Pub Date : 2024-08-06DOI: 10.1016/j.metabol.2024.155994
Jihao Wu , Xiong Chen , Ruijun Li , Qiying Lu , Yucheng Ba , Jiayun Fang , Yilin Liu , Ruijie Li , Yixuan Liu , Yiling Wang , Jinsi Chen , Yanbing Li , Yinong Huang
Background
Sarcopenia, characterized by progressive muscle mass and function loss, particularly affects the elderly, and leads to severe consequences such as falls and mortality. Despite its prevalence, targeted pharmacotherapies for sarcopenia are lacking. Utilizing large-sample genome-wide association studies (GWAS) data is crucial for cost-effective drug discovery.
Methods
Herein, we conducted four studies to understand the putative causal effects of genetic components on muscle mass and function. Study 1 employed a two-sample Mendelian randomization (MR) on 15,944 potential druggable genes, investigating their potential causality with muscle quantity and quality in a European population (N up to 461,089). Study 2 validated MR results through sensitivity analyses and colocalization analyses. Study 3 extended validation across other European cohorts, and study 4 conducted quantitative in vivo verification.
Results
MR analysis revealed significant causality between four genes (BLOC-1 related complex subunit 7, BORCS7; peptidase m20 domain containing 1, PM20D1; nuclear casein kinase and cyclin dependent kinase substrate 1, NUCKS1 and ubiquinol-cytochrome c reductase complex assembly factor 1, UQCC1) and muscle mass and function (p-values range 5.98 × 10−6 to 9.26 × 10−55). To be specific, BORCS7 and UQCC1 negatively regulated muscle quantity and quality, whereas enhancing PM20D1 and NUCKS1 expression showed promise in promoting muscle mass and function. Causal relationships remained robust across sensitivity analyses, with UQCC1 exhibiting notable colocalization effects (PP·H4 93.4 % to 95.8 %). Further validation and in vivo replication verified the potential causality between these genes and muscle mass as well as function.
Conclusions
Our druggable genome-wide MR analysis identifies BORCS7, PM20D1, NUCKS1, and UQCC1 as causally associated with muscle mass and function. These findings offer insights into the genetic basis of sarcopenia, paving the way for these genes to become promising drug targets in mitigating this debilitating condition.
{"title":"Identifying genetic determinants of sarcopenia-related traits: a Mendelian randomization study of druggable genes","authors":"Jihao Wu , Xiong Chen , Ruijun Li , Qiying Lu , Yucheng Ba , Jiayun Fang , Yilin Liu , Ruijie Li , Yixuan Liu , Yiling Wang , Jinsi Chen , Yanbing Li , Yinong Huang","doi":"10.1016/j.metabol.2024.155994","DOIUrl":"10.1016/j.metabol.2024.155994","url":null,"abstract":"<div><h3>Background</h3><p>Sarcopenia, characterized by progressive muscle mass and function loss, particularly affects the elderly, and leads to severe consequences such as falls and mortality. Despite its prevalence, targeted pharmacotherapies for sarcopenia are lacking. Utilizing large-sample genome-wide association studies (GWAS) data is crucial for cost-effective drug discovery.</p></div><div><h3>Methods</h3><p>Herein, we conducted four studies to understand the putative causal effects of genetic components on muscle mass and function. Study 1 employed a two-sample Mendelian randomization (MR) on 15,944 potential druggable genes, investigating their potential causality with muscle quantity and quality in a European population (N up to 461,089). Study 2 validated MR results through sensitivity analyses and colocalization analyses. Study 3 extended validation across other European cohorts, and study 4 conducted quantitative <em>in vivo</em> verification.</p></div><div><h3>Results</h3><p>MR analysis revealed significant causality between four genes (BLOC-1 related complex subunit 7, BORCS7; peptidase m20 domain containing 1, PM20D1; nuclear casein kinase and cyclin dependent kinase substrate 1, NUCKS1 and ubiquinol-cytochrome <em>c</em> reductase complex assembly factor 1, UQCC1) and muscle mass and function (<em>p</em>-values range 5.98 × 10<sup>−6</sup> to 9.26 × 10<sup>−55</sup>). To be specific, BORCS7 and UQCC1 negatively regulated muscle quantity and quality, whereas enhancing PM20D1 and NUCKS1 expression showed promise in promoting muscle mass and function. Causal relationships remained robust across sensitivity analyses, with UQCC1 exhibiting notable colocalization effects (PP·H4 93.4 % to 95.8 %). Further validation and <em>in vivo</em> replication verified the potential causality between these genes and muscle mass as well as function.</p></div><div><h3>Conclusions</h3><p>Our druggable genome-wide MR analysis identifies BORCS7, PM20D1, NUCKS1, and UQCC1 as causally associated with muscle mass and function. These findings offer insights into the genetic basis of sarcopenia, paving the way for these genes to become promising drug targets in mitigating this debilitating condition.</p></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"160 ","pages":"Article 155994"},"PeriodicalIF":10.8,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S002604952400221X/pdfft?md5=94d107e43d1b20236599dbec70875af3&pid=1-s2.0-S002604952400221X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907017","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 : 2024-08-05DOI: 10.1016/j.metabol.2024.155978
Shan Zhou , Xian Ling , Ye Liang , Qijian Feng , Chao Xie , Jiemei Li , Qiyan Chen , Jinhua Miao , Mengyao Zhang , Zhiru Li , Weiwei Shen , Xiaolong Li , Qinyu Wu , Xiaoxu Wang , Fan Fan Hou , Youhua Liu , Yaozhong Kong , Lili Zhou
Aims
Renal fibrosis is a common feature in various chronic kidney diseases (CKD). Tubular cell damage is a main characterization which results from dysregulated fatty acid oxidation (FAO) and lipid accumulation. Cannabinoid Receptor 2 (CB2) contributes to renal fibrosis, however, its role in FAO dysregulation in tubular cells is not clarified. In this study, we found CB2 plays a detrimental role in lipid metabolism in tubular cells.
