Pub Date : 2025-02-15DOI: 10.1016/j.metabol.2025.156161
Feng-Qing Huang , Hong-Fei Wang , Tong Yang , Dai Yang , Peian Liu , Raphael N. Alolga , Gaoxiang Ma , Baolin Liu , An Pan , Shi-Jia Liu , Lian-Wen Qi
The brain is rich in lipids, and disorders or abnormalities in lipid metabolism can induce neurotoxicity. Ceramides are the central intermediates of sphingolipid metabolism. This study was designed to investigate the potential lipotoxicity of ceramides in brain ischemia. First, a pseudo-targeted lipidomics analysis of plasma samples from stroke patients found significantly elevated levels of long-chain ceramides. A similar observation was made in mice subjected to permanent middle cerebral artery occlusion (pMCAO) surgery. In cultured cells, it was found that the altered ceramides were mainly derived from astrocytes via de novo pathway, and SPTLC2 was a key regulator because Sptlc2 knockdown largely blocked ceramide production. Ceramides induced astrocyte activation and triggered oxidative stress to impair mitochondrial homeostasis by increasing mitochondrial permeabilization. Moreover, ceramides triggered the formation of voltage-dependent anion channel (VDAC) oligomers in the mitochondrial outer membrane, through which mtDNA was released into the cytoplasm. Similar to oxygen and glucose depletion treatment, ceramides also increased cGAS activity and STING protein expression. However, this activity was diminished in the presence of the mitochondrial ROS scavenger SKQ1, indicating the involvement of oxidative stress in ceramide action. By facilitating cGAS/STING signaling cascades, ceramides resultantly induced interferon response to aggravate inflammatory damage in the ischemic brain. To address the impact of ceramides on brain ischemic injury in vivo, ceramide generation was blocked in the brain by injection of AAV9-Sptlc2 shRNA in pMCAO mice. Sptlc2 knockdown in the brain reduced ceramide generation and attenuated brain ischemic damage with astrocyte inactivation. As expected, Sptlc2 deficiency effectively blocked cGAS/STING pathway-dependent interferon responses. Together, these findings suggest a new therapeutic strategy for pharmacological intervention to attenuate neuroinflammation.
{"title":"Ceramides increase mitochondrial permeabilization to trigger mtDNA-dependent inflammation in astrocytes during brain ischemia","authors":"Feng-Qing Huang , Hong-Fei Wang , Tong Yang , Dai Yang , Peian Liu , Raphael N. Alolga , Gaoxiang Ma , Baolin Liu , An Pan , Shi-Jia Liu , Lian-Wen Qi","doi":"10.1016/j.metabol.2025.156161","DOIUrl":"10.1016/j.metabol.2025.156161","url":null,"abstract":"<div><div>The brain is rich in lipids, and disorders or abnormalities in lipid metabolism can induce neurotoxicity. Ceramides are the central intermediates of sphingolipid metabolism. This study was designed to investigate the potential lipotoxicity of ceramides in brain ischemia. First, a pseudo-targeted lipidomics analysis of plasma samples from stroke patients found significantly elevated levels of long-chain ceramides. A similar observation was made in mice subjected to permanent middle cerebral artery occlusion (pMCAO) surgery. In cultured cells, it was found that the altered ceramides were mainly derived from astrocytes via de novo pathway, and SPTLC2 was a key regulator because <em>Sptlc2</em> knockdown largely blocked ceramide production. Ceramides induced astrocyte activation and triggered oxidative stress to impair mitochondrial homeostasis by increasing mitochondrial permeabilization. Moreover, ceramides triggered the formation of voltage-dependent anion channel (VDAC) oligomers in the mitochondrial outer membrane, through which mtDNA was released into the cytoplasm. Similar to oxygen and glucose depletion treatment, ceramides also increased cGAS activity and STING protein expression. However, this activity was diminished in the presence of the mitochondrial ROS scavenger SKQ1, indicating the involvement of oxidative stress in ceramide action. By facilitating cGAS/STING signaling cascades, ceramides resultantly induced interferon response to aggravate inflammatory damage in the ischemic brain. To address the impact of ceramides on brain ischemic injury in vivo, ceramide generation was blocked in the brain by injection of AAV9-<em>Sptlc2</em> shRNA in pMCAO mice. <em>Sptlc2</em> knockdown in the brain reduced ceramide generation and attenuated brain ischemic damage with astrocyte inactivation. As expected, <em>Sptlc2</em> deficiency effectively blocked cGAS/STING pathway-dependent interferon responses. Together, these findings suggest a new therapeutic strategy for pharmacological intervention to attenuate neuroinflammation.