Pub Date : 2025-01-27DOI: 10.1016/j.metabol.2025.156144
Lifei Guo , Yuting Du , Heng Li , Ting He , Li Yao , Guodong Yang , Xuekang Yang
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.
{"title":"Metabolites-mediated posttranslational modifications in cardiac metabolic remodeling: Implications for disease pathology and therapeutic potential","authors":"Lifei Guo , Yuting Du , Heng Li , Ting He , Li Yao , Guodong Yang , 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}
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.
Methods
The Lyz2-Cre-Flox model selectively deletes FSH receptor (FSHR) from osteoclast precursor cells to generate Fshrf/f; Lyz2-Cre (Fshrf/f; 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.
Results
FSHR deficiency in osteoclasts protected bone from resorption under normal and ovariectomized conditions. FSHR-deficient osteoclasts have reduced nicotinamide adenine dinucleotide (NAD+) levels, impairing osteoclast activity and energy metabolism. Mechanistically, FSH influenced NAD+ levels via the CREB/MDH2 axis. Treatment with FSH monoclonal antibodies rescued bone loss in OVX mice and reduced bone marrow NAD+ levels.
Conclusions
Targeting FSH may be a promising metabolic modulation strategy for treating osteoporosis and other diseases associated with high osteoclast activity.
{"title":"FSH exacerbates bone loss by promoting osteoclast energy metabolism through the CREB-MDH2-NAD+ axis","authors":"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","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}
Pub Date : 2025-01-21DOI: 10.1016/j.metabol.2025.156134
Matheus Souza, Felipe S. Moura, Luan C.V. Lima, Marcio J.M. Amaral
Background & aims
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.
Methods
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 (>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.
Results
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 (n = 9 studies; HR 1.24, 95 % CI 1.14 to 1.34, I2 = 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 % (n = 4 studies; HR 1.13, 95 % CI 1.08 to 1.18, I2 = 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.
Conclusion
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.
{"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, Felipe S. Moura, Luan C.V. Lima, 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>&</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 (>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}
Pub Date : 2025-01-15DOI: 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
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.
{"title":"TGR5 attenuates DOCA-salt hypertension through regulating histone H3K4 methylation of ENaC in the kidney","authors":"Long Xu , Xinyan Wu , Luosha Long , Suchun Li , Meiying Huang , Meng Li , Pinning Feng , Moshe Levi , Wei Chen , Lei Wang , Chunling Li , 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}
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.
Methods
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.
Results
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.
Conclusion
The mechanisms underpinning the protective effects of DOC2b involve attenuation of IKKβ-NF-κB p65 and STAT-1 signaling, and reduced CXCL10 expression.
{"title":"DOC2b enrichment mitigates proinflammatory cytokine-induced CXCL10 expression by attenuating IKKβ and STAT-1 signaling in human islets","authors":"Diti Chatterjee Bhowmick , Miwon Ahn , Supriyo Bhattacharya , Arianne Aslamy , 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}
Pub Date : 2025-01-04DOI: 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
Aims
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.
Methods
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 (ZFP36AKO) 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.
Results
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, ZFP36AKO mice were more susceptible to HFD-induced obesity, along with insulin resistance, glucose tolerance, and increased metabolic disorders. The obesity of ZFP36AKO 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.
Conclusions
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.
{"title":"Adipose ZFP36 protects against diet-induced obesity and insulin resistance","authors":"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","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}
Pub Date : 2025-01-01DOI: 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
Background
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.
Methods
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-Ile191Val (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-Ile191Val 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.
Results
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.
Conclusions
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.
{"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 , Saki Kondo , Grace M. Link , Ian S. Brown , Richard E. Pratley , Kedryn K. Baskin , Bret H. Goodpaster , Paul M. Coen , 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}
Nutrient stress-responsive neuronal homeostasis relies on intricate autophagic mechanisms that modulate various organelle integrity and function. The selective autophagy of the Golgi, known as Golgiphagy, regulates secretory processes by modulating vesicle trafficking during nutrient starvation.
