American journal of physiology. Endocrinology and metabolism最新文献

{"title":"Endothelial Beta 1 Integrins are Necessary for Microvascular Function and Glucose Uptake.","authors":"Nathan C Winn, Deborah A Roby, Penn Mason McClatchey, Ian M Williams, Deanna P Bracy, Michelle N Bedenbaugh, Louise Lantier, Erin Plosa, Ambra Pozzi, Roy Zent, David H Wasserman","doi":"10.1152/ajpendo.00322.2024","DOIUrl":"10.1152/ajpendo.00322.2024","url":null,"abstract":"<p><p>Microvascular insulin delivery to myocytes is rate limiting for the onset of insulin-stimulated muscle glucose uptake. The structural integrity of capillaries of the microvasculature is regulated, in part, by a family of transmembrane adhesion receptors known as integrins, which are composed of an α and β subunit. The integrin β1 (itgb1) subunit is highly expressed in endothelial cells (EC). EC itgb1 is necessary for the formation of capillary networks during embryonic during development and its knockdown blunts the reactive hyperemia that manifests during ischemia reperfusion. We investigated the contribution of EC itgb1 in microcirculatory function and glucose uptake with emphasis in skeletal muscle. We hypothesized that loss of EC itgb1 would impair microvascular hemodynamics and glucose uptake during insulin stimulation, creating 'delivery'-mediated insulin resistance. An itgβ1 knockdown mouse model was developed to avoid lethality of embryonic gene knockout and the deteriorating health resulting from early post-natal inducible gene deletion. Mice with (itgb1^fl/flSCLcre) and without (itgb1^fl/fl) tamoxifen inducible stem cell leukemia cre recombinase (SLCcre) expression at 10 days post cre induction had comparable exercise tolerance and pulmonary and cardiac functions. Using robust in vivo experimental platforms (i.e., intravital microscopy and hyperinsulinemic-euglycemic clamp), we show that itgb1^fl/flSCLcre mice compared to itgb1^fl/fl littermates have, i) deficits in capillary flow rate, flow heterogeneity, and capillary density; ii) impaired insulin-stimulated glucose uptake despite sufficient transcapillary insulin efflux; and iii) reduced insulin-stimulated glucose uptake due to perfusion-limited glucose delivery. Thus, EC itgb1 is necessary for microcirculatory function and to meet the metabolic challenge of insulin stimulation.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492941","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":"Metabolic Effects of Medium-Chain Triacylglycerol Consumption are Preserved in Obesity.","authors":"Josephine M Kanta, Anne-Marie Lundsgaard, Jesper F Havelund, Sarah L Amour, Ole Bæk, Duc Ninh Nguyen, Erik A Richter, Jakob G Knudsen, Maximilian Kleinert, Nils Faergeman, Andreas M Fritzen, Bente Kiens","doi":"10.1152/ajpendo.00234.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00234.2024","url":null,"abstract":"<p><p>Several health beneficial effects are associated with intake of medium-chain triacylglycerol (MCT), however, the underlying mechanisms are unknown. Furthermore, it remains uncertain whether the acute metabolic effects of MCT differ between lean individuals and individuals with obesity - and whether these effects are sustained following chronic intake. This study aimed to elucidate the postprandial physiological and metabolic effects of MCT before and after eight days intake compared to intake of energy-matched triacylglycerol consisting of long-chain fatty acids (LCT) using a randomized cross-over design in lean individuals (n=8) and individuals with obesity (n=8). The study revealed that consumption of MCT increased ketogenesis and metabolic rate, while lowering blood glucose levels over five hours. The hypoglycemic action of MCT intake was accompanied by a concomitant transient increase in plasma insulin and glucagon levels. Interestingly, the effects on ketogenesis, metabolic rate, and glycemia were preserved in individuals with obesity and sustained after eight days of daily supplementation. Lipidomic plasma analysis in lean individuals (n=4) showed that a part of the ingested MCT bypasses the liver and entered the systemic circulation as medium-chain fatty acids (MCFA). The findings suggest that MCFA, along with ketone bodies from the liver, may act as signaling molecules and/or substrates in the peripheral tissues, thereby contributing to the effects of MCT intake. In summary, these findings underscore the health benefits of MCT in metabolically compromised individuals after daily supplementation. Moreover, we uncover novel aspects of MCFA biology, providing insights into how these fatty acids orchestrate physiological effects in humans.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492942","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 Acute and Chronic influence of Exercise on Mitochondrial Dynamics in Skeletal Muscle.","authors":"Elya Janis Ritenis, Camila S Padilha, Matthew B Cooke, Christos George Stathis, Andrew Philp, Donny M Camera","doi":"10.1152/ajpendo.00311.