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"166 ","pages":"Article 156161"},"PeriodicalIF":10.8,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143430152","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 : 2025-02-15DOI: 10.1016/j.metabol.2025.156160
Alberto Ouro , Amanda Rodríguez-Díaz , Tania López-González , Daniel Romaus-Sanjurjo , Ánxela Estévez-Salguero , Ramón Iglesias-Rey , Mariña Rodríguez-Arrizabalaga , Paola Fernández-Sanmartín , Mónica Castro-Mosquera , Manuel Debasa-Mouce , Antía Custodia , Marta Aramburu-Núñez , María Muñoz-González , Pablo Aguiar , Ismael González-García , Marc Schneeberger , Rubén Nogueiras , Carlos Diéguez , José Castillo , Tomás Sobrino , Miguel López
Background and aims
Smoking is a known risk factor for stroke. However, the ‘stroke paradox’ refers to the observation that stroke patients who smoke often have higher survival rates and better outcomes compared to non-smokers. In this sense, several studies have demonstrated that nicotine (3-[(2S)-1-methylpyrrolidin-2-yl]pyridine) exerts neuroprotective effects. Despite this, the molecular underpinnings of this phenomenon remain unclear. AMP-activated protein kinase (AMPK) is known to play a complex and controversial role in ischemic stroke, with recent evidence suggesting that AMPK inhibition has neuroprotective effects in acute ischemic injury. Nicotine has been shown to influence AMPK signaling in the brain, suppressing appetite and promoting brown fat thermogenesis via hypothalamic AMPK inhibition. Therefore, we hypothesized that the neuroprotective effect of nicotine in ischemia is due to its inhibitory action on AMPK. The aim of this study has been to investigate whether i) AMPK is involved in nicotine's neuroprotective effects on cerebral ischemia and ii) small extracellular vesicle (sEV)-mediated genetic inhibition of AMPK could replicate this effect in rodent models.
Methods
Male adult mice or rats subjected to transient middle cerebral artery occlusion (tMCAO) were compared with Sham and/or untreated controls groups. The stroke-induced lesion was evaluated by magnetic resonance imaging (MRI). Nicotine (2 mg/kg/12 h) and the AMPK activator AICAR (500 mg/kg/day) were given subcutaneously upon reperfusion until the end of the follow-up period to tMCAO rats. Control sEVs or sEVs loaded with a plasmid encoding a dominant negative isoform of AMPKα2 (AMPKα2-DN) were administered intravenously twice after reperfusion to tMCAO mice. Molecular pathways were analyzed by western blotting. Bederson and open-field tests were applied to evaluate behavioral parameters.
Results
Our MRI findings indicated that nicotine treatment reduced brain ischemic injury and improved neurological recovery, as demonstrated by Bederson test, through the inhibition of brain AMPK in ischemic rats. The AMPK activator AICAR reversed the effect of nicotine on injury size and neurological improvement, indicating that the neuroprotective action was dependent on AMPK inhibition. In addition, treatment with AMPKα2-DN sEVs reduced brain lesion and improved neurological recovery.
Conclusions
Our findings demonstrate that the regulation of brain AMPK provides an adequate neuroprotective target for cerebral ischemia, and that the sEV-mediated regulation of this kinase could be a potential clinical strategy against ischemic stroke. Further work, involving scalability in sEV production, immunogenicity, safety and efficacy will be demanding to develop effective and secure therapeutic strategies utilizing sEVs in clinical settings against ischemic stroke.
