Metabolism: clinical and experimental最新文献

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Combined loss of glyoxalase 1 and aldehyde dehydrogenase 3a1 amplifies dicarbonyl stress, impairs proteasome activity resulting in hyperglycemia and activated retinal angiogenesis
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-01-30 DOI: 10.1016/j.metabol.2025.156149
Shu Li , Hao Li , Katrin Bennewitz , Gernot Poschet , Michael Buettner , Ingrid Hausser , Julia Szendroedi , Peter Paul Nawroth , Jens Kroll
{"title":"Combined loss of glyoxalase 1 and aldehyde dehydrogenase 3a1 amplifies dicarbonyl stress, impairs proteasome activity resulting in hyperglycemia and activated retinal angiogenesis","authors":"Shu Li ,&nbsp;Hao Li ,&nbsp;Katrin Bennewitz ,&nbsp;Gernot Poschet ,&nbsp;Michael Buettner ,&nbsp;Ingrid Hausser ,&nbsp;Julia Szendroedi ,&nbsp;Peter Paul Nawroth ,&nbsp;Jens Kroll","doi":"10.1016/j.metabol.2025.156149","DOIUrl":"10.1016/j.metabol.2025.156149","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>Any energy consumption results in the generation of highly reactive dicarbonyls and the need to prevent excessive dicarbonyls accumulation through the activity of several interdependent detoxification enzymes. Glyoxalase 1 (GLO1) knockout zebrafish showed only moderately elevated methylglyoxal (MG) levels, but increased Aldehyde Dehydrogenases (ALDH) activity and increased <em>aldh3a1</em> expression. Elevated levels of 4-hydroxynonenal (4-HNE) but no MG increase were observed in ALDH3A1KO. The question of whether ALDH3A1 prevents MG formation as a compensatory mechanism in the absence of GLO1 remained unclear.</div></div><div><h3>Methods</h3><div>To investigate whether ALDH3A1 detoxifies MG as a compensatory mechanism in the absence of GLO1, the GLO1/ALDH3A1 double knockout (DKO) zebrafish was first generated. Various metabolites including advanced glycation end products (AGEs), as well as glucose metabolism and hyaloid vasculature were analyzed in GLO1KO, ALDH3A1KO and GLO1/ALDH3A1DKO zebrafish.</div></div><div><h3>Results</h3><div>In the absence of GLO1 and ALDH3A1, MG-H1 levels were increased. MG-H1 accumulation led to a severe deterioration of proteasome function, resulting in impaired glucose homeostasis and consequently amplified angiogenic activation of the hyaloid and retinal vasculature. Rescue of these pathological processes could be observed by using L-carnosine, and proteasome activator betulinic acid.</div></div><div><h3>Conclusion</h3><div>The present data, together with previous studies, suggest that ALDH3A1 and GLO1 are important detoxification enzymes that prevent the deleterious effects of MG-H1 accumulation on proteasome function, glucose homeostasis and vascular function.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"165 ","pages":"Article 156149"},"PeriodicalIF":10.8,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Exploring receptors for pro-resolving and non-pro-resolving mediators as therapeutic targets for sarcopenia
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-01-30 DOI: 10.1016/j.metabol.2025.156148
Tiantian Wang , Sihan Chen , Dong Zhou , Zhen Hong
{"title":"Exploring receptors for pro-resolving and non-pro-resolving mediators as therapeutic targets for sarcopenia","authors":"Tiantian Wang ,&nbsp;Sihan Chen ,&nbsp;Dong Zhou ,&nbsp;Zhen Hong","doi":"10.1016/j.metabol.2025.156148","DOIUrl":"10.1016/j.metabol.2025.156148","url":null,"abstract":"<div><div>Sarcopenia is defined by a reduction in both muscle strength and mass. Sarcopenia may be an inevitable component of the aging process, but it may also be accelerated by comorbidities and metabolic derangements. The underlying mechanisms contributing to these pathological changes remain poorly understood. We propose that chronic inflammation-mediated networks and metabolic defects that exacerbate muscle dysfunction are critical factors in sarcopenia and related diseases. Consequently, utilizing specialized pro-resolving mediators (SPMs) that function through specific G-protein coupled