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00311.2024","url":null,"abstract":"<p><p>Exercise and nutritional modulation are potent stimuli for eliciting increases in mitochondrial mass and function. Collectively, these beneficial adaptations are increasingly recognized to coincide with improvements to skeletal muscle health. Mitochondrial dynamics of fission and fusion are increasingly implicated as having a central role in mediating aspects of key organelle adaptions that are seen with exercise. Exercise-induced mitochondrial adaptations that dynamics have been implicated in are: 1) Increases to mitochondrial turnover, resulting from elevated rates of mitochondrial synthesis (biogenesis) and degradative (mitophagy) processes. 2) Morphological changes to the 3D tubular network, known as the mitochondrial reticulum, that mitochondria form in skeletal muscle. Notably, mitochondrial fission has also been implicated in coordinating increases in mitophagy, following acute exercise. Further, increased fusion following exercise training promotes increased connectivity of the mitochondrial reticulum and is associated with improved metabolism and mitochondrial function. However, the molecular basis and fashion in which exercise infers beneficial mitochondrial adaptations through mitochondrial dynamics remains poorly understood. This review attempts to highlight recent developments investigating the effects of exercise on mitochondrial dynamics, while attempting to offer a perspective of the methodological refinements and potential variables, such as substrate/glycogen availability, which should be considered going forward.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492945","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 of urine microRNA-7977/G6PD level in patients with diabetic kidney disease and its association with dysfunction of albumin-induced autophagy in proximal epithelial tubular cells.","authors":"Zhenzhen Shi, Xinran Li, Liyi Zhang, Jinlan Xie, Feifei Zhong, Zhenhong Guo, Zhongai Gao, Jingyu Wang, Roshan Kumar Mahto, Yuan Li, Shenglan Wang, Baocheng Chang, Robert C Stanton, Juhong Yang","doi":"10.1152/ajpendo.00399.2023","DOIUrl":"10.1152/ajpendo.00399.2023","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Diabetic kidney disease (DKD) remains as one of the leading long-term complications of type 2 diabetic mellitus (T2DM). Studies have shown that decreased expression of glucose-6-phosphate dehydrogenase (G6PD) plays an important role in DKD. However, the upstream and downstream pathways of G6PD downregulation leading to DKD have not been elucidated. We conducted a series of studies including clinical study, animal studies, and in vitro studies to explore this. First, a total of 90 subjects were evaluated including 30 healthy subjects, 30 patients with T2DM, and 30 patients with DKD. The urinary G6PD activity and its association with the clinical markers were analyzed. Multivariate linear regression analysis was used to analyze the risk factors of urinary G6PD in these patients. Then, microRNAs that were differentially expressed in urine and could bind and degrade G6PD were screened and verified in patients with DKD. After that, high glucose (HG)-cultured human kidney cells (HK-2) and Zucker diabetic fatty (ZDF) rats were used to test the roles of miR-7977/G6PD/albumin-induced autophagy in DKD. Beclin and P62 were used as markers of kidney autophagy indicators. A dual-luciferase reporter assay system was used to test the binding of G6PD by mir-7977. The plasma and urinary G6PD activity were decreased significantly in patients with DKD, accompanied by increased urinary mir-7977 level. The fasting plasma glucose (FPG), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and urinary albumin excretion were independent predictors of urinary G6PD activity, according to multiple linear regression analysis. The increased expression of miR-7977 and decreased expression of G6PD were also found in the kidney of ZDF rats with early renal tubular damage. The correlation analysis showed that beclin protein expression levels were positively correlated with kidney G6PD activity, whereas P62 protein expression was negatively correlated with kidney G6PD activity in rats. In HK-2 cells cultured with normal situation, a low level of albumin could induce autophagy along with the stimulation of G6PD, although this was impaired under high glucose. Overexpression of G6PD reversed albumin-induced autophagy in HK-2 cells under high glucose. Further study revealed that G6PD was a downstream target of miR-7977. Inhibition of miR-7977 expression led to significantly increased expression of G6PD and reversed the effects of high glucose on albumin-induced autophagy. In conclusion, our study supports a new mechanism of G6PD downregulation in DKD. Therapeutic measures targeting the miR-7977/G6PD/autophagy signaling pathway may help in the prevention and treatment of DKD.