sensitivity and beta-cell function after sleeve gastrectomy.","authors":"Marie-Louise Dichman, Nora Hedbäck, Amalie London, Nils B Jørgensen, Kirstine Nyvold Bojsen-Møller, Nicolai J Wewer Albrechtsen, Gerrit van Hall, Viggo B Kristiansen, Bolette Hartmann, Jens Juul Holst, Carsten Dirksen, Maria Saur Svane, Sten Madsbad","doi":"10.1152/ajpendo.00065.2026","DOIUrl":"10.1152/ajpendo.00065.2026","url":null,"abstract":"<p><p>Sleeve gastrectomy (SG) leads to substantial weight loss and improvement in type 2 diabetes, but the underlying mechanisms remain incompletely understood. Given that circulating ghrelin concentrations are reduced after SG, we hypothesized that lower ghrelin levels may contribute to enhanced insulin sensitivity and β-cell function after SG. This was a human, placebo-controlled, randomized, crossover study. We investigated the effect of elevating ghrelin by an intravenous ghrelin infusion on β-cell function and insulin sensitivity using the \"Botnia-clamp\" (intravenous glucose tolerance test combined with hyperinsulinemic-euglycemic clamp), compared with saline coinfusion. Twelve SG-operated [aged 51 ± 10.9 yr, BMI 32.1 ± 4.6 kg/m² (means ± SD)], and 10 sex-, age-, and body mass index (BMI)-matched unoperated controls without diabetes were included. Outcomes were peripheral insulin sensitivity (M/I) and β-cell function, assessed as the disposition index (DI), calculated as first phase insulin secretion × M/I. Ghrelin infusion significantly reduced peripheral insulin sensitivity (M/I) by 25% following SG and 29% in controls compared with saline infusion. Beta-cell function was significantly impaired with a 37% and 29% reduced first phase insulin secretion, and a 49% and 48% reduction in DI, respectively. No group differences were observed. Ghrelin infusion impairs insulin sensitivity and β-cell function in individuals who have undergone SG as well as in matched control. However, the present findings do not provide evidence that the lower circulating ghrelin concentrations following SG are directly responsible for improvements, as it remains unclear whether this relationship reflects a simple and reversible mechanism.<b>NEW & NOTEWORTHY</b> In a randomized, placebo-controlled crossover study, intravenous ghrelin infusion impaired insulin sensitivity and β-cell function in individuals with previous sleeve gastrectomy as well as in matched controls. Ghrelin reduced peripheral insulin sensitivity by 25%-29% and decreased β-cell function (disposition index) by 48%-49%. These findings suggest that the postoperative reduction in circulating ghrelin following sleeve gastrectomy may contribute to improved glucose metabolism, while underscoring the complex role of ghrelin in human glucose homeostasis.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E76-E86"},"PeriodicalIF":4.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142393","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":"Liver and kidney cross talk: liver-derived bile acids and kidney water retention.","authors":"Amanda Lynggaard Elkjær, Iben Skov Jensen, Mads Gabriel Tiddy, Gitte Rye Hinrichs, Per Svenningsen","doi":"10.1152/ajpendo.00557.2025","DOIUrl":"10.1152/ajpendo.00557.2025","url":null,"abstract":"<p><p>Edema formation and ascites are common features in liver disease. The excessive accumulation of body water is caused by increased kidney water retention; yet the mechanisms linking liver and kidney function remain incompletely understood. This review explores the emerging concept of a liver-kidney axis, with bile acids (BAs) as potential mediators for kidney water handling. In cholestatic liver disease, as seen in liver cirrhosis, impaired hepatic BA flow to the duodenum elevates systemic BA concentrations, which can modulate signaling pathways through the BA receptors Farnesoid X receptor (FXR, <i>NR1H4</i>) and G-protein-coupled bile acid receptor 1 (TGR5, <i>GPBAR1</i>), thereby increasing kidney Na⁺ and water retention in experimental models. Moreover, BAs can directly activate the sodium channel ENaC in isolated mouse collecting ducts and in mouse distal colon epithelial cells. Thus, BAs can promote sodium and water retention in parallel with the classical sodium- and water-retaining systems, such as the renin-angiotensin-aldosterone system. This effect may potentially contribute to water retention in pregnancy-associated conditions and in proteinuric kidney diseases, where liver function is affected, e.g., by loss of plasma proteins, altering hepatic BA metabolism. In this review, we will describe the synthesis of BAs, their modifications, and kidney BA metabolism in health and disease, and highlight a potential dynamic interplay between liver and kidney function, mediated in part by BAs, with implications for understanding and treating water retention disorders.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E98-E109"},"PeriodicalIF":4.