American journal of physiology. Endocrinology and metabolism最新文献

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Corrigendum for Rouabhi et al., volume 325, 2023, p. E711-E722. Rouabhi 等人的更正,第 325 卷,2023 年,第 E711-E722 页。
IF 4.2 2区 医学
American journal of physiology. Endocrinology and metabolism Pub Date : 2024-10-01 DOI: 10.1152/ajpendo.00174.2023_COR
{"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":null,"pages":null},"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}
引用次数: 0
Ethnic differences in postprandial fatty acid trafficking and utilization between overweight and obese White European and Black African-Caribbean men. 超重和肥胖的欧洲白人男子与非洲裔加勒比黑人男子之间在餐后脂肪酸贩运和利用方面的种族差异。
IF 4.2 2区 医学
American journal of physiology. Endocrinology and metabolism Pub Date : 2024-10-01 Epub Date: 2024-07-31 DOI: 10.1152/ajpendo.00164.2024
Reuben M Reed, Fariba Shojaee-Moradie, Gráinne Whelehan, Nicola Jackson, Oliver C Witard, Margot Umpleby, Barbara A Fielding, Martin B Whyte, Louise M Goff
{"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/m<sup>2</sup>] and BAC [<i>n</i> = 9, age 27.9 ± 1.0 yr; BMI = 27.5 (26.0-28.6) kg/m<sup>2</sup>] men consumed two consecutive (at 0 and 300 min) moderate-to-high-fat meals-the first labeled with [U-<sup>13</sup>C]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 <sup>13</sup>CO<sub>2</sub> 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<sub>0-480</sub>) = 671 (563-802) vs. 469 (354-623) mmol/L/min, <i>P</i> = 0.022] and VLDL-TAG [AUC<sub>0-480</sub> = 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<sub>0-480</sub> = 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<sub>300-480</sub> = 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":null,"pages":null},"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}
引用次数: 0
Maintenance of thermogenic adipose tissues despite loss of the H3K27 acetyltransferases p300 or CBP. 尽管丧失了 H3K27 乙酰转移酶 p300 或 CBP,但生热脂肪组织仍能维持。
IF 4.2 2区 医学
American journal of physiology. Endocrinology and metabolism Pub Date : 2024-10-01 Epub Date: 2024-08-14 DOI: 10.1152/ajpendo.00120.2024
Daniel Gamu, Makenna S Cameron, William T Gibson
{"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 β<sub>3</sub>-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 β<sub>3</sub>-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 β<sub>3</sub>-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":null,"pages":null},"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}
引用次数: 0
Acute hypoxic conditions preceding endotoxin administration result in an increased proinflammatory cytokine response in healthy men. 健康男性在服用内毒素之前的急性缺氧状态会导致促炎细胞因子反应的增加。
IF 4.2 2区 医学
American journal of physiology. Endocrinology and metabolism Pub Date : 2024-10-01 Epub Date: 2024-08-14 DOI: 10.1152/ajpendo.00247.2024
Marie Jakobs, Bastian Tebbe, Anna Lena Friedel, Tina Schönberger, Harald Engler, Benjamin Wilde, Joachim Fandrey, Tina Hörbelt-Grünheidt, Manfred Schedlowski
{"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":null,"pages":null},"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}
引用次数: 0
Key questions and gaps in understanding adipose tissue macrophages and early-life metabolic programming. 了解脂肪组织巨噬细胞和生命早期代谢编程的关键问题和差距。
IF 4.2 2区 医学
American journal of physiology. Endocrinology and metabolism Pub Date : 2024-10-01 Epub Date: 2024-08-22 DOI: 10.1152/ajpendo.00140.2024
Kaitlyn B Hill, Gregory P Mullen, Prabhakara R Nagareddy, Kurt A Zimmerman, Michael C Rudolph
{"title":"Key questions and gaps in understanding adipose tissue macrophages and early-life metabolic programming.","authors":"Kaitlyn B Hill, Gregory P Mullen, Prabhakara R Nagareddy, Kurt A Zimmerman, Michael C Rudolph","doi":"10.1152/ajpendo.00140.2024","DOIUrl":"10.1152/ajpendo.00140.2024","url":null,"abstract":"<p><p>The global obesity epidemic, with its associated comorbidities and increased risk of early mortality, underscores the urgent need for enhancing our understanding of the origins of this complex disease. It is increasingly clear that metabolism is programmed early in life and that metabolic programming can have life-long health consequences. As a critical metabolic organ sensitive to early-life stimuli, proper development of adipose tissue (AT) is crucial for life-long energy homeostasis. Early-life nutrients, especially fatty acids (FAs), significantly influence the programming of AT and shape its function and metabolism. Of growing interest are the dynamic responses during pre- and postnatal development to proinflammatory omega-6 (<i>n</i>6) and anti-inflammatory omega-3 (<i>n</i>3) FA exposures in AT. In