&lt;b&gt;NEW & NOTEWORTHY&lt;/b&gt; This study provides new evidence that reduced glucose-6-phosphate dehydrogenase (G6PD) may damage the endocytosis of renal tubular epithelial cells by reducing albumin-induced autophagy. More importantly, for the first time, our study has provided evidence from humans that ","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E512-E523"},"PeriodicalIF":4.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974851","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":"Intermittent fasting increases fat oxidation and promotes metabolic flexibility in lean mice but not obese type 2 diabetic mice.","authors":"Meghan O Conn, Daniel M Marko, Jonathan D Schertzer","doi":"10.1152/ajpendo.00255.2024","DOIUrl":"10.1152/ajpendo.00255.2024","url":null,"abstract":"<p><p>Obesity and type 2 diabetes (T2D) are associated with metabolic inflexibility, characterized by an impaired ability to switch between substrate storage and utilization pathways. Metabolic inflexibility during obesity is typified by lower engagement of fatty acid metabolism despite an ample supply of stored lipids. Intermittent fasting (IF) can promote metabolic flexibility. However, it is not clear how obesity and T2D alter metabolic flexibility after repeated IF. Male obese <i>db/db</i> and control <i>db/+</i> mice were fasted for 24 h twice a week for 10 wk. This 5:2 IF regimen did not alter body mass, body composition, food intake, or physical activity in <i>db/db</i> or <i>db/+</i> mice. After IF, <i>db/db</i> mice had lower fatty acid oxidation and higher carbohydrate oxidation in the fed state, indicating metabolic inflexibility to metabolize lipids. After IF, control <i>db/+</i> mice had higher fatty acid oxidation and lower carbohydrate oxidation in the fed state, characteristic of metabolic flexibility, and increased engagement of lipid metabolism. In the fasted state, IF lowered carbohydrate oxidation and increased fatty acid oxidation in control <i>db/+</i> mice but not in obese <i>db/db</i> mice. After IF, <i>db/db</i> mice also had lower serum β-hydroxybutyrate than control <i>db/+</i> mice. Ten weeks of IF decreased adipocyte size in visceral adipose tissue of control <i>db/+</i> mice, but this IF regimen did not change adipocyte size in obese <i>db/db</i> mice. Therefore, IF increases fatty acid oxidation and metabolic flexibility in lean mice, but this adaptation is absent in a mouse model of obesity and type 2 diabetes.<b>NEW & NOTEWORTHY</b> We show that a 5:2 intermittent fasting regimen can increase lipid oxidation without altering body mass in lean mice. Therefore, repeated intermittent fasting can increase metabolic flexibility without the need for (or prior to) weight loss. Intermittent fasting did not increase lipid oxidation in mice with obesity and type 2 diabetes, highlighting that obesity and/or type 2 diabetes limit changes in metabolic flexibility and mitigate increased fatty acid oxidation without weight loss during intermittent fasting.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E470-E477"},"PeriodicalIF":4.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085901","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":"Corrigendum for Rouabhi et al., volume 325, 2023, p. E711-E722.","authors":"","doi":"10.1152/ajpendo.00174.2023_COR","DOIUrl":"https://doi.org/10.1152/ajpendo.00174.2023_COR","url":null,"abstract":"","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"327 4","pages":"E469"},"PeriodicalIF":4.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339341","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":"Ethnic differences in postprandial fatty acid trafficking and utilization between overweight and obese White European and Black African-Caribbean men.","authors":"Reuben M Reed, Fariba Shojaee-Moradie, Gráinne Whelehan, Nicola Jackson, Oliver C Witard, Margot Umpleby, Barbara A Fielding, Martin B Whyte, Louise M Goff","doi":"10.1152/ajpendo.00164.2024","DOIUrl":"10.1152/ajpendo.00164.2024","url":null,"abstract":"<p><p>Black African-Caribbean (BAC) populations are at greater risk of cardiometabolic disease than White Europeans (WE), despite exhibiting lower fasting triacylglycerol (TAG) concentrations. However, limited data exist regarding postprandial fatty acid metabolism in BAC populations. This study determined the ethnic differences in postprandial fatty acid metabolism between overweight and obese WE and BAC men. WE [<i>n</i> = 10, age 33.3 ± 1.7 yr; body mass index (BMI) = 26.8 (25.8-31.0) kg/m²] and BAC [<i>n</i> = 9, age 27.9 ± 1.0 yr; BMI = 27.5 (26.0-28.6) kg/m²] men consumed two consecutive (at 0 and 300 min) moderate-to-high-fat meals-the first labeled with [U-¹³C]palmitate. The plasma concentration and appearance of meal-derived fatty acids in very-low-density lipoprotein (VLDL)-TAG, chylomicron-TAG, and nonesterified fatty acid (NEFA) were determined