{"title":"Neuroprotective effect of small extracellular vesicle-mediated targeting of AMPKα2 in cerebral ischemia","authors":"Alberto Ouro , Amanda Rodríguez-Díaz , Tania López-González , Daniel Romaus-Sanjurjo , Ánxela Estévez-Salguero , Ramón Iglesias-Rey , Mariña Rodríguez-Arrizabalaga , Paola Fernández-Sanmartín , Mónica Castro-Mosquera , Manuel Debasa-Mouce , Antía Custodia , Marta Aramburu-Núñez , María Muñoz-González , Pablo Aguiar , Ismael González-García , Marc Schneeberger , Rubén Nogueiras , Carlos Diéguez , José Castillo , Tomás Sobrino , Miguel López","doi":"10.1016/j.metabol.2025.156160","DOIUrl":"10.1016/j.metabol.2025.156160","url":null,"abstract":"<div><h3>Background and aims</h3><div>Smoking is a known risk factor for stroke. However, the ‘stroke paradox’ refers to the observation that stroke patients who smoke often have higher survival rates and better outcomes compared to non-smokers. In this sense, several studies have demonstrated that nicotine (3-[(2<em>S</em>)-1-methylpyrrolidin-2-yl]pyridine) exerts neuroprotective effects. Despite this, the molecular underpinnings of this phenomenon remain unclear. AMP-activated protein kinase (AMPK) is known to play a complex and controversial role in ischemic stroke, with recent evidence suggesting that AMPK inhibition has neuroprotective effects in acute ischemic injury. Nicotine has been shown to influence AMPK signaling in the brain, suppressing appetite and promoting brown fat thermogenesis via hypothalamic AMPK inhibition. Therefore, we hypothesized that the neuroprotective effect of nicotine in ischemia is due to its inhibitory action on AMPK. The aim of this study has been to investigate whether i) AMPK is involved in nicotine's neuroprotective effects on cerebral ischemia and ii) small extracellular vesicle (sEV)-mediated genetic inhibition of AMPK could replicate this effect in rodent models.</div></div><div><h3>Methods</h3><div>Male adult mice or rats subjected to transient middle cerebral artery occlusion (tMCAO) were compared with Sham and/or untreated controls groups. The stroke-induced lesion was evaluated by magnetic resonance imaging (MRI). Nicotine (2 mg/kg/12 h) and the AMPK activator AICAR (500 mg/kg/day) were given subcutaneously upon reperfusion until the end of the follow-up period to tMCAO rats. Control sEVs or sEVs loaded with a plasmid encoding a dominant negative isoform of AMPKα2 (AMPKα2-DN) were administered intravenously twice after reperfusion to tMCAO mice. Molecular pathways were analyzed by western blotting. Bederson and open-field tests were applied to evaluate behavioral parameters.</div></div><div><h3>Results</h3><div>Our MRI findings indicated that nicotine treatment reduced brain ischemic injury and improved neurological recovery, as demonstrated by Bederson test, through the inhibition of brain AMPK in ischemic rats. The AMPK activator AICAR reversed the effect of nicotine on injury size and neurological improvement, indicating that the neuroprotective action was dependent on AMPK inhibition. In addition, treatment with AMPKα2-DN sEVs reduced brain lesion and improved neurological recovery.</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate that the regulation of brain AMPK provides an adequate neuroprotective target for cerebral ischemia, and that the sEV-mediated regulation of this kinase could be a potential clinical strategy against ischemic stroke. Further work, involving scalability in sEV production, immunogenicity, safety and efficacy will be demanding to develop effective and secure therapeutic strategies utilizing sEVs in clinical settings against ischemic stroke.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"167 ","pages":"Article 156160"},"PeriodicalIF":10.8,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441496","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 : 2025-02-14DOI: 10.1016/j.metabol.2025.156159
Ting Wang , Yue Chen , Xinyi Zhu , Lihe Zheng , Yingyi Li , Xiaolei Ruan , Ziwei Yan , Zhaolan Guan , Wen Sun , Hua Wang
Background
Intraflagellar transport 80 (IFT80) is vital for primary cilia which can sense and transduce mechanical signals. Mechanical stimuli expedite osteoblastic differentiation and bone formation in mesenchymal stem cells (MSCs). However, how IFT80 regulates mechanical transduction in MSCs remains unclear.
Basic procedure
To investigate the role of IFT80 in bone development and mechanical transduction, MSC-specific knock-out IFT80 (Prx1Cre; IFT80f/f) mice were generated. These mice exhibited significant skeletal abnormalities. The study further examined the effects of IFT80 deficiency on mechanical stimulation-induced osteoblastic differentiation and bone formation, as well as the underlying molecular mechanisms involving TRPA1 and calcium signaling pathways.