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148203859","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":"Heterogeneity in postprandial glucose-insulin and triacylglycerol dynamics and associations with plasma metabolome and body composition in obesity.","authors":"Nikolai B Aunbakk, Siv Kjølsrud Bøhn, Johnny Laupsa-Borge, Cathrine Sommersten, Adrian McCann, Gülen Arslan Lied, Ottar Nygård, Jutta Dierkes, Gunnar Mellgren, Simon N Dankel, Kathrine Frey Frøslie","doi":"10.1152/ajpendo.00499.2025","DOIUrl":"10.1152/ajpendo.00499.2025","url":null,"abstract":"<p><p>We are only beginning to understand the extent and reasons for the individual variation in postprandial response dynamics in key hormones and metabolites such as insulin, glucose, and triacylglycerols (TAGs). More nuanced statistical approaches for postprandial curve analyses, coupled with phenotyping of curve-associated factors, may help uncover the underlying physiology and possible associations with disease risk. In a clinical trial of 190 adults (90 males and 100 females) with abdominal obesity (age: 21-56 yr, BMI: 26-54), we used functional principal component analysis (FPCA) to examine postprandial serum glucose, C-peptide, and TAGs after a 4-h standardized mixed meal test. Correlations were explored between identified curve patterns and more than 100 anthropometric and fasting biochemistry traits. Postprandial curve levels, peaks, and dips varied substantially. Although the primary patterns in postprandial glucose, C-peptide, and TAGs uncovered by FPCA corresponded with area under the curve (AUC), the presence and timing of curve peaks and dips were uncorrelated with AUC. Males had higher postprandial levels and larger variation than females. Over 40% of the participants had nonsynchronized postprandial glucose and C-peptide curves. A postprandial phenotype characterized by elevated and delayed postprandial peaks in glucose and C-peptide, and a high postprandial TAG level and peak, was strongly associated with multiple blood biomarkers and anthropometric traits linked to insulin resistance and liver pathologies (correlation range: -0.49, 0.63). Although our findings support the general usefulness of postprandial AUC, FPCA provided detailed insight into individual postprandial glucose and insulin dynamics, which may inform improved diagnostics and personalized dietary advice.<b>NEW & NOTEWORTHY</b> Functional principal component analysis (FPCA) revealed large individual and sex-specific differences in postprandial glucose, C-peptide, and triacylglycerol dynamics in obesity. Although the primary postprandial patterns correlated strongly with the area under the curve (AUC), the presence and timing of peaks varied independently of AUC. Over 40% of participants showed nonsynchronized postprandial glucose and C-peptide curves. High and delayed peaks were associated with markers of insulin resistance, altered amino acid metabolism, visceral adiposity, and liver dysfunction.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E20-E34"},"PeriodicalIF":4.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147985930","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":"Exercise combined with dietary switch improves MASLD by suppressing hepatic MOGAT1 and modulating metabolic stress pathways in HFD-fed mice.","authors":"Jong-Hwa Won, Kyung-Wan Baek, Ying-Ying Xiang, Ji-Seok Kim","doi":"10.1152/ajpendo.00568.2025","DOIUrl":"10.1152/ajpendo.00568.2025","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive liver disorder that can lead to irreversible hepatic damage when chronic inflammation and fibrosis develop. Exercise and dietary switch have been suggested as effective strategies for improving MASLD. However, their effects in severe MASLD induced by long-term obesity remain unclear. Therefore, this study investigated the combined effects of exercise and dietary switch in a mouse model of severe MASLD induced by long-term high-fat diet feeding. The combined intervention significantly reduced body weight and improved glucose tolerance compared with either intervention alone. In addition, exercise combined with a dietary switch was associated with reduced expression of lipogenesis-related proteins, including monoacylglycerol <i>O</i>-acyltransferase 1. The intervention was also accompanied by alterations in proteins related to mitochondrial regulation, antioxidant defense, and autophagy. Histological analysis further demonstrated improvements in hepatic steatosis and MASLD activity scores. In mice with severe MASLD, the combination of exercise and dietary switch was more effective than either intervention alone in improving hepatic lipid accumulation and molecular markers associated with MASLD.<b>NEW & NOTEWORTHY</b> In severe metabolic dysfunction-associated steatotic liver disease (MASLD) induced by long-term obesity, exercise or dietary switch alone had limited effects on hepatic steatosis. However, the combination of exercise and dietary switch significantly improved MASLD and was associated with reduced hepatic monoacylglycerol <i>O</i>-acyltransferase 1 expression and alterations in mitochondrial-, antioxidant-, and autophagy-related proteins. These findings highlight the importance of combined lifestyle interventions in advanced MASLD.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E1-E13"},"PeriodicalIF":4.