Methods
CB2 knockout mice were adopted to establish a folic acid-induced nephropathy (FAN) model. CB2-induced FAO dysfunction, lipid deposition, and fibrogenesis were assessed in vivo and vitro. To explore molecular mechanisms, β-catenin inhibitors and peroxisome proliferator-activated receptor alpha (PPARα) activators were also used in CB2-overexpressed cells. The mediative role of β-catenin in CB2-inhibited PPARα and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) activation was analyzed.
Results
CB2 activates β-catenin signaling, resulting in the suppression of PPARα/PGC-1α axis. This decreased FAO functions and led to lipid droplet formation in tubular cells. CB2 gene ablation effectively mitigated FAO dysfunction, lipid deposition and uremic toxins accumulation in FAN mice, consequently retarding renal fibrosis. Additionally, inhibition to β-catenin or PPARα activation could greatly inhibit lipid accumulation and fibrogenesis induced by CB2.
Conclusions
This study highlights CB2 disrupts FAO in tubular cells through β-catenin activation and subsequent inhibition on PPARα/PGC-1α activity. Targeted inhibition on CB2 offers a perspective therapeutic strategy to fight against renal fibrosis.
{"title":"Cannabinoid receptor 2 plays a key role in renal fibrosis through inhibiting lipid metabolism in renal tubular cells","authors":"Shan Zhou , Xian Ling , Ye Liang , Qijian Feng , Chao Xie , Jiemei Li , Qiyan Chen , Jinhua Miao , Mengyao Zhang , Zhiru Li , Weiwei Shen , Xiaolong Li , Qinyu Wu , Xiaoxu Wang , Fan Fan Hou , Youhua Liu , Yaozhong Kong , Lili Zhou","doi":"10.1016/j.metabol.2024.155978","DOIUrl":"10.1016/j.metabol.2024.155978","url":null,"abstract":"<div><h3>Aims</h3><p>Renal fibrosis is a common feature in various chronic kidney diseases (CKD). Tubular cell damage is a main characterization which results from dysregulated fatty acid oxidation (FAO) and lipid accumulation. Cannabinoid Receptor 2 (CB2) contributes to renal fibrosis, however, its role in FAO dysregulation in tubular cells is not clarified. In this study, we found CB2 plays a detrimental role in lipid metabolism in tubular cells.</p></div><div><h3>Methods</h3><p>CB2 knockout mice were adopted to establish a folic acid-induced nephropathy (FAN) model. CB2-induced FAO dysfunction, lipid deposition, and fibrogenesis were assessed in vivo and vitro. To explore molecular mechanisms, β-catenin inhibitors and peroxisome proliferator-activated receptor alpha (PPARα) activators were also used in CB2-overexpressed cells. The mediative role of β-catenin in CB2-inhibited PPARα and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) activation was analyzed.</p></div><div><h3>Results</h3><p>CB2 activates β-catenin signaling, resulting in the suppression of PPARα/PGC-1α axis. This decreased FAO functions and led to lipid droplet formation in tubular cells. CB2 gene ablation effectively mitigated FAO dysfunction, lipid deposition and uremic toxins accumulation in FAN mice, consequently retarding renal fibrosis. Additionally, inhibition to β-catenin or PPARα activation could greatly inhibit lipid accumulation and fibrogenesis induced by CB2.</p></div><div><h3>Conclusions</h3><p>This study highlights CB2 disrupts FAO in tubular cells through β-catenin activation and subsequent inhibition on PPARα/PGC-1α activity. Targeted inhibition on CB2 offers a perspective therapeutic strategy to fight against renal fibrosis.</p></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"159 ","pages":"Article 155978"},"PeriodicalIF":10.8,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0026049524002051/pdfft?md5=e28e79cf77dadbaf4f05a0c568e9ef3e&pid=1-s2.0-S0026049524002051-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889696","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 : 2024-08-02DOI: 10.1016/j.metabol.2024.155984
Konstantinos Stefanakis , Martina Samiotaki , Vassiliki Papaevangelou , Laura Valenzuela-Vallejo , Nick Giannoukakis , Christos S. Mantzoros
<div><h3>Background</h3><p>Leptin is known for its metabolic, immunomodulatory and neuroendocrine properties, but the full spectrum of molecules downstream of leptin and relevant underlying mechanisms remain to be fully clarified. Our objective was to identify proteins and pathways influenced by leptin through untargeted proteomics in two clinical trials involving leptin administration in lean individuals.</p></div><div><h3>Methods</h3><p>We performed untargeted liquid chromatography-tandem mass spectrometry serum proteomics across two studies a) Short-term randomized controlled crossover study of lean male and female humans undergoing a 72-h fast with concurrent administration of either placebo or high-dose leptin; b) Long-term (36-week) randomized controlled trial of leptin replacement therapy in human females with acquired relative energy deficiency and hypoleptinemia. We explored longitudinal proteomic changes and run adjusted mixed models followed by post-hoc tests. We further attempted to identify ontological pathways modulated during each experimental condition and/or comparison, through integrated qualitative pathway and enrichment analyses. We also explored dynamic longitudinal relationships between the circulating proteome with clinical and hormonal outcomes.</p></div><div><h3>Results</h3><p>289 and 357 unique proteins were identified per each respective study. Short-term leptin administration during fasting markedly upregulated several proinflammatory molecules, notably C-reactive protein (CRP) and cluster of differentiation (CD) 14, and downregulated lecithin cholesterol acyltransferase and several immunoglobulin variable chains, in contrast with placebo, which produced minimal changes. Quantitative pathway enrichment further indicated an upregulation of the acute phase response and downregulation of immunoglobulin- and B cell-mediated immunity by leptin. These changes were independent of participants' biological sex. In the long term study, leptin likewise robustly and persistently upregulated proteins of the acute phase response, and downregulated immunoglobulin-mediated immunity. Leptin also significantly and differentially affected a wide array of proteins related to immune function, defense response, coagulation, and inflammation compared with placebo. These changes were more notable at the 24-week visit, coinciding with the highest measured levels of serum leptin. We further identified distinct co-regulated clusters of proteins and clinical features during leptin administration indicating robust longitudinal correlations between the regulation of immunoglobulins, immune-related molecules, serpins (including cortisol and thyroxine-binding globulins), lipid transport molecules and growth factors, in contrast with placebo, which did not produce similar associations.</p></div><div><h3>Conclusions</h3><p>These high-throughput longitudinal results provide unique functional insights into leptin physiology, and pave the way for affinity