receptors (GPCRs) may offer effective therapeutic options for these disorders. However, challenges such as a limited understanding of SPM/receptor signaling pathways, rapid inactivation of SPMs, and the complexities of SPM synthesis impede their practical application. In this context, stable small-molecule SPM mimetics and receptor agonists present promising alternatives. Moreover, the aged adipose-skeletal axis may contribute to this process. Activating non-SPM GPCRs on adipocytes, immune cells, and muscle cells under conditions of systemic, chronic, low-grade inflammation (SCLGI) could help alleviate inflammation and metabolic dysfunction. Recent preclinical studies indicate that both SPM GPCRs and non-SPM GPCRs can mitigate symptoms of aging-related diseases such as obesity and diabetes, which are driven by chronic inflammation and metabolic disturbances. These findings suggest that targeting these receptors could provide a novel strategy for addressing various chronic inflammatory conditions, including sarcopenia.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"165 ","pages":"Article 156148"},"PeriodicalIF":10.8,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Disrupted metabolic flux balance between pyruvate dehydrogenase and pyruvate carboxylase in human fatty liver
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-01-29 DOI: 10.1016/j.metabol.2025.156151
Jae Mo Park , Sung-Han Lin , Jeannie D. Baxter , Crystal E. Harrison , Jennine Leary , Corey Mozingo , Jeff Liticker , Craig R. Malloy , Eunsook S. Jin
{"title":"Disrupted metabolic flux balance between pyruvate dehydrogenase and pyruvate carboxylase in human fatty liver","authors":"Jae Mo Park ,&nbsp;Sung-Han Lin ,&nbsp;Jeannie D. Baxter ,&nbsp;Crystal E. Harrison ,&nbsp;Jennine Leary ,&nbsp;Corey Mozingo ,&nbsp;Jeff Liticker ,&nbsp;Craig R. Malloy ,&nbsp;Eunsook S. Jin","doi":"10.1016/j.metabol.2025.156151","DOIUrl":"10.1016/j.metabol.2025.156151","url":null,"abstract":"<div><div>Hepatic metabolism involving pyruvate carboxylase (PC) and pyruvate dehydrogenase (PDH) may be abnormal in fatty livers. In this study, [<sup>13</sup>C]bicarbonate production from [1-<sup>13</sup>C<sub>1</sub>]pyruvate in the liver and glycerol glyceroneogenesis were examined in relation to hepatic fat content using hyperpolarized [1-<sup>13</sup>C<sub>1</sub>]pyruvate and oral [U-<sup>13</sup>C<sub>3</sub>]glycerol. After an overnight fast, 15 subjects with a range of hepatic fat content received hyperpolarized [1-<sup>13</sup>C<sub>1</sub>]pyruvate intravenously to assess its conversion to [1-<sup>13</sup>C<sub>1</sub>]lactate and [<sup>13</sup>C]bicarbonate in the liver. They also received oral [U-<sup>13</sup>C<sub>3</sub>]glycerol, followed by venous blood sampling to examine glucose and the glycerol backbone of the triglycerides released primarily from the liver. From hyperpolarized [1-<sup>13</sup>C<sub>1</sub>]pyruvate, participants with high intrahepatic fat fraction produced higher [1-<sup>13</sup>C<sub>1</sub>]lactate and lower [<sup>13</sup>C]bicarbonate than those with low liver fat. The fraction of plasma triglycerides derived from oral [U-<sup>13</sup>C<sub>3</sub>]glycerol via the TCA cycle was similar between groups. The fraction of plasma [5,6-<sup>13</sup>C<sub>2</sub>]glucose, which reflects PC flux, decreased in subjects with fatty liver. In contrast, the fraction of [4,5-<sup>13</sup>C<sub>2</sub>]glucose + [6-<sup>13</sup>C<sub>1</sub>]glucose, which can be produced via either PC or PDH, was comparable between groups. The study results suggest a shift in pyruvate metabolism in fatty liver, with a decreased metabolic flux ratio of PC/PDH. The methodology in this study provides insights into fatty liver metabolism of human subjects inaccessible previously and is applicable to advanced liver diseases such as cirrhosis and hepatomas.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"165 ","pages":"Article 156151"},"PeriodicalIF":10.8,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Metabolites-mediated posttranslational modifications in cardiac metabolic remodeling: Implications for disease pathology and therapeutic potential
