American journal of physiology. Endocrinology and metabolism最新文献

{"title":"Small molecule inhibition of glycogen synthase I reduces muscle glycogen content and improves biomarkers in a mouse model of Pompe disease.","authors":"Rafael Calais Gaspar, Ikki Sakuma, Ali Nasiri, Brandon T Hubbard, Traci E LaMoia, Brooks P Leitner, Samnang Tep, Yannan Xi, Eric M Green, Julie C Ullman, Kitt Falk Petersen, Gerald I Shulman","doi":"10.1152/ajpendo.00175.2024","DOIUrl":"10.1152/ajpendo.00175.2024","url":null,"abstract":"<p><p>Pompe disease is a rare genetic disorder caused by a deficiency of the enzyme acid alpha-glucosidase (GAA). This enzyme is responsible for breaking down glycogen, leading to the abnormal accumulation of glycogen, which results in progressive muscle weakness and metabolic dysregulation. In this study, we investigated the hypothesis that the small molecule inhibition of glycogen synthase I (GYS1) may reduce muscle glycogen content and improve metabolic dysregulation in a mouse model of Pompe disease. To address this hypothesis, we studied four groups of male mice: a control group of wild-type (WT) B6129SF1/J mice fed either regular chow or a GYS1 inhibitor (MZ-101) diet (WT-GYS1), and Pompe model mice B6;129-Gaatm1Rabn/J fed either regular chow (GAA-KO) or MZ-101 diet (GAA-GYS1) for 7 days. Our findings revealed that GAA-KO mice exhibited abnormal glycogen accumulation in the gastrocnemius, heart, and diaphragm. In contrast, inhibiting GYS1 reduced glycogen levels in all tissues compared with GAA-KO mice. Furthermore, GAA-KO mice displayed reduced spontaneous activity during the dark cycle compared with WT mice, whereas GYS1 inhibition counteracted this effect. Compared with GAA-KO mice, GAA-GYS1 mice exhibited improved glucose tolerance and whole body insulin sensitivity. These improvements in insulin sensitivity could be attributed to increased AMP-activated protein kinase phosphorylation in the gastrocnemius of WT-GYS1 and GAA-GYS1 mice. Additionally, the GYS1 inhibitor led to a reduction in the phosphorylation of GS^S641 and the LC3 autophagy marker. Together, our results suggest that targeting GYS1 could serve as a potential strategy for treating glycogen storage disorders and metabolic dysregulation.<b>NEW & NOTEWORTHY</b> We investigated the effects of small molecule inhibition of glycogen synthase I (GYS1) on glucose metabolism in a mouse model of Pompe disease. GYS1 inhibition reduces abnormal glycogen accumulation and molecular biomarkers associated with Pompe disease while also improving glucose intolerance. Our results collectively demonstrate that the GYS1 inhibitor represents a novel approach to substrate reduction therapy for Pompe disease.</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/PMC11482269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016098","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":"Synergistic effects of glucose tolerance and BMI on cardiovascular events and all-cause mortality in a healthy population: CA.ME.LI.A study 7 years follow-up.","authors":"Monica Bignotto, Elena Bianco, Lucia Centofanti, Antonio Russo, Michele Dei Cas, Paola Zermiani, Camillo Morano, Federica Samartin, Emanuela Bertolini, Francesco Bifari, Cesare Berra, Massimo Zuin, Rita Paroni, Pier Maria Battezzati, Franco Folli","doi":"10.1152/ajpendo.00181.2024","DOIUrl":"10.1152/ajpendo.00181.2024","url":null,"abstract":"<p><p>The CA.ME.LI.A (CArdiovascular risks, MEtabolic syndrome, LIver and Autoimmune disease) epidemiological study was conducted in Abbiategrasso (Milan, Italy) to identify risk factors for metabolic and cardiovascular disease in an apparently healthy population of northern Italy. The population (<i>n</i> = 2,545, 1,251 men, 1,254 women) was stratified according to body mass index [normal body weight (NBW): <25 kg/m²; overweight-obese (OWO): ≥25 kg/m²] and according to fasting blood glucose [normal fasting glucose: <100 mg/dL; impaired fasting glucose (IFG): 100-125 mg/dL; diabetes mellitus (DM): ≥126 mg/dL]. The incidence of cardiovascular (CV) events and overall mortality were studied by the Kaplan-Meier method using the log rank test. Univariate analysis was conducted with time-dependent Cox models. During the 7-yr follow-up period, 80 deaths and 149 CV events occurred. IFG [hazard ratio (HR): 2.81; confidence interval (CI): 1.37-5.77; <i>P</i> = 0.005], DM (HR: 4.88; CI: 1.47-16; <i>P</i> = 0.010), or OWO (HR: 2.78; CI:1.68-4.59; <i>P</i> < 0.001) all produced significant increases in CV events and deaths. In the combination IFG/OWO (HR: 5.51; CI: 3.34-9.08; <i>P</i> < 0.001), there was an apparent additive effect of the two conditions, whereas in the combination DM/OWO (HR: 12.71; CI: 7.48-22; <i>P</i> < 0.001), there was an apparent multiplicative effect on the risk for CV events and deaths. In males, the DM/NBW group had a higher incidence of cardiovascular events and deaths than the IFG/OWO group. In contrast, in females, the IFG/OWO group had a higher incidence of cardiovascular events and deaths than the DM/NBW group. In women, there was a greater incidence of CV events in the IFG/OWO group (HR: 6.23; CI: 2.88-13; <i>P</i> < 0.001) than in men in the same group (HR: 4.27; CI: 2.15-8.47; <i>P</i> < 0.001). Consistent with these data, also all-cause mortality was progressively increased by IFG/DM and OWO, with an apparently exponential effect in the combination DM/OWO (HR: 11.78; CI: 6.11-23; <i>P</i> < 0.001). IFG/DM and OWO, alone or in combination, had major effects in increasing mortality for all causes and CV events. The relative contributions of hyperglycemia and overweight/obesity on cardiovascular events and deaths were apparently, to a certain extent, sex dependent. Females were more affected by overweight/obesity either alone or combined with IFG, as compared with males.