over an 8-h postprandial period. Indirect calorimetry with ¹³CO₂ enrichment determined total and meal-derived fatty acid oxidation rates, and plasma β-hydroxybutyrate (3-OHB) concentration was measured to assess ketogenesis. BAC exhibited lower postprandial TAG [area under the curve (AUC_0-480) = 671 (563-802) vs. 469 (354-623) mmol/L/min, <i>P</i> = 0.022] and VLDL-TAG [AUC_0-480 = 288 ± 30 vs. 145 ± 27 mmol/L/min, <i>P</i> = 0.003] concentrations than WE. The appearance of meal-derived fatty acids in VLDL-TAG was lower in BAC than in WE (AUC_0-480 = 133 ± 12 vs. 78 ± 13 mmol/L/min, <i>P</i> = 0.007). Following the second meal, BAC showed a trend for lower chylomicron-TAG concentration [AUC_300-480 = 69 (51-93) vs. 43 (28-67) mmol/L/min, <i>P</i> = 0.057]. There were no ethnic differences in the appearance of chylomicron-TAG, cumulative fatty acid oxidation, and the NEFA:3-OHB ratio (<i>P</i> > 0.05). In conclusion, BAC exhibit lower postprandial TAG concentrations compared with WE men, driven by lower VLDL-TAG concentrations and possibly lower chylomicron-TAG in the late postprandial period. These findings suggest that postprandial fatty acid trafficking may be a less important determinant of cardiometabolic risk in BAC than in WE men.<b>NEW & NOTEWORTHY</b> Postprandial TAG is lower in Black African-Caribbean men than in White European men, and this is likely driven by lower meal-derived VLDL-TAG in Black African-Caribbean men. This observation could suggest that fatty acid trafficking may be a less important determinant of cardiometabolic risk in Black Africans than in White European men.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E585-E597"},"PeriodicalIF":4.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854497","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":"Maintenance of thermogenic adipose tissues despite loss of the H3K27 acetyltransferases p300 or CBP.","authors":"Daniel Gamu, Makenna S Cameron, William T Gibson","doi":"10.1152/ajpendo.00120.2024","DOIUrl":"10.1152/ajpendo.00120.2024","url":null,"abstract":"<p><p>Brown and beige adipose tissues are specialized for thermogenesis and are important for energy balance in mice. Mounting evidence suggests that chromatin-modifying enzymes are integral for the development, maintenance, and functioning of thermogenic adipocytes. p300 and cAMP-response element binding protein (CREB)-binding protein (CBP) are histone acetyltransferases (HATs) responsible for writing the transcriptionally activating mark H3K27ac. Despite their homology, p300 and CBP do have unique tissue- and context-dependent roles, which have yet to be examined in brown and beige adipocytes specifically. We assessed the requirement of p300 or CBP in thermogenic fat using uncoupling protein 1 (<i>Ucp1</i>)<i>-</i>Cre-mediated knockdown in mice to determine whether their loss impacted tissue development, susceptibility to diet-induced obesity, and response to pharmacological induction via β₃-agonism. Despite successful knockdown, brown adipose tissue mass and expression of thermogenic markers were unaffected by loss of either HAT. As such, knockout mice developed a comparable degree of diet-induced obesity and glucose intolerance to that of floxed controls. Furthermore, \"browning\" of white adipose tissue by the β₃-adrenergic agonist CL-316,243 remained largely intact in knockout mice. Although p300 and CBP have nonoverlapping roles in other tissues, our results indicate that they are individually dispensable within thermogenic fats specifically, possibly due to functional compensation by one another.<b>NEW & NOTEWORTHY</b> The role of transcriptionally activating H3K27ac epigenetic mark has yet to be examined in mouse thermogenic fats specifically, which we achieved here via <i>Ucp1</i>-Cre-driven knockdown of the histone acetyltransferases (HAT) p300 or CBP under several metabolic contexts. Despite successful knockdown of either HAT, brown adipose tissue was maintained at room temperature. As such, knockout mice were indistinguishable to controls when fed an obesogenic diet or when given a β₃-adrenergic receptor agonist to induce browning of white fat. Unlike other tissues, thermogenic fats are resilient to p300 or CBP ablation, likely due to sufficient functional overlap between them.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E459-E468"},"PeriodicalIF":4.