{"title":"Longitudinal proteomics of leptin treatment in humans with acute and chronic energy deficiency-induced hypoleptinemia reveal novel, mainly immune-related, pleiotropic effects","authors":"Konstantinos Stefanakis , Martina Samiotaki , Vassiliki Papaevangelou , Laura Valenzuela-Vallejo , Nick Giannoukakis , Christos S. Mantzoros","doi":"10.1016/j.metabol.2024.155984","DOIUrl":"10.1016/j.metabol.2024.155984","url":null,"abstract":"<div><h3>Background</h3><p>Leptin is known for its metabolic, immunomodulatory and neuroendocrine properties, but the full spectrum of molecules downstream of leptin and relevant underlying mechanisms remain to be fully clarified. Our objective was to identify proteins and pathways influenced by leptin through untargeted proteomics in two clinical trials involving leptin administration in lean individuals.</p></div><div><h3>Methods</h3><p>We performed untargeted liquid chromatography-tandem mass spectrometry serum proteomics across two studies a) Short-term randomized controlled crossover study of lean male and female humans undergoing a 72-h fast with concurrent administration of either placebo or high-dose leptin; b) Long-term (36-week) randomized controlled trial of leptin replacement therapy in human females with acquired relative energy deficiency and hypoleptinemia. We explored longitudinal proteomic changes and run adjusted mixed models followed by post-hoc tests. We further attempted to identify ontological pathways modulated during each experimental condition and/or comparison, through integrated qualitative pathway and enrichment analyses. We also explored dynamic longitudinal relationships between the circulating proteome with clinical and hormonal outcomes.</p></div><div><h3>Results</h3><p>289 and 357 unique proteins were identified per each respective study. Short-term leptin administration during fasting markedly upregulated several proinflammatory molecules, notably C-reactive protein (CRP) and cluster of differentiation (CD) 14, and downregulated lecithin cholesterol acyltransferase and several immunoglobulin variable chains, in contrast with placebo, which produced minimal changes. Quantitative pathway enrichment further indicated an upregulation of the acute phase response and downregulation of immunoglobulin- and B cell-mediated immunity by leptin. These changes were independent of participants' biological sex. In the long term study, leptin likewise robustly and persistently upregulated proteins of the acute phase response, and downregulated immunoglobulin-mediated immunity. Leptin also significantly and differentially affected a wide array of proteins related to immune function, defense response, coagulation, and inflammation compared with placebo. These changes were more notable at the 24-week visit, coinciding with the highest measured levels of serum leptin. We further identified distinct co-regulated clusters of proteins and clinical features during leptin administration indicating robust longitudinal correlations between the regulation of immunoglobulins, immune-related molecules, serpins (including cortisol and thyroxine-binding globulins), lipid transport molecules and growth factors, in contrast with placebo, which did not produce similar associations.</p></div><div><h3>Conclusions</h3><p>These high-throughput longitudinal results provide unique functional insights into leptin physiology, and pave the way for affinity","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"159 ","pages":"Article 155984"},"PeriodicalIF":10.8,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889697","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 : 2024-07-30DOI: 10.1016/j.metabol.2024.155982
Jeong Suk Kang , Nam-Jun Cho , Seong Woo Lee , Jeong Geon Lee , Ji-Hye Lee , Jawoon Yi , Min Sun Choi , Samel Park , Hyo-Wook Gil , Joon Cheol Oh , Seung Seob Son , Mi Ju Park , Jong-Seok Moon , Donghyeong Lee , So-Young Kim , Seung-Hoon Yang , Sang Soo Kim , Eun Soo Lee , Choon Hee Chung , Jihwan Park , Eun Young Lee
Background
Receptor-interacting protein kinase (RIPK)3 is an essential molecule for necroptosis and its role in kidney fibrosis has been investigated using various kidney injury models. However, the relevance and the underlying mechanisms of RIPK3 to podocyte injury in albuminuric diabetic kidney disease (DKD) remain unclear. Here, we investigated the role of RIPK3 in glomerular injury of DKD.
Methods
We analyzed RIPK3 expression levels in the kidneys of patients with biopsy-proven DKD and animal models of DKD. Additionally, to confirm the clinical significance of circulating RIPK3, RIPK3 was measured by ELISA in plasma obtained from a prospective observational cohort of patients with type 2 diabetes, and estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR), which are indicators of renal function, were followed up during the observation period. To investigate the role of RIPK3 in glomerular damage in DKD, we induced a DKD model using a high-fat diet in Ripk3 knockout and wild-type mice. To assess whether mitochondrial dysfunction and albuminuria in DKD take a Ripk3-dependent pathway, we used single-cell RNA sequencing of kidney cortex and immortalized podocytes treated with high glucose or overexpressing RIPK3.