the US maternal diet, the ratio of \"<i>pro-inflammatory</i>\" <i>n</i>6- to \"<i>anti-inflammatory</i>\" <i>n</i>3-FAs has grown dramatically due to the greater prevalence of <i>n</i>6-FAs. Notably, AT macrophages (ATMs) form a significant population within adipose stromal cells, playing not only an instrumental role in AT formation and maintenance but also acting as key mediators of cell-to-cell lipid and cytokine signaling. Despite rapid advances in ATM and immunometabolism fields, research has focused on responses to obesogenic diets and during adulthood. Consequently, there is a significant gap in identifying the mechanisms contributing metabolic health, especially regarding lipid exposures during the establishment of ATM physiology. Our review highlights the current understanding of ATM diversity, their critical role in AT, their potential role in early-life metabolic programming, and the broader implications for metabolism and health.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016097","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}
引用次数: 0
Secreted GDF15 maintains transcriptional responses during DNA damage-mediated senescence in human beta cells. 分泌的 GDF15 可在 DNA 损伤介导的人类 β 细胞衰老过程中维持转录反应。
IF 4.2 2区 医学
American journal of physiology. Endocrinology and metabolism Pub Date : 2024-10-01 Epub Date: 2024-08-28 DOI: 10.1152/ajpendo.00257.2024
Nayara Rampazzo Morelli, Camille Préfontaine, Jasmine Pipella, Peter J Thompson
{"title":"Secreted GDF15 maintains transcriptional responses during DNA damage-mediated senescence in human beta cells.","authors":"Nayara Rampazzo Morelli, Camille Préfontaine, Jasmine Pipella, Peter J Thompson","doi":"10.1152/ajpendo.00257.2024","DOIUrl":"10.1152/ajpendo.00257.2024","url":null,"abstract":"<p><p>Type 1 diabetes (T1D) is a chronic metabolic disease resulting from an autoimmune destruction of pancreatic beta cells. Beta cells activate various stress responses during the development of T1D, including senescence, which involves cell cycle arrest, prosurvival signaling, and a proinflammatory secretome termed the senescence-associated secretory phenotype (SASP). We previously identified growth and differentiation factor 15 (GDF15) as a major SASP factor in human islets and human EndoC-βH5 beta cells in a model of DNA damage-mediated senescence that recapitulates features of senescent beta cells in T1D. Soluble GDF15 has been shown to exert protective effects on human and mouse beta cells during various forms of stress relevant to T1D; therefore, we hypothesized that secreted GDF15 may play a prosurvival role during DNA damage-mediated senescence in human beta cells. We found that elevated GDF15 secretion was associated with endogenous senescent beta cells in an islet preparation from a T1D donor, supporting the validity of our DNA damage model. Using antibody-based neutralization, we found that secreted endogenous GDF15 was not required for senescent human islet or EndoC cell viability. Rather, neutralization of GDF15 led to reduced expression of specific senescence-associated genes, including <i>GDF15</i> itself and the prosurvival gene BCL2-like protein 1 (<i>BCL2L1</i>). Taken together, these data suggest that SASP factor GDF15 is not required to sustain senescent human islet viability, but it is required to maintain senescence-associated transcriptional responses.<b>NEW & NOTEWORTHY</b> Beta cell senescence is an emerging contributor to the pathogenesis of type 1 diabetes, but candidate therapeutic targets have not been identified in human beta cells. In this study, we examined the role of a secreted factor, GDF15, and found that although it is not required to maintain viability during senescence, it is required to fine-tune gene expression programs involved in the senescence response during DNA damage in human beta cells.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085902","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}
引用次数: 0
Delayed and diminished postprandial lactate shuttling in healthy older men and women. 健康老年男性和女性的餐后乳酸穿梭延迟和减少。
IF 4.2 2区 医学
American journal of physiology. Endocrinology and metabolism Pub Date : 2024-10-01 Epub Date: 2024-08-07 DOI: 10.1152/ajpendo.00183.2024
Jose A Arevalo, Robert G Leija, Adam D Osmond, Casey C Curl, Justin J Duong, Melvin J Huie, Umesh Masharani, George A Brooks
{"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-<sup>13</sup>C]lactate and [6,6-<sup>2</sup>H]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<sup>-1</sup>·min<sup>-1</sup>. Lactate Rox was higher throughout the entire trial in young participants by a difference of ∼0.5 mg·kg<sup>-1</sup>·min<sup>-1</sup>. 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><sup>2</sup> = 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":null,"pages":null},"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}