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-01-27 DOI: 10.1016/j.metabol.2025.156144
Lifei Guo , Yuting Du , Heng Li , Ting He , Li Yao , Guodong Yang , Xuekang Yang
{"title":"Metabolites-mediated posttranslational modifications in cardiac metabolic remodeling: Implications for disease pathology and therapeutic potential","authors":"Lifei Guo ,&nbsp;Yuting Du ,&nbsp;Heng Li ,&nbsp;Ting He ,&nbsp;Li Yao ,&nbsp;Guodong Yang ,&nbsp;Xuekang Yang","doi":"10.1016/j.metabol.2025.156144","DOIUrl":"10.1016/j.metabol.2025.156144","url":null,"abstract":"<div><div>The nonenergy – producing functions of metabolism are attracting increasing attention, as metabolic changes are involved in discrete pathways modulating enzyme activity and gene expression. Substantial evidence suggests that myocardial metabolic remodeling occurring during diabetic cardiomyopathy, heart failure, and cardiac pathological stress (e.g., myocardial ischemia, pressure overload) contributes to the progression of pathology. Within the rewired metabolic network, metabolic intermediates and end-products can directly alter protein function and/or regulate epigenetic modifications by providing acyl groups for posttranslational modifications, thereby affecting the overall cardiac stress response and providing a direct link between cellular metabolism and cardiac pathology. This review provides a comprehensive overview of the functional diversity and mechanistic roles of several types of metabolite-mediated histone and nonhistone acylation, namely O-GlcNAcylation, lactylation, crotonylation, β-hydroxybutyrylation, and succinylation, as well as fatty acid-mediated modifications, in regulating physiological processes and contributing to the progression of heart disease. Furthermore, it explores the potential of these modifications as therapeutic targets for disease intervention.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"165 ","pages":"Article 156144"},"PeriodicalIF":10.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
FSH exacerbates bone loss by promoting osteoclast energy metabolism through the CREB-MDH2-NAD+ axis
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-01-27 DOI: 10.1016/j.metabol.2025.156147
Jingqiu Chen , Yilin Liao , Yue Sheng, Hantao Yao, Ting Li, Zhenru He, Weng Wan Yue Ye, Mengjie Yin, Huilin Tang, Yaoyu Zhao, Peiqi Zhang, Yuting Wang, Xiazhou Fu, Yaoting Ji
{"title":"FSH exacerbates bone loss by promoting osteoclast energy metabolism through the CREB-MDH2-NAD+ axis","authors":"Jingqiu Chen ,&nbsp;Yilin Liao ,&nbsp;Yue Sheng,&nbsp;Hantao Yao,&nbsp;Ting Li,&nbsp;Zhenru He,&nbsp;Weng Wan Yue Ye,&nbsp;Mengjie Yin,&nbsp;Huilin Tang,&nbsp;Yaoyu Zhao,&nbsp;Peiqi Zhang,&nbsp;Yuting Wang,&nbsp;Xiazhou Fu,&nbsp;Yaoting Ji","doi":"10.1016/j.metabol.2025.156147","DOIUrl":"10.1016/j.metabol.2025.156147","url":null,"abstract":"<div><h3>Aims</h3><div>Osteoclast energy metabolism is a promising target for treating diseases characterized by high osteoclast activity, such as osteoporosis. However, the regulatory factors involved in osteoclast bioenergetic processes are still in the early stages of being fully understood. This study reveals the effects of follicle-stimulating hormone (FSH) on osteoclast energy metabolism.</div></div><div><h3>Methods</h3><div>The <em>Lyz2</em>-Cre-Flox model selectively deletes FSH receptor (FSHR) from osteoclast precursor cells to generate <em>Fshr</em><sup><em>f/f</em></sup><em>; Lyz2-Cre</em> (<em>Fshr</em><sup>f/f</sup>; Cre) mice. Bone quality was assessed using micro-computed tomography, histomorphometric analysis, and dual-fluorescence labeling. The in vitro assays measured oxygen consumption rate, extracellular acidification rate, pyruvate content, and mitochondrial membrane potential to determine metabolic flux. RNA-seq, LC-MS, dual-luciferase reporter assays, and chromatin immunoprecipitation (ChIP) assays were used to elucidate the underlying mechanisms.