Results
RIPK3 expression was increased in podocytes of diabetic glomeruli with increased albuminuria and decreased podocyte numbers. Plasma RIPK3 levels were significantly elevated in albuminuric diabetic patients than in non-diabetic controls (p = 0.002) and non-albuminuric diabetic patients (p = 0.046). The participants in the highest tertile of plasma RIPK3 had a higher incidence of renal progression (hazard ratio [HR] 2.29 [1.05–4.98]) and incident chronic kidney disease (HR 4.08 [1.10–15.13]). Ripk3 knockout improved albuminuria, podocyte loss, and renal ultrastructure in DKD mice. Increased mitochondrial fragmentation, upregulated mitochondrial fission-related proteins such as phosphoglycerate mutase family member 5 (PGAM5) and dynamin-related protein 1 (Drp1), and mitochondrial ROS were decreased in podocytes of Ripk3 knockout DKD mice. In cultured podocytes, RIPK3 inhibition attenuated mitochondrial fission and mitochondrial dysfunction by decreasing p-mixed lineage kinase domain-like protein (MLKL), PGAM5, and p-Drp1 S616 and mitochondrial translocation of Drp1.
Conclusions
The study demonstrates that RIPK3 reflects deterioration of renal function of DKD. In addition, RIPK3 induces diabetic podocytopathy by regulating mitochondrial fission via PGAM5-Drp1 signaling through MLKL. Inhibition of RIPK3 might be a promising therapeutic option for treating DKD.
{"title":"RIPK3 causes mitochondrial dysfunction and albuminuria in diabetic podocytopathy through PGAM5-Drp1 signaling","authors":"Jeong Suk Kang , Nam-Jun Cho , Seong Woo Lee , Jeong Geon Lee , Ji-Hye Lee , Jawoon Yi , Min Sun Choi , Samel Park , Hyo-Wook Gil , Joon Cheol Oh , Seung Seob Son , Mi Ju Park , Jong-Seok Moon , Donghyeong Lee , So-Young Kim , Seung-Hoon Yang , Sang Soo Kim , Eun Soo Lee , Choon Hee Chung , Jihwan Park , Eun Young Lee","doi":"10.1016/j.metabol.2024.155982","DOIUrl":"10.1016/j.metabol.2024.155982","url":null,"abstract":"<div><h3>Background</h3><p>Receptor-interacting protein kinase (RIPK)3 is an essential molecule for necroptosis and its role in kidney fibrosis has been investigated using various kidney injury models. However, the relevance and the underlying mechanisms of RIPK3 to podocyte injury in albuminuric diabetic kidney disease (DKD) remain unclear. Here, we investigated the role of RIPK3 in glomerular injury of DKD.</p></div><div><h3>Methods</h3><p>We analyzed RIPK3 expression levels in the kidneys of patients with biopsy-proven DKD and animal models of DKD. Additionally, to confirm the clinical significance of circulating RIPK3, RIPK3 was measured by ELISA in plasma obtained from a prospective observational cohort of patients with type 2 diabetes, and estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR), which are indicators of renal function, were followed up during the observation period. To investigate the role of RIPK3 in glomerular damage in DKD, we induced a DKD model using a high-fat diet in <em>Ripk3</em> knockout and wild-type mice. To assess whether mitochondrial dysfunction and albuminuria in DKD take a Ripk3-dependent pathway, we used single-cell RNA sequencing of kidney cortex and immortalized podocytes treated with high glucose or overexpressing RIPK3.</p></div><div><h3>Results</h3><p>RIPK3 expression was increased in podocytes of diabetic glomeruli with increased albuminuria and decreased podocyte numbers. Plasma RIPK3 levels were significantly elevated in albuminuric diabetic patients than in non-diabetic controls (<em>p</em> = 0.002) and non-albuminuric diabetic patients (<em>p</em> = 0.046). The participants in the highest tertile of plasma RIPK3 had a higher incidence of renal progression (hazard ratio [HR] 2.29 [1.05–4.98]) and incident chronic kidney disease (HR 4.08 [1.10–15.13]). <em>Ripk3</em> knockout improved albuminuria, podocyte loss, and renal ultrastructure in DKD mice. Increased mitochondrial fragmentation, upregulated mitochondrial fission-related proteins such as phosphoglycerate mutase family member 5 (PGAM5) and dynamin-related protein 1 (Drp1), and mitochondrial ROS were decreased in podocytes of <em>Ripk3</em> knockout DKD mice. In cultured podocytes, RIPK3 inhibition attenuated mitochondrial fission and mitochondrial dysfunction by decreasing p-mixed lineage kinase domain-like protein (MLKL), PGAM5, and p-Drp1 S616 and mitochondrial translocation of Drp1.</p></div><div><h3>Conclusions</h3><p>The study demonstrates that RIPK3 reflects deterioration of renal function of DKD. In addition, RIPK3 induces diabetic podocytopathy by regulating mitochondrial fission via PGAM5-Drp1 signaling through MLKL. Inhibition of RIPK3 might be a promising therapeutic option for treating DKD.</p></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"159 ","pages":"Article 155982"},"PeriodicalIF":10.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875348","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 : 2024-07-30DOI: 10.1016/j.metabol.2024.155983
Dominic Arold , Stefan R. Bornstein , Nikolaos Perakakis , Stefan Ehrlich , Fabio Bernardoni
Background
Steatotic liver disease (SLD) is characterized by excessive accumulation of lipids in the liver. It is associated with elevated risk of hepatic and cardiometabolic diseases, as well as mental disorders such as depression. Previous studies revealed global gray matter reduction in SLD. To investigate a possible shared neurobiology with depression, we examined liver fat-related regional gray matter alterations in SLD and its most significant clinical subgroup metabolic dysfunction-associated steatotic liver disease (MASLD).