Results
In this study, we explored a genetic screen of BAR-domain-containing proteins to elucidate the role of formin-binding protein 1 (FNBP1) as a Golgiphagy receptor in modulating Golgi dynamics in response to varying nutrient availability in neurons. Mapping the systems network of FNBP1 and its interacting proteins reveals the putative involvement of FNBP1 in autophagy and Golgi-associated processes. While nutrient depletion causes Golgi fragmentation, FNBP1 preferentially localizes to the fragmented Golgi membrane through its 284FEDYTQ289 motif during nutrient stress. Simultaneously, FNBP1 engages in molecular interactions with LC3B through a conserved 131WKQL134 LC3 interacting region, thereby sequestering the fragmented Golgi membrane in neuronal autophagosomes. Increased aggregation of GM130, abnormal clumping of RAB11-positive secretory granules, and enhanced senescent death of FNBP1-depleted starved neurons indicate disruptions of neuronal homeostasis under metabolic stress.
Conclusion
The identification of FNBP1 as a nutrient stress-responsive Golgiphagy receptor expands our insights into the molecular mechanisms underlying Golgiphagy, establishing the crosstalk between nutrient sensing and membrane tension-sensing regulatory autophagic processes of Golgi turnover in neurons.
{"title":"Membrane tension sensing formin-binding protein 1 is a neuronal nutrient stress-responsive Golgiphagy receptor","authors":"Smita Saha , Anirban Mandal , Akash Ranjan , Debasish Kumar Ghosh","doi":"10.1016/j.metabol.2024.156040","DOIUrl":"10.1016/j.metabol.2024.156040","url":null,"abstract":"<div><h3>Background</h3><div>Nutrient stress-responsive neuronal homeostasis relies on intricate autophagic mechanisms that modulate various organelle integrity and function. The selective autophagy of the Golgi, known as Golgiphagy, regulates secretory processes by modulating vesicle trafficking during nutrient starvation.</div></div><div><h3>Results</h3><div>In this study, we explored a genetic screen of BAR-domain-containing proteins to elucidate the role of formin-binding protein 1 (FNBP1) as a Golgiphagy receptor in modulating Golgi dynamics in response to varying nutrient availability in neurons. Mapping the systems network of FNBP1 and its interacting proteins reveals the putative involvement of FNBP1 in autophagy and Golgi-associated processes. While nutrient depletion causes Golgi fragmentation, FNBP1 preferentially localizes to the fragmented Golgi membrane through its <sup>284</sup>FEDYTQ<sup>289</sup> motif during nutrient stress. Simultaneously, FNBP1 engages in molecular interactions with LC3B through a conserved <sup>131</sup>WKQL<sup>134</sup> LC3 interacting region, thereby sequestering the fragmented Golgi membrane in neuronal autophagosomes. Increased aggregation of GM130, abnormal clumping of RAB11-positive secretory granules, and enhanced senescent death of FNBP1-depleted starved neurons indicate disruptions of neuronal homeostasis under metabolic stress.</div></div><div><h3>Conclusion</h3><div>The identification of FNBP1 as a nutrient stress-responsive Golgiphagy receptor expands our insights into the molecular mechanisms underlying Golgiphagy, establishing the crosstalk between nutrient sensing and membrane tension-sensing regulatory autophagic processes of Golgi turnover in neurons.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156040"},"PeriodicalIF":10.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350221","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}
Pub Date : 2025-01-01DOI: 10.1016/j.metabol.2024.156077
Grigorios Tsaknakis , Erasmia Boutakoglou , Irene Mavroudi , Christos S. Mantzoros , Maria Veiga-da Cunha , Helen A. Papadaki