引用次数: 0
GCN2 drives diurnal patterns in the hepatic integrated stress response and maintains circadian rhythms in whole body metabolism during amino acid insufficiency. GCN2 驱动肝脏综合应激反应的昼夜模式,并在氨基酸不足时维持全身代谢的昼夜节律。
IF 4.2 2区 医学
American journal of physiology. Endocrinology and metabolism Pub Date : 2024-10-01 Epub Date: 2024-08-28 DOI: 10.1152/ajpendo.00129.2024
Jordan L Levy, Emily T Mirek, Esther M Rodriguez, Maria J Tolentino, Brian A Zalma, Troy A Roepke, Ronald C Wek, Ruifeng Cao, Tracy G Anthony
{"title":"GCN2 drives diurnal patterns in the hepatic integrated stress response and maintains circadian rhythms in whole body metabolism during amino acid insufficiency.","authors":"Jordan L Levy, Emily T Mirek, Esther M Rodriguez, Maria J Tolentino, Brian A Zalma, Troy A Roepke, Ronald C Wek, Ruifeng Cao, Tracy G Anthony","doi":"10.1152/ajpendo.00129.2024","DOIUrl":"10.1152/ajpendo.00129.2024","url":null,"abstract":"<p><p>Disruptions in circadian rhythms are associated with an increased risk of developing metabolic diseases. General control nonderepressible 2 (GCN2), a primary sensor of amino acid insufficiency and activator of the integrated stress response (ISR), has emerged as a conserved regulator of the circadian clock in multiple organisms. The objective of this study was to examine diurnal patterns in hepatic ISR activation in the liver and whole body rhythms in metabolism. We hypothesized that GCN2 activation cues hepatic ISR signaling over a natural 24-h feeding-fasting cycle. To address our objective, wild-type (WT) and whole body <i>Gcn2</i> knockout (GCN2 KO) mice were housed in metabolic cages and provided free access to either a control or leucine-devoid diet (LeuD) for 8 days in total darkness. On the last day, blood and livers were collected at <i>CT3</i> (CT = circadian time) and <i>CT15</i>. In livers of WT mice, GCN2 phosphorylation followed a diurnal pattern that was guided by intracellular branched-chain amino acid concentrations (<i>r</i><sup>2</sup> = 0.93). Feeding LeuD to WT mice increased hepatic ISR activation at <i>CT15</i> only. Diurnal oscillations in hepatic ISR signaling, the hepatic transcriptome including lipid metabolic genes, and triglyceride concentrations were substantially reduced or absent in GCN2 KO mice. Furthermore, mice lacking GCN2 were unable to maintain circadian rhythms in whole body energy expenditure, respiratory exchange ratio, and physical activity when fed LeuD. In conclusion, GCN2 activation functions to maintain diurnal ISR activation in the liver and has a vital role in the mechanisms by which nutrient stress affects whole body metabolism.<b>NEW & NOTEWORTHY</b> This work reveals that the eIF2 kinase GCN2 functions to support diurnal patterns in the hepatic integrated stress response during natural feeding and is necessary to maintain circadian rhythms in energy expenditure, respiratory exchange ratio, and physical activity during amino acid stress.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085859","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}
引用次数: 0
Paternal obesity decreases infant MSC mitochondrial functional capacity. 父亲肥胖会降低婴儿间充质干细胞线粒体的功能能力。
IF 4.2 2区 医学
American journal of physiology. Endocrinology and metabolism Pub Date : 2024-10-01 Epub Date: 2024-08-14 DOI: 10.1152/ajpendo.00239.2024
Filip Jevtovic, Alex Claiborne, Ericka M Biagioni, David N Collier, James E DeVente, Steven Mouro, Tomoko Kaneko-Tarui, Perrie F O-Tierney-Ginn, Laurie J Goodyear, Joseph A Houmard, Nicholas T Broskey, Linda E May
{"title":"Paternal obesity decreases infant MSC mitochondrial functional capacity.","authors":"Filip Jevtovic, Alex Claiborne, Ericka M Biagioni, David N Collier, James E DeVente, Steven Mouro, Tomoko Kaneko-Tarui, Perrie F O-Tierney-Ginn, Laurie J Goodyear, Joseph A Houmard, Nicholas T Broskey, Linda E May","doi":"10.1152/ajpendo.00239.2024","DOIUrl":"10.1152/ajpendo.00239.2024","url":null,"abstract":"<p><p>Besides the well-recognized influence of maternal health on fetal in utero development, recent epidemiological studies appoint paternal preconception metabolic health as a significant factor in shaping fetal metabolic programming and subsequently offspring metabolic health; however, mechanisms behind these adaptations remain confined to animal models. To elucidate the effects of paternal obesity (P-OB) on infant metabolism