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974848","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":"Delayed and diminished postprandial lactate shuttling in healthy older men and women.","authors":"Jose A Arevalo, Robert G Leija, Adam D Osmond, Casey C Curl, Justin J Duong, Melvin J Huie, Umesh Masharani, George A Brooks","doi":"10.1152/ajpendo.00183.2024","DOIUrl":"10.1152/ajpendo.00183.2024","url":null,"abstract":"<p><p>Lactate, a product of glycolysis, is formed under aerobic conditions. Extensive work has shown lactate flux in young and exercising humans; however, the effect of age is not known. We tested the hypothesis that postprandial lactate shuttling (PLS) would be diminished in older adults. We used [3-¹³C]lactate and [6,6-²H]glucose tracers, an oral glucose tolerance test (OGTT), and arterialized blood sampling to determine postprandial lactate rates of appearance (Ra), disappearance (Rd), and oxidation (Rox) in 15 young (28.1 ± 1.4 yr) and 13 older (70.6 ± 2.4 yr) healthy men and women. In young participants, fasting blood [lactate] (≈0.5 mM) rose after the glucose challenge, peaked at 15 min, dipped to a nadir at 30 min, and rose again peaking at 60 min (≈1.0 mM). Initial responses in lactate Ra of older participants were delayed and diminished until 90 min rising by 0.83 mg·kg^-1·min^-1. Lactate Rox was higher throughout the entire trial in young participants by a difference of ∼0.5 mg·kg^-1·min^-1. Initial peaks in lactate Ra and concentration in all volunteers demonstrated the presence of an enteric PLS following an OGTT. Notably, in the systemic, but not enteric, PLS phase, lactate Ra correlated highly with glucose Rd (<i>r</i>² = 0.92). Correspondence of second peaks in lactate Ra and concentration and glucose Rd shows dependence of lactate Ra on glucose Rd. Although results show both enteric and systemic PLS phases in young and older study cohorts, metabolic responses were delayed and diminished in healthy older individuals.<b>NEW & NOTEWORTHY</b> We used isotope tracers, an oral glucose tolerance test, and arterialized blood sampling to determine postprandial lactate flux rates in healthy young and older men and women. Lactate rates of appearance and oxidation and the lactate-pyruvate exchange were delayed and diminished in both enteric and systemic postprandial lactate shuttle phases in older participants.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E430-E440"},"PeriodicalIF":4.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896535","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":"Acute hypoxic conditions preceding endotoxin administration result in an increased proinflammatory cytokine response in healthy men.","authors":"Marie Jakobs, Bastian Tebbe, Anna Lena Friedel, Tina Schönberger, Harald Engler, Benjamin Wilde, Joachim Fandrey, Tina Hörbelt-Grünheidt, Manfred Schedlowski","doi":"10.1152/ajpendo.00247.2024","DOIUrl":"10.1152/ajpendo.00247.2024","url":null,"abstract":"<p><p>Tissues often experience hypoxia at sites of inflammation due to malperfusion, massive immune cell recruitment, and increased oxygen consumption. Organisms adapt to these hypoxic conditions through the transcriptional activation of various genes. In fact, there is significant crosstalk between the transcriptional responses to hypoxia and inflammatory processes. This interaction, named inflammatory hypoxia, plays a crucial role in various diseases including malignancies, chronic inflammatory lung diseases, and sepsis. To further elucidate the crosstalk between hypoxia and inflammation in vivo and assess its potential for innovative therapies, our study aimed at investigating the impact of acute hypoxic conditions on inflammation-induced immune responses. To this end, we exposed healthy human subjects to hypoxia either before (hypoxia priming) or after a single intravenous (i.v.) injection of 0.4 ng/kg LPS. Our data show that hypoxia exposure prior to LPS injection (hypoxia priming) amplified the proinflammatory response. This was reflected by an increase in body temperature, plasma noradrenaline levels, and the production of proinflammatory cytokines (i.e., IL-6 and TNF-α), compared with LPS control conditions. These effects were not observed when participants were exposed to hypoxia after LPS administration, demonstrating that the interaction between hypoxia and inflammation highly depends on the timing of both stimuli. Our findings suggest that acute hypoxia (i.e., hypoxia priming) modulates transient inflammation, leading to an enhanced proinflammatory response in healthy human subjects. This highlights the need for further investigations to understand the pathology of various hypoxia-inducible factor (HIF)-associated inflammatory diseases and to develop suitable, innovative therapies.<b>NEW & NOTEWORTHY</b> To our knowledge, this is the first in vivo study investigating the effects of hypoxia preceding (hypoxia priming) or following LPS administration on the endotoxin-induced inflammatory response in healthy human subjects. The data show that hypoxia priming amplified the proinflammatory response, reflected by an increased body temperature, increased plasma noradrenaline levels, and higher production of proinflammatory cytokines (i.e., IL-6 and TNF-α) compared with LPS control conditions.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E422-E429"},"PeriodicalIF":4.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974847","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}