Main findings
In our study, Prx1Cre; IFT80f/f mice results in pronounced skeletal abnormalities including dwarfism, bone formation defect, malformations in the skull, limbs, and sternum, and abnormal joint structures. Furthermore, IFT80 deficiency in MSCs inhibits mechanical stimulation induced osteoblastic differentiation. Exercise training could not improve the bone formation in Prx1Cre; IFT80f/f mice. Mechanistically, IFT80 deficiency in MSCs downregulated the expression of transient receptor potential ankyrin 1 (TRPA1) and TRPA1-mediated Ca2+ influx, which further inhibited osteoblastic differentiation under mechanical stimulation by AKT and ERK signaling pathways. Finally, TRPA1 overexpression reversed impaired bone formation in Prx1Cre; IFT80f/f mice under exercise training.
Principal conclusions
IFT80 and TRPA1 cooperatively regulate osteoblastic differentiation and bone formation in response to mechanical stimulation. These findings suggest that IFT80 and TRPA1 are critical for skeletal homeostasis and may serve as potential therapeutic targets for skeletal disorders.
{"title":"IFT80 and TRPA1 cooperatively regulate bone formation by calcium signaling in response to mechanical stimuli","authors":"Ting Wang , Yue Chen , Xinyi Zhu , Lihe Zheng , Yingyi Li , Xiaolei Ruan , Ziwei Yan , Zhaolan Guan , Wen Sun , Hua Wang","doi":"10.1016/j.metabol.2025.156159","DOIUrl":"10.1016/j.metabol.2025.156159","url":null,"abstract":"<div><h3>Background</h3><div>Intraflagellar transport 80 (IFT80) is vital for primary cilia which can sense and transduce mechanical signals. Mechanical stimuli expedite osteoblastic differentiation and bone formation in mesenchymal stem cells (MSCs). However, how IFT80 regulates mechanical transduction in MSCs remains unclear.</div></div><div><h3>Basic procedure</h3><div>To investigate the role of IFT80 in bone development and mechanical transduction, MSC-specific knock-out IFT80 (Prx1<sup>Cre</sup>; IFT80<sup>f/f</sup>) mice were generated. These mice exhibited significant skeletal abnormalities. The study further examined the effects of IFT80 deficiency on mechanical stimulation-induced osteoblastic differentiation and bone formation, as well as the underlying molecular mechanisms involving TRPA1 and calcium signaling pathways.</div></div><div><h3>Main findings</h3><div>In our study, Prx1<sup>Cre</sup>; IFT80<sup>f/f</sup> mice results in pronounced skeletal abnormalities including dwarfism, bone formation defect, malformations in the skull, limbs, and sternum, and abnormal joint structures. Furthermore, IFT80 deficiency in MSCs inhibits mechanical stimulation induced osteoblastic differentiation. Exercise training could not improve the bone formation in Prx1<sup>Cre</sup>; IFT80<sup>f/f</sup> mice. Mechanistically, IFT80 deficiency in MSCs downregulated the expression of transient receptor potential ankyrin 1 (TRPA1) and TRPA1-mediated Ca<sup>2+</sup> influx, which further inhibited osteoblastic differentiation under mechanical stimulation by AKT and ERK signaling pathways. Finally, TRPA1 overexpression reversed impaired bone formation in Prx1<sup>Cre</sup>; IFT80<sup>f/f</sup> mice under exercise training.</div></div><div><h3>Principal conclusions</h3><div>IFT80 and TRPA1 cooperatively regulate osteoblastic differentiation and bone formation in response to mechanical stimulation. These findings suggest that IFT80 and TRPA1 are critical for skeletal homeostasis and may serve as potential therapeutic targets for skeletal disorders.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"166 ","pages":"Article 156159"},"PeriodicalIF":10.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425813","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 : 2025-02-11DOI: 10.1016/j.metabol.2025.156158
Fadi Khalaf , Dalia Barayan , Sean Saldanha , Marc G. Jeschke
With age, our metabolic systems undergo significant alterations, which can lead to a cascade of adverse effects that are implicated in both metabolic disorders, such as diabetes, and in the body's ability to respond to acute stress and trauma. To elucidate the metabolic imbalances arising from aging, we introduce the concept of “metabolaging.” This framework encompasses the broad spectrum of metabolic disruptions associated with the hallmarks of aging, including the functional decline of key metabolically active organs, like the adipose tissue. By examining how these organs interact with essential nutrient-sensing pathways, “metabolaging” provides a more comprehensive view of the systemic metabolic imbalances that occur with age. This concept extends to understanding how age-related metabolic disturbances can influence the response to acute stressors, like burn injuries, highlighting the interplay between metabolic dysfunction and the ability to handle severe physiological challenges. Finally, we propose potential interventions that hold promise in mitigating the effects of metabolaging and its downstream consequences.