<b>NEW & NOTEWORTHY</b> For the first time, the combined effects of glucose tolerance and BMI have been investigated in an apparently healthy large population sample of a city in the north of Italy. We found that there are synergistic effects of glucose levels with BMI to increase not only cardiovascular events and deaths but also cancer-related deaths and all-cause mortality.</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/PMC11482241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085903","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":"Enhanced ECCD36 signaling promotes skeletal muscle insulin resistance in female mice.","authors":"Austin Dada, Javad Habibi, Huma Naz, Dongqing Chen, Guido Lastra, Brian P Bostick, Adam Whaley-Connell, Michael A Hill, James R Sowers, Guanghong Jia","doi":"10.1152/ajpendo.00246.2024","DOIUrl":"10.1152/ajpendo.00246.2024","url":null,"abstract":"<p><p>Consumption of a Western diet (WD) increases CD36 expression in vascular, hepatic, and skeletal muscle tissues promoting lipid metabolic disorders and insulin resistance. We further examined the role of endothelial cell-specific CD36 (ECCD36) signaling in contributing to skeletal muscle lipid metabolic disorders, insulin resistance, and their underlying molecular mechanisms. Female ECCD36 wild-type (ECCD36^+/+) and knock-out (ECCD36^-/-) mice, aged 6 wk, were provided with either a WD or a standard chow diet for a duration of 16 wk. ECCD36^+/+ WD mice were characterized by elevated fasting plasma glucose and insulin levels, increased homeostatic model assessment for insulin resistance, and glucose intolerance that was blunted in ECCD36^-/- mice. Improved insulin sensitivity in ECCD36^-/- mice was characterized by increased phosphoinositide 3-kinases/protein kinase B signaling that further augmented glucose transporter type 4 expression and glucose uptake. Meanwhile, 16 wk of WD feeding also increased skeletal muscle free fatty acid (FFA) and lipid accumulation, without any observed changes in plasma FFA levels. These lipid metabolic disorders were blunted in ECCD36^-/- mice. Moreover, ECCD36 also mediated in vitro palmitic acid-induced lipid accumulation in cultured ECs, subsequently leading to the release of FFAs into the culture media. Furthermore, consumption of a WD increased FFA oxidation, mitochondrial dysfunction, impaired mitochondrial respiratory, skeletal muscle fiber type transition, and fibrosis. These WD-induced abnormalities were blunted in ECCD36^-/- mice. These findings demonstrate that endothelial-specific ECCD36 signaling participates in skeletal muscle FFA uptake, ectopic lipid accumulation, mitochondrial dysfunction, insulin resistance, and associated skeletal muscle dysfunction in diet-induced obesity.<b>NEW & NOTEWORTHY</b> ECCD36 exerts \"extra endothelial cell\" actions in skeletal muscle insulin resistance. ECCD36 is a major mediator of Western diet-induced lipid metabolic disorders and insulin resistance in skeletal muscle. Mitochondrial dysfunction is associated with diet-induced CD36 activation and related skeletal muscle insulin resistance.</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/PMC11482271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085858","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":"Perineuronal nets' role in metabolism.","authors":"Nan Zhang, Beite Song, Peng Bai, Li Du, Lulu Chen, Yong Xu, Tianshu Zeng","doi":"10.1152/ajpendo.00154.2024","DOIUrl":"10.1152/ajpendo.00154.2024","url":null,"abstract":"<p><p>Perineuronal nets (PNNs), specialized extracellular matrix (ECM) structures that envelop neurons, have recently been recognized as key players in the regulation of metabolism. This review explores the growing body of knowledge concerning PNNs and their role in metabolic control, drawing insights from recent research and relevant studies. The pivotal role of PNNs in the context of energy balance and whole body blood glucose is examined. This review also highlights novel findings, including the effects of astroglia, microglia, sex and gonadal hormones, nutritional regulation, circadian rhythms, and age on PNNs dynamics. These findings illuminate the complex and multifaceted role of PNNs in metabolic 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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974850","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":"Characterization of Ucp1-iCre knockin mice reveals the recombination activity in male germ cells.","authors":"Meng-Yue Li, Ming Lu, Dong-Mei Cao, Qing Han, Xian-Hua