Methods
We analyzed regional cortical thickness and area obtained from brain MRI in 29,051 participants in UK Biobank. Liver fat amount was computed as proton density fat fraction (PDFF) from liver MRI scans. We examined the relationship between brain structure and PDFF, adjusting for sociodemographic, physical, lifestyle, and environmental factors, as well as alcohol intake and a spectrum of cardiometabolic covariates. Finally, we compared patterns of brain alterations in SLD/MASLD and major depressive disorder (MDD) using previously published results.
Results
PDFF-related gray matter alterations were region-specific, involving both increases and decreases in cortical thickness, and increased cortical area. In several regions, PDFF effects on gray matter could also be attributed to cardiometabolic covariates. However, PDFF was consistently associated with lower cortical thickness in middle and superior temporal regions and higher cortical thickness in pericalcarine and right frontal pole regions. PDFF-related alterations for the SLD and the MASLD group correlated with those observed in MDD (Pearson r = 0.45–0.54, p < 0.01).
Conclusion
These findings suggest the presence of shared biological mechanisms linking MDD to SLD and MASLD. They might explain the well-known elevated risk of depression in these groups and support early lifestyle interventions and treatment of metabolic risk factors for the successful management of the interconnected diseases depression and SLD/MASLD.
背景：脂肪性肝病（SLD）的特点是肝脏中脂类过度积聚。它与肝脏和心脏代谢疾病以及抑郁症等精神疾病的高风险有关。先前的研究显示，SLD 患者的整体灰质减少。为了研究可能与抑郁症共享的神经生物学，我们研究了SLD及其最重要的临床亚组代谢功能障碍相关脂肪性肝病（MASLD）中与肝脏脂肪相关的区域灰质改变：我们分析了英国生物库（UK Biobank）中29051名参与者脑部核磁共振成像获得的区域皮质厚度和面积。肝脏脂肪量根据肝脏核磁共振扫描的质子密度脂肪分数（PDFF）计算得出。我们研究了大脑结构与质子密度脂肪分数之间的关系，并对社会人口、身体、生活方式和环境因素以及酒精摄入量和一系列心脏代谢协变量进行了调整。最后，我们利用以前发表的结果比较了SLD/MASLD和重度抑郁障碍（MDD）的大脑改变模式：结果：与 PDFF 相关的灰质改变具有区域特异性，涉及皮质厚度的增加和减少，以及皮质面积的增加。在一些区域，PDFF对灰质的影响也可归因于心脏代谢协变量。然而，PDFF始终与中颞区和上颞区较低的皮质厚度以及脐周区和右额极区较高的皮质厚度相关。SLD和MASLD组与PDFF相关的改变与MDD中观察到的改变相关（Pearson r = 0.45-0.54, p 结论）：这些研究结果表明，存在共同的生物机制将 MDD 与 SLD 和 MASLD 联系起来。它们可以解释这些群体中众所周知的抑郁风险升高，并支持早期生活方式干预和代谢风险因素治疗，以成功控制相互关联的抑郁症和 SLD/MASLD 疾病。
{"title":"Regional gray matter changes in steatotic liver disease provide a neurobiological link to depression: A cross-sectional UK Biobank cohort study","authors":"Dominic Arold , Stefan R. Bornstein , Nikolaos Perakakis , Stefan Ehrlich , Fabio Bernardoni","doi":"10.1016/j.metabol.2024.155983","DOIUrl":"10.1016/j.metabol.2024.155983","url":null,"abstract":"<div><h3>Background</h3><p>Steatotic liver disease (SLD) is characterized by excessive accumulation of lipids in the liver. It is associated with elevated risk of hepatic and cardiometabolic diseases, as well as mental disorders such as depression. Previous studies revealed global gray matter reduction in SLD. To investigate a possible shared neurobiology with depression, we examined liver fat-related regional gray matter alterations in SLD and its most significant clinical subgroup metabolic dysfunction-associated steatotic liver disease (MASLD).</p></div><div><h3>Methods</h3><p>We analyzed regional cortical thickness and area obtained from brain MRI in 29,051 participants in UK Biobank. Liver fat amount was computed as proton density fat fraction (PDFF) from liver MRI scans. We examined the relationship between brain structure and PDFF, adjusting for sociodemographic, physical, lifestyle, and environmental factors, as well as alcohol intake and a spectrum of cardiometabolic covariates. Finally, we compared patterns of brain alterations in SLD/MASLD and major depressive disorder (MDD) using previously published results.</p></div><div><h3>Results</h3><p>PDFF-related gray matter alterations were region-specific, involving both increases and decreases in cortical thickness, and increased cortical area. In several regions, PDFF effects on gray matter could also be attributed to cardiometabolic covariates. However, PDFF was consistently associated with lower cortical thickness in middle and superior temporal regions and higher cortical thickness in pericalcarine and right frontal pole regions. PDFF-related alterations for the SLD and the MASLD group correlated with those observed in MDD (Pearson <em>r</em> = 0.45–0.54, <em>p</em> < 0.01).</p></div><div><h3>Conclusion</h3><p>These findings suggest the presence of shared biological mechanisms linking MDD to SLD and MASLD. They might explain the well-known elevated risk of depression in these groups and support early lifestyle interventions and treatment of metabolic risk factors for the successful management of the interconnected diseases depression and SLD/MASLD.</p></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"159 ","pages":"Article 155983"},"PeriodicalIF":10.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0026049524002105/pdfft?md5=da8b588e1676fdd5e8ff321ebd5d845a&pid=1-s2.0-S0026049524002105-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875347","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 : 2024-07-23DOI: 10.1016/j.metabol.2024.155977
Songren Shu , Hao Cui , Zirui Liu , Hang Zhang , Yicheng Yang , Xiao Chen , Zhiwei Zeng , Leilei Du , Mengxia Fu , Ziang Yang , Peizhi Wang , Chuangshi Wang , Huimin Gao , Qiaoxi Yang , Xiaojun Lin , Tianshuo Yang , Zhice Chen , Sijin Wu , Xiaohu Wang , Ruojin Zhao , Jiangping Song
Background
Although metabolic disturbance is a characteristic of diabetic cardiomyopathy (DbCM), the detailed pathogenesis of DbCM remains unknown.