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148004266","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":"Alterations in glucocorticoid homeostasis following sleeve gastrectomy in male mice.","authors":"Seraina O Moser, Andrei Moscalu, Cullen F Roberts, Philipp M Späne, Denise V Winter, Friedrich L Joos, Cristina Gómez, Eric G Sheu, Alex Odermatt","doi":"10.1152/ajpendo.00385.2025","DOIUrl":"10.1152/ajpendo.00385.2025","url":null,"abstract":"<p><p>Elevated intratissue levels of active glucocorticoids in patients with obesity are associated with insulin resistance, diabetes, impaired immune regulation, and other adverse effects. Sleeve gastrectomy (SG) induces significant weight loss and improves metabolic outcomes, including insulin resistance and hyperlipidemia. Among the enzymes controlling intracellular concentrations of active glucocorticoids, 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1 and SDR26C1) has been extensively studied concerning obesity and postgastric surgery interventions. However, most studies focused on either a single tissue, circulating glucocorticoid levels, or HSD11B1 activity. In this work, we showed that the circulating active/inactive glucocorticoid ratio [corticosterone (B)/11-dehydrocorticosterone (A)] negatively correlated with glucose tolerance. In male C57BL/6 mice, SG slightly reduced circulating mineralocorticoids and reversed the elevated B/A ratio seen in sham-operated mice after a high-fat diet, while improving glucose tolerance. This change was likely due to increased renal 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2 and SDR9C3) activity after SG. To provide a comprehensive overview of the systemic effects postsurgery, we evaluated enzymes involved in glucocorticoid homeostasis across tissues on mRNA, protein, and activity levels. Moreover, mRNA expression levels of transcription factors CCAAT enhancer-binding protein alpha and beta and nuclear factor kappa b, as well as cytokines influencing <i>Hsd11b1</i> and <i>Hsd11b2</i> gene expression, were analyzed. The results emphasize the stronger influence of renal HSD11B2 than hepatic HSD11B1 activity on the circulating B/A ratio, supported by intrarenal and intrahepatic B/A ratios. The improved glucocorticoid homeostasis following SG, indicated by decreased B/A ratios, proposes a lower risk of glucocorticoid-mediated adverse health effects, including chronic kidney disease, hypertension, and metabolic disturbances.<b>NEW & NOTEWORTHY</b> This study revealed improved glucocorticoid homeostasis after sleeve gastrectomy (SG), with lower circulating ratios of active (corticosterone, B)/inactive (11-dehydrocorticosterone, A) glucocorticoids and a better glucose tolerance compared with Sham mice. SG enhanced renal HSD11B2 activity, whereas hepatic HSD11B1 oxoreductase activity was unchanged. These findings suggest that SG reverses some adverse metabolic effects of a high-fat diet by enhancing renal HSD11B2 activity, potentially lowering the risk of chronic kidney disease, hypertension, and metabolic disease.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E49-E67"},"PeriodicalIF":4.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147947560","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":"Skeletal muscle carnitine-acylcarnitine translocase deletion reveals vulnerability of oxidative muscle to fatty acid oxidation deficiency.","authors":"Filip Jevtovic, Nicholas C Williamson, Andrea S Pereyra, Molly K Alexander, Espen E Spangenburg, Jessica M Ellis","doi":"10.1152/ajpendo.00117.2026","DOIUrl":"10.1152/ajpendo.00117.2026","url":null,"abstract":"<p><p>Fatty acid oxidation (FAO) is a critical bioenergetic source for skeletal muscle, with FAO impairments being linked to metabolic and contractile dysfunction. FAO is regulated by the carnitine shuttle, in which FAO-eligible fatty acids, in the form of acylcarnitines, are transported into the mitochondrial matrix by carnitine-acylcarnitine translocase (CACT); however, the role of CACT in muscle in vivo has remained unexplored. To determine the requirement of CACT in muscle FAO and its influence on muscle mitochondrial bioenergetics, lipid profile, and muscle contractility, a novel conditional skeletal muscle-specific CACT knockout mouse (<i>Cact</i>^Sk-/-) was generated. The requirement of CACT for long-chain FAO was confirmed by the complete abrogation of FAO flux in <i>Cact</i>^Sk-/- muscle mitochondria. CACT was also required for the oxidative flux of medium-chain octanoyl-carnitine and acetyl-carnitine. CACT loss disrupted the lipid profile of skeletal muscle, with long-chain acylcarnitine accumulation and a shift in the saturation profile of phospholipids away from saturated and highly unsaturated and toward di- and tri-saturated phospholipids. Elevated mitochondrial content was demonstrated by increased phospholipid content and mitochondrial staining in <i>Cact</i>^Sk-/- muscles, occurring to a greater extent in oxidative muscles. Loss of CACT reduced muscle-specific force production by ∼70% in oxidative soleus muscle despite increased fiber size and compensatory mitochondrial accumulation that preserved muscle metabolic capacity. These findings demonstrate the crucial role of CACT in muscle FAO and show that oxidative muscles, in particular, undergo extensive lipid compositional, metabolic, and structural remodeling that coincides with impaired contractile function.<b>NEW & NOTEWORTHY</b> Novel model of CACT loss in muscle to demonstrate that CACT is required for long, medium, and short-chain fatty acid oxidation in skeletal muscle. Deletion of CACT drives oxidative and glycolytic muscle lipid remodeling and impairs oxidative, but not glycolytic, muscle contractile capacity. Oxidative soleus muscle mitochondria compensate for CACT loss by increasing mitochondrial content and muscle capacity for oxidation of nonfatty acid substrates.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E68-E75"},"PeriodicalIF":4.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148136666","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}