</div></div><div><h3>Results</h3><div>FSHR deficiency in osteoclasts protected bone from resorption under normal and ovariectomized conditions. FSHR-deficient osteoclasts have reduced nicotinamide adenine dinucleotide (NAD<sup>+</sup>) levels, impairing osteoclast activity and energy metabolism. Mechanistically, FSH influenced NAD<sup>+</sup> levels via the CREB/MDH2 axis. Treatment with FSH monoclonal antibodies rescued bone loss in OVX mice and reduced bone marrow NAD<sup>+</sup> levels.</div></div><div><h3>Conclusions</h3><div>Targeting FSH may be a promising metabolic modulation strategy for treating osteoporosis and other diseases associated with high osteoclast activity.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"165 ","pages":"Article 156147"},"PeriodicalIF":10.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Association between higher consumption of ultra-processed foods and risk of diabetes and its complications: A systematic review & updated meta-analysis
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-01-21 DOI: 10.1016/j.metabol.2025.156134
Matheus Souza, Felipe S. Moura, Luan C.V. Lima, Marcio J.M. Amaral
{"title":"Association between higher consumption of ultra-processed foods and risk of diabetes and its complications: A systematic review & updated meta-analysis","authors":"Matheus Souza,&nbsp;Felipe S. Moura,&nbsp;Luan C.V. Lima,&nbsp;Marcio J.M. Amaral","doi":"10.1016/j.metabol.2025.156134","DOIUrl":"10.1016/j.metabol.2025.156134","url":null,"abstract":"<div><h3>Background <em>&amp;</em> aims</h3><div>Recent epidemiologic studies on the association between higher consumption of ultra-processed foods (UPFs) and risk of incident diabetes have reported conflicting results in populations worldwide. We conducted an updated systematic review and meta-analysis to quantify the magnitude of this association.</div></div><div><h3>Methods</h3><div>PubMed and Embase databases were systematically searched (from 2009 to November 14, 2024) for prospective cohort studies reporting data on the association between UPF intake (defined by the NOVA classification) and the risk of incident diabetes or its complications in adults (&gt;18 years). Meta-analysis was performed using random-effects modelling to obtain pooled hazard ratios (HRs) with 95 % confidence intervals (CIs), and the GRADE approach was applied to evaluate the certainty of evidence.</div></div><div><h3>Results</h3><div>We included 14 prospective cohort studies with a total of 692,508 participants. The highest UPF consumption was significantly associated with an increased risk of diabetes (<em>n</em> = 9 studies; HR 1.24, 95 % CI 1.14 to 1.34, I<sup>2</sup> = 69 %) compared with the lowest UPF intake (very low certainty of evidence). Subgroup analysis showed that studies published in 2024 had a smaller effect size compared with earlier studies. There were no significant differences between subgroups based on study location, duration of follow-up, method and frequency of dietary intake assessment, and risk of bias. Sensitivity analyses did not change these findings. Each 10 % increase in total UPF consumption was associated with a 13 % (<em>n</em> = 4 studies; HR 1.13, 95 % CI 1.08 to 1.18, I<sup>2</sup> = 37 %) increased risk of diabetes. Preliminary data from 4 cohort studies also suggest that high UPF consumption may be associated with complications in diabetic patients, including microvascular/cardiovascular disease, chronic kidney disease, and mortality.</div></div><div><h3>Conclusion</h3><div>UPF consumption is associated with a higher risk of incident diabetes and may contribute to its complications. Urgent public health efforts should prioritize the reduction of UPF consumption.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"165 ","pages":"Article 156134"},"PeriodicalIF":10.8,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
TGR5 attenuates DOCA-salt hypertension through regulating histone H3K4 methylation of ENaC in the kidney TGR5通过调节肾ENaC的组蛋白H3K4甲基化来减轻doca盐高血压。