Methods
We used a heart transplantation (HTx) cohort to explore the effect of diabetes mellitus on heart failure (HF) progression dependent of myocardium. Microscopic and ultramicroscopic pathology were used to depict the pathological features of human myocardium of DbCM. We performed targeted metabolomics to characterize the metabolic phenotype of human DbCM. Transcriptomics data were analyzed and weighted gene co-expression network analysis was performed to explore the potential upstream regulator for metabolic remodeling of DbCM. In vivo and in vitro experiments were further conducted to demonstrate the therapeutic effects and molecular mechanisms.
Results
DbCM promoted the progression of HF and increased death or HF-rehospitalization after HTx. Lipid accumulation and mitochondrial fission were the obvious pathological features of DbCM myocardium. The concentrations of C14:0-CoA and C16:1-CoA were significantly increased in the myocardium, and they were positively correlated with the accelerated HF progression and RCAN1 expression in DbCM patients. Knockdown of RCAN1 improved cardiac dysfunction, lipid accumulation, and mitochondrial fission in db/db mice. In vitro studies showed that RCAN1 knockdown improved mitochondrial dysfunction in DbCM cardiomyocytes via the RCAN1-p-Drp1 Ser616 axis.
Conclusions
Diabetes is associated with faster progression of HF and causes poor prognosis after HTx, accompanied by metabolic remodeling in the myocardium. Accumulation of long chain acyl-CoA in the myocardium is the metabolic hallmark of human DbCM and is associated with more rapid disease progression for DbCM patients. Upregulation of RCAN1 in the myocardium is associated with the metabolic signatures of DbCM and RCAN1 is a potential therapeutic target for DbCM.
{"title":"Suppression of RCAN1 alleviated lipid accumulation and mitochondrial fission in diabetic cardiomyopathy","authors":"Songren Shu , Hao Cui , Zirui Liu , Hang Zhang , Yicheng Yang , Xiao Chen , Zhiwei Zeng , Leilei Du , Mengxia Fu , Ziang Yang , Peizhi Wang , Chuangshi Wang , Huimin Gao , Qiaoxi Yang , Xiaojun Lin , Tianshuo Yang , Zhice Chen , Sijin Wu , Xiaohu Wang , Ruojin Zhao , Jiangping Song","doi":"10.1016/j.metabol.2024.155977","DOIUrl":"10.1016/j.metabol.2024.155977","url":null,"abstract":"<div><h3>Background</h3><p>Although metabolic disturbance is a characteristic of diabetic cardiomyopathy (DbCM), the detailed pathogenesis of DbCM remains unknown.</p></div><div><h3>Methods</h3><p>We used a heart transplantation (HTx) cohort to explore the effect of diabetes mellitus on heart failure (HF) progression dependent of myocardium. Microscopic and ultramicroscopic pathology were used to depict the pathological features of human myocardium of DbCM. We performed targeted metabolomics to characterize the metabolic phenotype of human DbCM. Transcriptomics data were analyzed and weighted gene co-expression network analysis was performed to explore the potential upstream regulator for metabolic remodeling of DbCM. In vivo and in vitro experiments were further conducted to demonstrate the therapeutic effects and molecular mechanisms.</p></div><div><h3>Results</h3><p>DbCM promoted the progression of HF and increased death or HF-rehospitalization after HTx. Lipid accumulation and mitochondrial fission were the obvious pathological features of DbCM myocardium. The concentrations of C14:0-CoA and C16:1-CoA were significantly increased in the myocardium, and they were positively correlated with the accelerated HF progression and <em>RCAN1</em> expression in DbCM patients. Knockdown of <em>RCAN1</em> improved cardiac dysfunction, lipid accumulation, and mitochondrial fission in db/db mice. In vitro studies showed that <em>RCAN1</em> knockdown improved mitochondrial dysfunction in DbCM cardiomyocytes via the RCAN1-p-Drp1 Ser<sup>616</sup> axis.</p></div><div><h3>Conclusions</h3><p>Diabetes is associated with faster progression of HF and causes poor prognosis after HTx, accompanied by metabolic remodeling in the myocardium. Accumulation of long chain acyl-CoA in the myocardium is the metabolic hallmark of human DbCM and is associated with more rapid disease progression for DbCM patients. Upregulation of RCAN1 in the myocardium is associated with the metabolic signatures of DbCM and RCAN1 is a potential therapeutic target for DbCM.</p></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"158 ","pages":"Article 155977"},"PeriodicalIF":10.8,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759784","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 : 2024-07-23DOI: 10.1016/j.metabol.2024.155980
Tian-Zi Wen , Tian-Ran Li , Xin-Yu Chen , He-Yuan Chen , Shuai Wang , Wen-Juan Fu , Shi-Qi Xiao , Jie Luo , Rui Tang , Jia-Le Ji , Jia-Feng Huang , Zhi-Cheng He , Tao Luo , Hong-Liang Zhao , Cong Chen , Jing-Ya Miao , Qin Niu , Yan Wang , Xiu-Wu Bian , Xiao-Hong Yao
Background
The effect of coronavirus disease 2019 (COVID-19) on adrenal endocrine metabolism in critically ill patients remains unclear. This study aimed to investigate the alterations in adrenal steroidogenic activity, elucidate underlying mechanisms, provide in situ histopathological evidence, and examine the clinical implications.