Ma, Chun-Chun Wei, Weiping J Zhang","doi":"10.1152/ajpendo.00128.2024","DOIUrl":"10.1152/ajpendo.00128.2024","url":null,"abstract":"<p><p><i>Ucp1</i> promoter-driven Cre transgenic mice are useful in the manipulation of gene expression specifically in thermogenic adipose tissues. However, the wildly used Ucp1-Cre line was generated by random insertion into the genome and showed ectopic activity in some tissues beyond adipose tissues. Here, we characterized a knockin mouse line Ucp1-iCre generated by targeting IRES-Cre cassette immediately downstream the stop codon of the <i>Ucp1</i> gene. The Cre insertion had little to no effect on uncoupling protein 1 (UCP1) levels in brown adipose tissue. Ucp1-iCre mice of both genders exhibited normal thermogenesis and cold tolerance. When crossed with Rosa-tdTomato reporter mice, Ucp1-iCre mice showed robust Cre activity in thermogenic adipose tissues. In addition, limited Cre activity was sparsely present in the ventromedial hypothalamus (VMH), choroid plexus, kidney, adrenal glands, ovary, and testis in Ucp1-iCre mice, albeit to a much lesser extent and with reduced intensity compared with the conventional Ucp1-Cre line. Single-cell transcriptome analysis revealed <i>Ucp1</i> mRNA expression in male spermatocytes. Moreover, male Ucp1-iCre mice displayed a high frequency of Cre-mediated recombination in the germline, whereas no such effect was observed in female Ucp1-iCre mice. These findings suggest that Ucp1-iCre mice offer promising utility in the context of conditional gene manipulation in thermogenic adipose tissues, while also highlighting the need for caution in mouse mating and genotyping procedures.<b>NEW & NOTEWORTHY</b> <i>Ucp1</i> promoter-driven Cre transgenic mice are useful in the manipulation of gene expression specifically in thermogenic adipose tissues. The widely used Ucp1-Cre mouse line (Ucp1-Cre^Evdr), which was generated using the bacterial artificial chromosome (BAC) strategy, exhibits major brown and white fat transcriptomic dysregulation and ectopic activity beyond adipose tissues. Here, we comprehensively validate Ucp1-iCre knockin mice, which serve as another optional model besides Ucp1-Cre^Evdr mice for specific genetic manipulation in thermogenic tissue.</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":"142124562","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":"Comparable glucagon-stimulated amino acid suppression in individuals with and without hepatic steatosis or steatohepatitis","authors":"Sara Heebøll, Gregers Wegener, Henning Grønbæk, Søren Nielsen","doi":"10.1152/ajpendo.00187.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00187.2024","url":null,"abstract":"American Journal of Physiology-Endocrinology and Metabolism, Ahead of Print. <br/>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266645","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":"Hydrolyzed collagen supplementation prior to resistance exercise augments collagen synthesis in a dose-response manner in resistance-trained, middle-aged men","authors":"Christopher D. Nulty, Jonathan C.Y. Tang, John Dutton, Rachel Dunn, William D. Fraser, Kevin Enright, Claire E. Stewart, Robert M. Erskine","doi":"10.1152/ajpendo.00252.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00252.2024","url":null,"abstract":"American Journal of Physiology-Endocrinology and Metabolism, Ahead of Print. <br/>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142183599","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":"Menstrual cycle phase differences in myofiber damage and macrophage infiltration following electrical stimulation-induced muscle injury","authors":"Brandon Pfeifer, Briell King, Mohadeseh Ahmadi, Jamie P. Kaluhiokalani, Krista S. Shimizu, W. Noah Hunter, Collin Deshler, Madeline N. Nielson, Chad R. Hancock, W. Bradley Nelson, Robert D. Hyldahl","doi":"10.1152/ajpendo.00168.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00168.2024","url":null,"abstract":"American Journal of Physiology-Endocrinology and Metabolism, Ahead of Print. <br/>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142183602","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 adrenoceptor alpha-1b plays a key role in energy and glucose homeostasis in female mice.","authors":"Anisia Silva, Mathilde Mouchiroud, Olivier Lavoie, Sarra Beji, Joel K. Elmquist, Alexandre Caron","doi":"10.1152/ajpendo.00153.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00153.2024","url":null,"abstract":"American Journal of Physiology-Endocrinology and Metabolism, Ahead of Print. <br/>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142183604","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":"Contractile regulation of the glucocorticoid-sensitive transcriptome in young and aged skeletal muscle","authors":"Grant R. Laskin, David S. Waddell, Cynthia Vied, Bradley S. Gordon","doi":"10.1152/ajpendo.00223.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00223.2024","url":null,"abstract":"American Journal of Physiology-Endocrinology and Metabolism, Ahead of Print. <br/>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142183600","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}