{"title":"Metabolaging: a new geroscience perspective linking aging pathologies and metabolic dysfunction","authors":"Fadi Khalaf , Dalia Barayan , Sean Saldanha , Marc G. Jeschke","doi":"10.1016/j.metabol.2025.156158","DOIUrl":"10.1016/j.metabol.2025.156158","url":null,"abstract":"<div><div>With age, our metabolic systems undergo significant alterations, which can lead to a cascade of adverse effects that are implicated in both metabolic disorders, such as diabetes, and in the body's ability to respond to acute stress and trauma. To elucidate the metabolic imbalances arising from aging, we introduce the concept of “metabolaging.” This framework encompasses the broad spectrum of metabolic disruptions associated with the hallmarks of aging, including the functional decline of key metabolically active organs, like the adipose tissue. By examining how these organs interact with essential nutrient-sensing pathways, “metabolaging” provides a more comprehensive view of the systemic metabolic imbalances that occur with age. This concept extends to understanding how age-related metabolic disturbances can influence the response to acute stressors, like burn injuries, highlighting the interplay between metabolic dysfunction and the ability to handle severe physiological challenges. Finally, we propose potential interventions that hold promise in mitigating the effects of metabolaging and its downstream consequences.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"166 ","pages":"Article 156158"},"PeriodicalIF":10.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143395815","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 : 2025-02-11DOI: 10.1016/j.metabol.2025.156156
Jian Huang
{"title":"A systematic review & updated meta-analysis on the association between higher consumption of ultra processed foods and risk of diabetes and its complications: Letter to the editor","authors":"Jian Huang","doi":"10.1016/j.metabol.2025.156156","DOIUrl":"10.1016/j.metabol.2025.156156","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"166 ","pages":"Article 156156"},"PeriodicalIF":10.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414646","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 : 2025-02-11DOI: 10.1016/j.metabol.2025.156157
Kristyna Brejchova , Michal Rahm , Andrea Benova , Veronika Domanska , Paul Reyes-Gutierez , Martina Dzubanova , Radka Trubacova , Michaela Vondrackova , Tomas Cajka , Michaela Tencerova , Milan Vrabel , Ondrej Kuda
Objective
Insulin-sensitizing drugs, despite their broad use against type 2 diabetes, can adversely affect bone health, and the mechanisms underlying these side effects remain largely unclear. Here, we investigated the different metabolic effects of a series of thiazolidinediones, including rosiglitazone, pioglitazone, and the second-generation compound MSDC-0602K, on human mesenchymal stem cells (MSCs).
Methods
We developed 13C subcellular metabolomic tracer analysis measuring separate mitochondrial and cytosolic metabolite pools, lipidomic network-based isotopologue models, and bioorthogonal click chemistry, to demonstrate that MSDC-0602K differentially affected bone marrow-derived MSCs (BM-MSCs) and adipose tissue-derived MSCs (AT-MSCs). In BM-MSCs, MSDC-0602K promoted osteoblastic differentiation and suppressed adipogenesis. This effect was clearly distinct from that of the earlier drugs and that on AT-MSCs.
Results
Fluxomic data reveal unexpected differences between this drug's effect on MSCs and provide mechanistic insight into the pharmacologic inhibition of mitochondrial pyruvate carrier 1 (MPC). Our study demonstrates that MSDC-0602K retains the capacity to inhibit MPC, akin to rosiglitazone but unlike pioglitazone, enabling the utilization of alternative metabolic pathways. Notably, MSDC-0602K exhibits a limited lipogenic potential compared to both rosiglitazone and pioglitazone, each of which employs a distinct lipogenic strategy.