{"title":"Successful repurposing of empagliflozin to treat neutropenia in a severe congenital neutropenia patient with G6PC3 mutations","authors":"Grigorios Tsaknakis , Erasmia Boutakoglou , Irene Mavroudi , Christos S. Mantzoros , Maria Veiga-da Cunha , Helen A. Papadaki","doi":"10.1016/j.metabol.2024.156077","DOIUrl":"10.1016/j.metabol.2024.156077","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156077"},"PeriodicalIF":10.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668470","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}
Pub Date : 2025-01-01DOI: 10.1016/j.metabol.2024.156042
Dandan Wang , Tianjiao Wei , Xiaona Cui , Li Xia , Yafei Jiang , Deshan Yin , Xinyue Liao , Fei Li , Jian Li , Qi Wu , Xiafang Lin , Shan Lang , Yunyi Le , Jichun Yang , Jin Yang , Rui Wei , Tianpei Hong
<div><h3>Background</h3><div>Fam3a has been demonstrated to regulate pancreatic β-cell function and glucose homeostasis. However, the role and mechanism of Fam3a in regulating α-cell function remain unexplored.</div></div><div><h3>Methods</h3><div>Glucagon and glucagon-like peptide-1 (GLP-1) levels in pancreas and plasma were measured in global <em>Fam3a</em> knockout (<em>Fam3a</em><sup>−/−</sup>) mice. Human islet single-cell RNA sequencing (scRNA-seq) datasets were utilized to analyze gene expression correlations between <em>FAM3A</em> and <em>PCSK1</em> (encoding PC1/3, which processes proglucagon into GLP-1). Mouse pancreatic α-cell line αTC1.9 cells were transfected with <em>Fam3a</em> siRNA or plasmid for <em>Fam3a</em> knockdown or overexpression to explore the effects of Fam3a on PC1/3 expression and GLP-1 production. The downstream mediator (including Nr4a2) was identified by transcriptomic analysis, and its role was confirmed by <em>Fam3a</em> knockdown or overexpression in αTC1.9 cells. Based on the interacted protein of Nr4a2 and the direct binding to <em>Pcsk1</em> promoter, the transcription factor Foxa2 was selected for further verification. Nuclear translocation assay and dual-luciferase reporter assay were used to clarify the involvement of Fam3a-Nr4a2-Foxa2 pathway in PC1/3 expression and GLP-1 production. Moreover, α-cell-specific <em>Fam3a</em> knockout (<em>Fam3a</em><sup>α−/−</sup>) mice were constructed to evaluate the metabolic variables and hormone levels under normoglycemic, high-fat diet (HFD)-fed and streptozotocin (STZ)-induced diabetic conditions. Exendin 9–39 (Ex9), a GLP-1 receptor antagonist, was used to investigate GLP-1 paracrine effects in <em>Fam3a</em><sup>α−/−</sup> mice and in their primary islets.</div></div><div><h3>Results</h3><div>Compared with wild-type mice, pancreatic and plasma active GLP-1 levels were increased in <em>Fam3a</em><sup>−/−</sup> mice. Analysis of human islet scRNA-seq datasets showed a significant negative correction between <em>FAM3A</em> and <em>PCSK1</em> in α-cells. <em>Fam3a</em> knockdown upregulated PC1/3 expression and GLP-1 production in αTC1.9 cells, while <em>Fam3a</em> overexpression displayed inverse effects. Transcriptomic analysis identified <em>Nr4a2</em> as a key downstream mediator of Fam3a, and Nr4a2 expression in αTC1.9 cells was downregulated and upregulated by <em>Fam3a</em> knockdown and overexpression, respectively. <em>Nr4a2</em> silencing increased PC1/3 expression, albeit Nr4a2 did not directly bind to <em>Pcsk1</em> promoter. Instead, Nr4a2 formed a complex with Foxa2 to facilitate Fam3a-mediated Foxa2 nuclear translocation. Foxa2 negatively regulated PC1/3 expression and GLP-1 production. Besides, Foxa2 inhibited the transcriptional activity of <em>Pcsk1</em> promoter at specific binding sites 10 and 6, and this inhibition was intensified by Nr4a2 in αTC1.9 cells. Compared with Flox/cre littermates, improved glucose tolerance, increased active GLP-1 level