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-01-15 DOI: 10.1016/j.metabol.2025.156133
Long Xu , Xinyan Wu , Luosha Long , Suchun Li , Meiying Huang , Meng Li , Pinning Feng , Moshe Levi , Wei Chen , Lei Wang , Chunling Li , Weidong Wang
{"title":"TGR5 attenuates DOCA-salt hypertension through regulating histone H3K4 methylation of ENaC in the kidney","authors":"Long Xu ,&nbsp;Xinyan Wu ,&nbsp;Luosha Long ,&nbsp;Suchun Li ,&nbsp;Meiying Huang ,&nbsp;Meng Li ,&nbsp;Pinning Feng ,&nbsp;Moshe Levi ,&nbsp;Wei Chen ,&nbsp;Lei Wang ,&nbsp;Chunling Li ,&nbsp;Weidong Wang","doi":"10.1016/j.metabol.2025.156133","DOIUrl":"10.1016/j.metabol.2025.156133","url":null,"abstract":"<div><div>Epithelial sodium channel (ENaC), located in the collecting duct principal cells of the kidney, is responsible for the reabsorption of sodium and plays a critical role in the regulation of extracellular fluid volume and consequently blood pressure. The G protein-coupled bile acid receptor (TGR5) is a membrane receptor mediating effects of bile acid and is implicated in kidney diseases. The current study aims to investigate whether TGR5 activation in the kidney regulated ENaC expression and potential mechanism. Lithocholic acid (LCA), a TGR5 agonist, markedly decreased systolic blood pressure induced by DOCA-salt in mice, which was associated with decreased ENaC expression in the kidney. DOCA-salt treatment increased renal expression of histone H3 lysine 4 trimethylation (H3K4me3) and decreased expression of lysine-specific demethylase 5A (KDM5A), a lysine demethylase, which was markedly reversed by LCA. TGR5 knockout caused further increased systolic blood pressure and ENaC expression in mice with DOCA-salt in association with increased H3K4me3 and decreased KDM5A. In immortalized mouse cortical collecting duct (mpkCCD) cells LCA markedly inhibited aldosterone-induced ENaC-mediated current. LCA treatment or TGR5 overexpression markedly inhibited ENaC and H3K4me3 protein expression in association with decreased KDM5A in mpkCCD cells treated with either aldosterone or angiotensin II. Inhibition or knockdown of KDM5A in mpkCCD cells prevented LCA-induced downregulation of ENaC expression by promoting H3K4me3 on the ENaC transcription start site. LCA upregulated KDM5A expression was likely through JNK/c-Jun signal pathway. In conclusion, LCA decreased blood pressure and ENaC protein expression in the kidney of mice with DOCA-salt, likely through activating TGR5 and upregulating KDM5A-induced H3K4me3 demethylation in ENaC promoter region.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"165 ","pages":"Article 156133"},"PeriodicalIF":10.8,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
DOC2b enrichment mitigates proinflammatory cytokine-induced CXCL10 expression by attenuating IKKβ and STAT-1 signaling in human islets DOC2b富集通过减弱人胰岛中IKKβ和STAT-1信号通路,减轻促炎细胞因子诱导的CXCL10表达。
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-01-11 DOI: 10.1016/j.metabol.2025.156132
Diti Chatterjee Bhowmick , Miwon Ahn , Supriyo Bhattacharya , Arianne Aslamy , Debbie C. Thurmond
{"title":"DOC2b enrichment mitigates proinflammatory cytokine-induced CXCL10 expression by attenuating IKKβ and STAT-1 signaling in human islets","authors":"Diti Chatterjee Bhowmick ,&nbsp;Miwon Ahn ,&nbsp;Supriyo Bhattacharya ,&nbsp;Arianne Aslamy ,&nbsp;Debbie C. Thurmond","doi":"10.1016/j.metabol.2025.156132","DOIUrl":"10.1016/j.metabol.2025.156132","url":null,"abstract":"<div><h3>Introduction</h3><div>Type 1 diabetic human islet β-cells are deficient in double C 2 like domain beta (DOC2b) protein. Further, DOC2b protects against cytokine-induced pancreatic islet β-cell stress and apoptosis. However, the mechanisms underpinning the protective effects of DOC2b remain unknown.</div></div><div><h3>Methods</h3><div>Biochemical studies, qPCR, proteomics, and immuno-confocal microscopy were conducted to determine the underlying protective mechanisms of DOC2b in β-cells. DOC2b-enriched or -depleted primary islets (human and mouse) and β-cell lines challenged with or without proinflammatory cytokines, global DOC2b heterozygous knockout mice subjected to multiple-low-dose-streptozotocin (MLD-STZ), were used for these studies.