Conclusions
These findings indicate that the new-generation drugs do not compromise bone structure, offering a safer alternative for treating insulin resistance. Moreover, these results highlight the ability of cell compartment-specific metabolite labeling by click reactions and tracer metabolomics analysis of complex lipids to discover molecular mechanisms within the intersection of carbohydrate and lipid metabolism.
{"title":"Uncovering mechanisms of thiazolidinediones on osteogenesis and adipogenesis using spatial fluxomics","authors":"Kristyna Brejchova , Michal Rahm , Andrea Benova , Veronika Domanska , Paul Reyes-Gutierez , Martina Dzubanova , Radka Trubacova , Michaela Vondrackova , Tomas Cajka , Michaela Tencerova , Milan Vrabel , Ondrej Kuda","doi":"10.1016/j.metabol.2025.156157","DOIUrl":"10.1016/j.metabol.2025.156157","url":null,"abstract":"<div><h3>Objective</h3><div>Insulin-sensitizing drugs, despite their broad use against type 2 diabetes, can adversely affect bone health, and the mechanisms underlying these side effects remain largely unclear. Here, we investigated the different metabolic effects of a series of thiazolidinediones, including rosiglitazone, pioglitazone, and the second-generation compound MSDC-0602K, on human mesenchymal stem cells (MSCs).</div></div><div><h3>Methods</h3><div>We developed <sup>13</sup>C subcellular metabolomic tracer analysis measuring separate mitochondrial and cytosolic metabolite pools, lipidomic network-based isotopologue models, and bioorthogonal click chemistry, to demonstrate that MSDC-0602K differentially affected bone marrow-derived MSCs (BM-MSCs) and adipose tissue-derived MSCs (AT-MSCs). In BM-MSCs, MSDC-0602K promoted osteoblastic differentiation and suppressed adipogenesis. This effect was clearly distinct from that of the earlier drugs and that on AT-MSCs.</div></div><div><h3>Results</h3><div>Fluxomic data reveal unexpected differences between this drug's effect on MSCs and provide mechanistic insight into the pharmacologic inhibition of mitochondrial pyruvate carrier 1 (MPC). Our study demonstrates that MSDC-0602K retains the capacity to inhibit MPC, akin to rosiglitazone but unlike pioglitazone, enabling the utilization of alternative metabolic pathways. Notably, MSDC-0602K exhibits a limited lipogenic potential compared to both rosiglitazone and pioglitazone, each of which employs a distinct lipogenic strategy.</div></div><div><h3>Conclusions</h3><div>These findings indicate that the new-generation drugs do not compromise bone structure, offering a safer alternative for treating insulin resistance. Moreover, these results highlight the ability of cell compartment-specific metabolite labeling by click reactions and tracer metabolomics analysis of complex lipids to discover molecular mechanisms within the intersection of carbohydrate and lipid metabolism.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"166 ","pages":"Article 156157"},"PeriodicalIF":10.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403518","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 : 2025-02-11DOI: 10.1016/j.metabol.2025.156155
Matheus Souza, Felipe S. Moura, Luan C.V. Lima, Marcio J.M. Amaral
{"title":"A systematic review & updated meta-analysis on the association between higher consumption of ultra processed foods and risk of diabetes and its complications: Response Letter","authors":"Matheus Souza, Felipe S. Moura, Luan C.V. Lima, Marcio J.M. Amaral","doi":"10.1016/j.metabol.2025.156155","DOIUrl":"10.1016/j.metabol.2025.156155","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"166 ","pages":"Article 156155"},"PeriodicalIF":10.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414649","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 : 2025-02-06DOI: 10.1016/j.metabol.2025.156154
Lucía Barbier-Torres , María Luque-Urbano , Jyoti Chhimwal , Aaron E. Robinson , David Fernández-Ramos , Fernando Lopitz-Otsoa , Jennifer E. Van Eyk , Oscar Millet , José M. Mato , Shelly C. Lu
Objective
Aldolases (ALDO) are sensors that regulate AMPK via binding to fructose 1,6-biphosphate (FBP), an intermediate of glucose and fructose metabolism. Fructose consumption is linked to metabolic dysfunction-associated steatotic liver disease (MASLD) progression but whether ALDO-AMPK signaling is involved is unknown. Methionine adenosyltransferase alpha 1 (Mat1a) knockout (KO) mice have low hepatic S-adenosylmethionine (SAMe) level and spontaneously develop steatohepatitis. ALDOB methylation has not been reported and here we investigated whether SAMe level regulates ALDOB and ALDOB-AMPK signaling and whether fructose feeding accelerates MASLD progression by disrupting ALDOB-AMPK signaling.