Methods
The comparative analyses of the adrenal cortices from 24 patients with fatal COVID-19 and 20 matched controls were performed, excluding patients previously treated with glucocorticoids. SARS-CoV-2 and its receptors were identified and pathological alterations were examined. Furthermore, histological examinations, immunohistochemical staining and ultrastructural analyses were performed to assess corticosteroid biosynthesis. The zona glomerulosa (ZG) and zona fasciculata (ZF) were then dissected for proteomic analyses. The biological processes that affected steroidogenesis were analyzed by integrating histological, proteomic, and clinical data. Finally, the immunoreactivity and responsive genes of mineralocorticoid and glucocorticoid receptors in essential tissues were quantitatively measured to evaluate corticosteroid responsiveness.
Findings
The demographic characteristics of COVID-19 patients were comparable with those of controls. SARS-CoV-2-like particles were identified in the adrenocortical cells of three patients; however, these particles did not affect cellular morphology or steroid synthesis compared with SARS-CoV-2-negative specimens. Although the adrenals exhibited focal necrosis, vacuolization, microthrombi, and inflammation, widespread degeneration was not evident. Notably, corticosteroid biosynthesis was significantly enhanced in both the ZG and ZF of COVID-19 patients. The increase in the inflammatory response and cellular differentiation in the adrenal cortices of patients with critical COVID-19 was positively correlated with heightened steroidogenic activity. Additionally, the appearance of more dual-ZG/ZF identity cells in COVID-19 adrenals was in accordance with the increased steroidogenic function. However, activated mineralocorticoid and glucocorticoid receptors and their responsive genes in vital tissues were markedly reduced in patients with critical COVID-19.
Interpretation
Critical COVID-19 was characterized by potentiated adrenal steroidogenesis, associated with increased inflammation, enhanced differentiation and elevated dual-ZG/ZF identity cells, alongside suppressed corticosteroid responsiveness. These alterations implied the reduced effectiveness of conventional corticosteroid therapy and underscored the need for evaluation of the adrenal axis and corticosteroid sensitivity.
{"title":"Increased adrenal steroidogenesis and suppressed corticosteroid responsiveness in critical COVID-19","authors":"Tian-Zi Wen , Tian-Ran Li , Xin-Yu Chen , He-Yuan Chen , Shuai Wang , Wen-Juan Fu , Shi-Qi Xiao , Jie Luo , Rui Tang , Jia-Le Ji , Jia-Feng Huang , Zhi-Cheng He , Tao Luo , Hong-Liang Zhao , Cong Chen , Jing-Ya Miao , Qin Niu , Yan Wang , Xiu-Wu Bian , Xiao-Hong Yao","doi":"10.1016/j.metabol.2024.155980","DOIUrl":"10.1016/j.metabol.2024.155980","url":null,"abstract":"<div><h3>Background</h3><p>The effect of coronavirus disease 2019 (COVID-19) on adrenal endocrine metabolism in critically ill patients remains unclear. This study aimed to investigate the alterations in adrenal steroidogenic activity, elucidate underlying mechanisms, provide <em>in situ</em> histopathological evidence, and examine the clinical implications.</p></div><div><h3>Methods</h3><p>The comparative analyses of the adrenal cortices from 24 patients with fatal COVID-19 and 20 matched controls were performed, excluding patients previously treated with glucocorticoids. SARS-CoV-2 and its receptors were identified and pathological alterations were examined. Furthermore, histological examinations, immunohistochemical staining and ultrastructural analyses were performed to assess corticosteroid biosynthesis. The zona glomerulosa (ZG) and zona fasciculata (ZF) were then dissected for proteomic analyses. The biological processes that affected steroidogenesis were analyzed by integrating histological, proteomic, and clinical data. Finally, the immunoreactivity and responsive genes of mineralocorticoid and glucocorticoid receptors in essential tissues were quantitatively measured to evaluate corticosteroid responsiveness.</p></div><div><h3>Findings</h3><p>The demographic characteristics of COVID-19 patients were comparable with those of controls. SARS-CoV-2-like particles were identified in the adrenocortical cells of three patients; however, these particles did not affect cellular morphology or steroid synthesis compared with SARS-CoV-2-negative specimens. Although the adrenals exhibited focal necrosis, vacuolization, microthrombi, and inflammation, widespread degeneration was not evident. Notably, corticosteroid biosynthesis was significantly enhanced in both the ZG and ZF of COVID-19 patients. The increase in the inflammatory response and cellular differentiation in the adrenal cortices of patients with critical COVID-19 was positively correlated with heightened steroidogenic activity. Additionally, the appearance of more dual-ZG/ZF identity cells in COVID-19 adrenals was in accordance with the increased steroidogenic function. However, activated mineralocorticoid and glucocorticoid receptors and their responsive genes in vital tissues were markedly reduced in patients with critical COVID-19.</p></div><div><h3>Interpretation</h3><p>Critical COVID-19 was characterized by potentiated adrenal steroidogenesis, associated with increased inflammation, enhanced differentiation and elevated dual-ZG/ZF identity cells, alongside suppressed corticosteroid responsiveness. These alterations implied the reduced effectiveness of conventional corticosteroid therapy and underscored the need for evaluation of the adrenal axis and corticosteroid sensitivity.</p></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"160 ","pages":"Article 155980"},"PeriodicalIF":10.8,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0026049524002075/pdfft?md5=6000c8c96ffac260d051082fb3f8e995&pid=1-s2.0-S0026049524002075-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759756","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 : 2024-07-22DOI: 10.1016/j.metabol.2024.155981
Joo Hee Jeong , Yun Gi Kim , Kyung-Do Han , Seung-Young Roh , Hyoung Seok Lee , Yun Young Choi , Sun Young Yim , Jaemin Shim , Young-Hoon Kim , Jong-Il Choi
Background
Metabolic dysfunction-associated steatotic liver disease (MASLD) contributes to cardiovascular events. Therefore, we aimed to identify the association of MASLD, as indicated by the fatty liver index (FLI), on sudden cardiac arrest (SCA) in young adults.