{"title":"Fam3a-mediated prohormone convertase switch in α-cells regulates pancreatic GLP-1 production in an Nr4a2-Foxa2-dependent manner","authors":"Dandan Wang , Tianjiao Wei , Xiaona Cui , Li Xia , Yafei Jiang , Deshan Yin , Xinyue Liao , Fei Li , Jian Li , Qi Wu , Xiafang Lin , Shan Lang , Yunyi Le , Jichun Yang , Jin Yang , Rui Wei , Tianpei Hong","doi":"10.1016/j.metabol.2024.156042","DOIUrl":"10.1016/j.metabol.2024.156042","url":null,"abstract":"<div><h3>Background</h3><div>Fam3a has been demonstrated to regulate pancreatic β-cell function and glucose homeostasis. However, the role and mechanism of Fam3a in regulating α-cell function remain unexplored.</div></div><div><h3>Methods</h3><div>Glucagon and glucagon-like peptide-1 (GLP-1) levels in pancreas and plasma were measured in global <em>Fam3a</em> knockout (<em>Fam3a</em><sup>−/−</sup>) mice. Human islet single-cell RNA sequencing (scRNA-seq) datasets were utilized to analyze gene expression correlations between <em>FAM3A</em> and <em>PCSK1</em> (encoding PC1/3, which processes proglucagon into GLP-1). Mouse pancreatic α-cell line αTC1.9 cells were transfected with <em>Fam3a</em> siRNA or plasmid for <em>Fam3a</em> knockdown or overexpression to explore the effects of Fam3a on PC1/3 expression and GLP-1 production. The downstream mediator (including Nr4a2) was identified by transcriptomic analysis, and its role was confirmed by <em>Fam3a</em> knockdown or overexpression in αTC1.9 cells. Based on the interacted protein of Nr4a2 and the direct binding to <em>Pcsk1</em> promoter, the transcription factor Foxa2 was selected for further verification. Nuclear translocation assay and dual-luciferase reporter assay were used to clarify the involvement of Fam3a-Nr4a2-Foxa2 pathway in PC1/3 expression and GLP-1 production. Moreover, α-cell-specific <em>Fam3a</em> knockout (<em>Fam3a</em><sup>α−/−</sup>) mice were constructed to evaluate the metabolic variables and hormone levels under normoglycemic, high-fat diet (HFD)-fed and streptozotocin (STZ)-induced diabetic conditions. Exendin 9–39 (Ex9), a GLP-1 receptor antagonist, was used to investigate GLP-1 paracrine effects in <em>Fam3a</em><sup>α−/−</sup> mice and in their primary islets.</div></div><div><h3>Results</h3><div>Compared with wild-type mice, pancreatic and plasma active GLP-1 levels were increased in <em>Fam3a</em><sup>−/−</sup> mice. Analysis of human islet scRNA-seq datasets showed a significant negative correction between <em>FAM3A</em> and <em>PCSK1</em> in α-cells. <em>Fam3a</em> knockdown upregulated PC1/3 expression and GLP-1 production in αTC1.9 cells, while <em>Fam3a</em> overexpression displayed inverse effects. Transcriptomic analysis identified <em>Nr4a2</em> as a key downstream mediator of Fam3a, and Nr4a2 expression in αTC1.9 cells was downregulated and upregulated by <em>Fam3a</em> knockdown and overexpression, respectively. <em>Nr4a2</em> silencing increased PC1/3 expression, albeit Nr4a2 did not directly bind to <em>Pcsk1</em> promoter. Instead, Nr4a2 formed a complex with Foxa2 to facilitate Fam3a-mediated Foxa2 nuclear translocation. Foxa2 negatively regulated PC1/3 expression and GLP-1 production. Besides, Foxa2 inhibited the transcriptional activity of <em>Pcsk1</em> promoter at specific binding sites 10 and 6, and this inhibition was intensified by Nr4a2 in αTC1.9 cells. Compared with Flox/cre littermates, improved glucose tolerance, increased active GLP-1 level","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156042"},"PeriodicalIF":10.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372341","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}
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