</div></div><div><h3>Results</h3><div>A significant elevation of stress-induced CXCL10 mRNA was observed in DOC2b-depleted β-cells and primary mouse islets. Further, DOC2b enrichment markedly attenuated cytokine-induced CXCL10 levels in primary non-diabetic human islets and β-cells. DOC2b enrichment also reduced total-NF-κB p65 protein levels in human islets challenged with T1D mimicking proinflammatory cytokines. IKKβ, NF-κB p65, and STAT-1 are capable of associating with DOC2b in cytokine-challenged β-cells. DOC2b enrichment in cytokine-stressed human islets and β-cells corresponded with a significant reduction in activated and total IKKβ protein levels. Total IκBβ protein was increased in DOC2b-enriched human islets subjected to acute cytokine challenge. Cytokine-induced activated and total STAT-1 protein and mRNA levels were markedly reduced in DOC2b-enriched human islets. Intriguingly, DOC2b also prevents ER-stress-IKKβ and STAT-1 crosstalk in the rat INS1-832/13 β-cell line.</div></div><div><h3>Conclusion</h3><div>The mechanisms underpinning the protective effects of DOC2b involve attenuation of IKKβ-NF-κB p65 and STAT-1 signaling, and reduced CXCL10 expression.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156132"},"PeriodicalIF":10.8,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Adipose ZFP36 protects against diet-induced obesity and insulin resistance 脂肪ZFP36防止饮食引起的肥胖和胰岛素抵抗。
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-01-04 DOI: 10.1016/j.metabol.2024.156131
Yang Hu , Jinghan Hai , Yun Ti , Binghui Kong , Guoqing Yao , Yuan Zhao , Chen Zhang , Xuehui Zheng , Chunmei Zhang , Xiangping Ma , Huaitao Yu , Xiaoning Qin , Pavel Kovarik , Cheng Zhang , Shaozhuang Liu , Wencheng Zhang , Jingyuan Li , Peili Bu
{"title":"Adipose ZFP36 protects against diet-induced obesity and insulin resistance","authors":"Yang Hu ,&nbsp;Jinghan Hai ,&nbsp;Yun Ti ,&nbsp;Binghui Kong ,&nbsp;Guoqing Yao ,&nbsp;Yuan Zhao ,&nbsp;Chen Zhang ,&nbsp;Xuehui Zheng ,&nbsp;Chunmei Zhang ,&nbsp;Xiangping Ma ,&nbsp;Huaitao Yu ,&nbsp;Xiaoning Qin ,&nbsp;Pavel Kovarik ,&nbsp;Cheng Zhang ,&nbsp;Shaozhuang Liu ,&nbsp;Wencheng Zhang ,&nbsp;Jingyuan Li ,&nbsp;Peili Bu","doi":"10.1016/j.metabol.2024.156131","DOIUrl":"10.1016/j.metabol.2024.156131","url":null,"abstract":"<div><h3>Aims</h3><div>Obesity, as a worldwide healthcare problem, has become more prevalent. ZFP36 is a well-known RNA-binding protein and involved in the posttranscriptional regulation of many physiological processes. Whether the adipose ZFP36 plays a role in obesity and insulin resistance remains unclear.</div></div><div><h3>Methods</h3><div>The expression levels of ZFP36 were analyzed in adipose tissues of obese patients, diet-induced obese mice, ob/ob mice and db/db mice. To determine whether adipose ZFP36 protects against the diet-induced obesity, we generated adipose-specific ZFP36 knockout (ZFP36<sup>AKO</sup>) mice, which were subjected to high-fat-diet (HFD) for 16 weeks. To explore the specific molecular mechanisms of ZFP36 regulating metabolic disorders, we used gene array assay of control and ZFP36-deficient adipose tissue, and assessed the pathways in vitro and vivo.</div></div><div><h3>Results</h3><div>Western blotting and RT-PCR were performed to determine the downregulating level of ZFP36 in adipose tissues of obese patients, diet-induced obese mice, ob/ob mice and db/db mice. Relative to control mice, ZFP36<sup>AKO</sup> mice were more susceptible to HFD-induced obesity, along with insulin resistance, glucose tolerance, and increased metabolic disorders. The obesity of ZFP36<sup>AKO</sup> mice was attributed to hypertrophy of adipocytes in white adipose tissue via decreased expression of Perilipin1 (PLIN1), adipose triglyceride lipase (ATGL), and hormone-sensitive lipase (HSL). We discovered that ZFP36 oppositely regulated RNF128 expression by repressing the mRNA stability and translation of RNF128, a negative regulator of Sirt1 expression.