Methods
Mass spectrometry identified ALDOB methylation sites and recombinant in vitro approaches assessed how methylation at those sites affects ALDOB oligomerization and activity. Primary hepatocytes cultured with high/low glucose and/or fructose and wild type (WT) and Mat1a KO mice fed with a high-fructose diet examined AMPK-ALDOB signaling and MASLD progression.
Results
In Mat1a KO livers ALDOB R173 is hypomethylated while ALDOB activity is enhanced. Recombinant ALDOB is methylated at R173 and R304 by protein arginine methyltransferase 1. Low hepatic SAMe level results in hypomethylated ALDOB, which favors the tetrameric form that has higher enzymatic activity, and higher capacity to signal to activate AMPK. Fructose, independently of glucose levels, inhibited AMPK activity and induced lipid accumulation in hepatocytes. Mat1a KO mice have hyperactivated AMPK and fructose feeding inhibits it, enhancing the accumulation of fat in the liver and the progression of MASLD.
Conclusion
Hepatic SAMe levels regulate ALDOB oligomeric state and enzymatic activity impacting on AMPK signaling and fructose-induced MASLD progression.
{"title":"Fructose-induced progression of steatohepatitis involves disrupting aldolase B-AMPK signaling in methionine adenosyltransferase 1A deficient mice","authors":"Lucía Barbier-Torres , María Luque-Urbano , Jyoti Chhimwal , Aaron E. Robinson , David Fernández-Ramos , Fernando Lopitz-Otsoa , Jennifer E. Van Eyk , Oscar Millet , José M. Mato , Shelly C. Lu","doi":"10.1016/j.metabol.2025.156154","DOIUrl":"10.1016/j.metabol.2025.156154","url":null,"abstract":"<div><h3>Objective</h3><div>Aldolases (ALDO) are sensors that regulate AMPK via binding to fructose 1,6-biphosphate (FBP), an intermediate of glucose and fructose metabolism. Fructose consumption is linked to metabolic dysfunction-associated steatotic liver disease (MASLD) progression but whether ALDO-AMPK signaling is involved is unknown. Methionine adenosyltransferase alpha 1 (<em>Mat1a</em>) knockout (KO) mice have low hepatic S-adenosylmethionine (SAMe) level and spontaneously develop steatohepatitis. ALDOB methylation has not been reported and here we investigated whether SAMe level regulates ALDOB and ALDOB-AMPK signaling and whether fructose feeding accelerates MASLD progression by disrupting ALDOB-AMPK signaling.</div></div><div><h3>Methods</h3><div>Mass spectrometry identified ALDOB methylation sites and recombinant in vitro approaches assessed how methylation at those sites affects ALDOB oligomerization and activity. Primary hepatocytes cultured with high/low glucose and/or fructose and wild type (WT) and <em>Mat1a</em> KO mice fed with a high-fructose diet examined AMPK-ALDOB signaling and MASLD progression.</div></div><div><h3>Results</h3><div>In <em>Mat1a</em> KO livers ALDOB R173 is hypomethylated while ALDOB activity is enhanced. Recombinant ALDOB is methylated at R173 and R304 by protein arginine methyltransferase 1. Low hepatic SAMe level results in hypomethylated ALDOB, which favors the tetrameric form that has higher enzymatic activity, and higher capacity to signal to activate AMPK. Fructose, independently of glucose levels, inhibited AMPK activity and induced lipid accumulation in hepatocytes. <em>Mat1a</em> KO mice have hyperactivated AMPK and fructose feeding inhibits it, enhancing the accumulation of fat in the liver and the progression of MASLD.</div></div><div><h3>Conclusion</h3><div>Hepatic SAMe levels regulate ALDOB oligomeric state and enzymatic activity impacting on AMPK signaling and fructose-induced MASLD progression.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"165 ","pages":"Article 156154"},"PeriodicalIF":10.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143349452","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}
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