in humans, we examined mesenchymal stem cells (MSCs), which give rise to infant tissue, remain involved in mature tissue maintenance, and resemble the phenotype of the offspring donor. Here, we assessed mitochondrial functional capacity, content, and insulin action in MSC from infants of fathers with overweight [body mass index (BMI: 25-30 kg/m<sup>2</sup>); paternal overweight (P-OW)] or obesity (BMI ≥ 30 kg/m<sup>2</sup>; P-OB) while controlling for maternal intrauterine environment. Compared with P-OW, infant MSCs in the P-OB group had lower intact cell respiration, OXPHOS, and electron transport system capacity, independent of any changes in mitochondrial content. Furthermore, glucose handling, insulin action, lipid content, and oxidation were similar between groups. Importantly, infants in the P-OB group had a greater weight-to-length ratio, which could be in part due to changes in MSC metabolic functioning, which precedes and, therefore, influences infant growth trajectories. These data suggest that P-OB negatively influences infant MSC mitochondria. ClinicalTrials.gov Identifier: NCT03838146.<b>NEW & NOTEWORTHY</b> Paternal obesity decreases infant mesenchymal stem cell (MSC) basal and maximal respiration. Lower OXPHOS and electron transport system capacity could be explained by lower complex I and IV respiratory capacity but not changes in OXPHOS expression in infant MSC from fathers with obesity. Paternal obesity and altered MSC mitochondrial functional capacity are associated with a greater infant weight-to-length ratio at birth.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482215/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974849","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}
引用次数: 0
A ketogenic diet, regardless of fish oil content, does not affect glucose homeostasis or muscle insulin response in male rats. 无论鱼油含量多少,生酮饮食都不会影响雄性大鼠的葡萄糖稳态或肌肉胰岛素反应。
IF 4.2 2区 医学
American journal of physiology. Endocrinology and metabolism Pub Date : 2024-10-01 Epub Date: 2024-08-14 DOI: 10.1152/ajpendo.00236.2024
Joshua M Budd, Nicole M Notaro, Blair MacLeod, David M Mutch, David J Dyck
{"title":"A ketogenic diet, regardless of fish oil content, does not affect glucose homeostasis or muscle insulin response in male rats.","authors":"Joshua M Budd, Nicole M Notaro, Blair MacLeod, David M Mutch, David J Dyck","doi":"10.1152/ajpendo.00236.2024","DOIUrl":"10.1152/ajpendo.00236.2024","url":null,"abstract":"<p><p>Ketogenic diets (KDs) are very high in fat and low in carbohydrates. Evidence supports that KDs improve glucose metabolism in humans and rodents that are obese and/or insulin resistant. Conversely, findings in healthy rodents suggest that KDs may impair glucose homeostasis. In addition, most experimental KDs are composed of saturated and monounsaturated fatty acids, with almost no omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA). Evidence supports a beneficial role for n-3 LCPUFA on glucose homeostasis in the context of a metabolic challenge. To our knowledge, no study has examined whether the inclusion of n-3 LCPUFA affects the impact of a KD on glucose homeostasis. The objective of this study was to examine the impact of a KD on whole body glucose tolerance and skeletal muscle insulin response in rats and to determine if increasing the n-3 LCPUFA content in a KD with menhaden oil could improve metabolic outcomes. Male Sprague-Dawley rats were pair-fed one of a low-fat diet, high-fat diet, KD, or a KD supplemented with menhaden oil for 8 wk. No significant differences in whole body glucose tolerance, skeletal muscle insulin signaling, or skeletal muscle insulin-stimulated glucose uptake were detected between the dietary groups. Our findings suggest that KD feeding, with or without supplementation of n-3 LCPUFA, does not affect whole body glucose homeostasis or skeletal muscle insulin response under pair-feeding conditions.<b>NEW & NOTEWORTHY</b> Ketogenic diets (KDs) improve glucose metabolism in humans and rodents that are insulin resistant, but their impact is unclear in a healthy context. Furthermore, standard KDs typically lack beneficial omega-3 long-chain polyunsaturated fatty acids (n3-LCPUFA). This study assessed whether supplementing a KD with n3-LCPUFA could alter glucose homeostasis or skeletal muscle insulin response. No differences were observed between a standard KD and a KD with n3-LCPUFA when energy intake was controlled.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974846","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}
引用次数: 0
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