</div></div><div><h3>Conclusions</h3><div>This study suggests that ZFP36 in adipose tissue plays an important role in diet-induced obesity, and identifies a novel molecular signaling pathway of ZFP36/RNF128/Sirt1 involved in obesity.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156131"},"PeriodicalIF":10.8,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 partial loss-of-function variant (Ile191Val) of the TAS1R2 glucose receptor is associated with enhanced responses to exercise training in older adults with obesity: A translational study TAS1R2葡萄糖受体的部分功能缺失变体(Ile191Val)与肥胖症老年人对运动训练的反应增强有关:一项转化研究。
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-01-01 DOI: 10.1016/j.metabol.2024.156045
Joan Serrano , Saki Kondo , Grace M. Link , Ian S. Brown , Richard E. Pratley , Kedryn K. Baskin , Bret H. Goodpaster , Paul M. Coen , George A. Kyriazis
{"title":"A partial loss-of-function variant (Ile191Val) of the TAS1R2 glucose receptor is associated with enhanced responses to exercise training in older adults with obesity: A translational study","authors":"Joan Serrano ,&nbsp;Saki Kondo ,&nbsp;Grace M. Link ,&nbsp;Ian S. Brown ,&nbsp;Richard E. Pratley ,&nbsp;Kedryn K. Baskin ,&nbsp;Bret H. Goodpaster ,&nbsp;Paul M. Coen ,&nbsp;George A. Kyriazis","doi":"10.1016/j.metabol.2024.156045","DOIUrl":"10.1016/j.metabol.2024.156045","url":null,"abstract":"<div><h3>Background</h3><div>The TAS1R2 receptor, known for its role in taste perception, has also emerged as a key regulator of muscle physiology. Previous studies have shown that genetic ablation of TAS1R2 in mice enhances muscle fitness mimicking responses to endurance exercise training. However, the translational relevance of these findings to humans remains uncertain.</div></div><div><h3>Methods</h3><div>We explored responses to endurance exercise training in mice and humans with genetic deficiency of TAS1R2. First, we assessed the effects of muscle-specific deletion of TAS1R2 in mice (mKO) or wild type controls (mWT) following 4 weeks of voluntary wheel running (VWR). Next, we investigated the effects of the TAS1R2<sup>-Ile191Val</sup> (rs35874116) partial loss-of-function variant on responses to a 6-month diet-induced weight loss with exercise training (WLEX), weight loss alone (WL), or education control (CON) interventions in older individuals with obesity. Participants were retrospectively genotyped for the TAS1R2<sup>-Ile191Val</sup> polymorphism and classified as conventional function (Ile/Ile) or partial loss-of-function (Val carriers: Ile/Val and Val/Val). Body composition, cardiorespiratory fitness, and skeletal muscle mitochondrial function were assessed before and after the intervention.</div></div><div><h3>Results</h3><div>In response to VWR, mKO mice demonstrated enhanced running endurance and mitochondrial protein content. Similarly, TAS1R2 Val carriers exhibited distinctive improvements in body composition, including increased muscle mass, along with enhanced cardiorespiratory fitness and mitochondrial function in skeletal muscle following the WLEX intervention compared to Ile/Ile counterparts. Notably, every Val carrier demonstrated substantial responses to exercise training and weight loss, surpassing all Ile/Ile participants in overall performance metrics.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that TAS1R2 partial loss-of-function confers beneficial effects on muscle function and metabolism in humans in response to exercise training, akin to observations in TAS1R2 muscle-deficient mice. Targeting TAS1R2 may help enhancing exercise training adaptations in individuals with compromised exercise tolerance or metabolic disorders, presenting a potential avenue for personalized exercise interventions.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156045"},"PeriodicalIF":10.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11637915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
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