Methods
We analyzed data from adults aged 20–39 years, who underwent health examinations between 2009 and 2012, sourced from the Korean National Health Insurance Service database. The presence of MASLD was determined using the FLI, which was calculated based on an individual's body mass index, waist circumference, gamma-glutamyl transferase and triglyceride levels. The primary outcome was the occurrence of SCA during the follow-up period, until December 2020.
Results
Of the total 5,398,082 individuals analyzed, 4,021,056 (74.5 %) had a normal FLI (FLI <30), 837,943 (15.5 %) were within the intermediate range (30–60), and 539,083 (10.0 %) demonstrated a high FLI (≥60). Individuals with a high FLI were older, and comprised a higher proportion of men with hypertension, diabetes mellitus, dyslipidemia, heart failure, and myocardial infarction. During follow-up, SCA occurred in 4255 individuals (0.08 %). The group with a high FLI exhibited an increased incidence (incidence rate, 0.19) and elevated risk of SCA (hazard ratio, 3.04). Adjustment of covariates revealed a 55 % increased risk of SCA in the high FLI group (adjusted hazard ratio 1.55, 95 % confidence interval 1.41–1.70, p < 0.001). Moreover, the influence of a high FLI on SCA risk was more pronounced in women compared to men. Additionally, an increase in relevant cardiometabolic conditions was associated with an elevated risk of SCA.
Conclusions
Among young adults, a high risk of MASLD, as indicated by the FLI, revealed an increased risk of SCA. Furthermore, the association of FLI with the risk of SCA varied by sex and cardiometabolic conditions.
{"title":"Association of fatty liver index with sudden cardiac arrest in young adults","authors":"Joo Hee Jeong , Yun Gi Kim , Kyung-Do Han , Seung-Young Roh , Hyoung Seok Lee , Yun Young Choi , Sun Young Yim , Jaemin Shim , Young-Hoon Kim , Jong-Il Choi","doi":"10.1016/j.metabol.2024.155981","DOIUrl":"10.1016/j.metabol.2024.155981","url":null,"abstract":"<div><h3>Background</h3><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) contributes to cardiovascular events. Therefore, we aimed to identify the association of MASLD, as indicated by the fatty liver index (FLI), on sudden cardiac arrest (SCA) in young adults.</p></div><div><h3>Methods</h3><p>We analyzed data from adults aged 20–39 years, who underwent health examinations between 2009 and 2012, sourced from the Korean National Health Insurance Service database. The presence of MASLD was determined using the FLI, which was calculated based on an individual's body mass index, waist circumference, gamma-glutamyl transferase and triglyceride levels. The primary outcome was the occurrence of SCA during the follow-up period, until December 2020.</p></div><div><h3>Results</h3><p>Of the total 5,398,082 individuals analyzed, 4,021,056 (74.5 %) had a normal FLI (FLI <30), 837,943 (15.5 %) were within the intermediate range (30–60), and 539,083 (10.0 %) demonstrated a high FLI (≥60). Individuals with a high FLI were older, and comprised a higher proportion of men with hypertension, diabetes mellitus, dyslipidemia, heart failure, and myocardial infarction. During follow-up, SCA occurred in 4255 individuals (0.08 %). The group with a high FLI exhibited an increased incidence (incidence rate, 0.19) and elevated risk of SCA (hazard ratio, 3.04). Adjustment of covariates revealed a 55 % increased risk of SCA in the high FLI group (adjusted hazard ratio 1.55, 95 % confidence interval 1.41–1.70, <em>p</em> < 0.001). Moreover, the influence of a high FLI on SCA risk was more pronounced in women compared to men. Additionally, an increase in relevant cardiometabolic conditions was associated with an elevated risk of SCA.</p></div><div><h3>Conclusions</h3><p>Among young adults, a high risk of MASLD, as indicated by the FLI, revealed an increased risk of SCA. Furthermore, the association of FLI with the risk of SCA varied by sex and cardiometabolic conditions.</p></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"158 ","pages":"Article 155981"},"PeriodicalIF":10.8,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759755","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 : 2024-07-20DOI: 10.1016/j.metabol.2024.155979
Mengmeng Zhao , Zican Shen , Zihui Zheng , Yao Xu , Jishou Zhang , Jianfang Liu , Shanshan Peng , Jun Wan , Juan-Juan Qin , Menglong Wang
Aims
The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, and conventional drug therapy cannot correct the progression of diabetic cardiomyopathy. We assessed the potential role and therapeutic value of LGR6 (G protein-coupled receptor containing leucine-rich repeats 6) in diabetic cardiomyopathy.
Methods and results
Type 2 diabetes models were established using high-fat diet/streptozotocin-induced diabetes in mice. LGR6 knockout mice were generated. Recombinant adeno-associated virus serotype 9 carrying LGR6 under the cardiac troponin T promoter was injected into diabetic mice. Cardiomyocytes incubated with high glucose (HG) were used to imitate diabetic cardiomyopathy in vitro. The molecular mechanism was explored through RNA sequencing and a chromatin immunoprecipitation assay. We found that LGR6 expression was upregulated in diabetic hearts and HL1 cardiomyocytes treated with HG. The LGR6 knockout aggravated, but cardiomyocyte-specific LGR6 overexpression ameliorated, cardiac dysfunction and remodeling in diabetic mice. Mechanistically, in vivo and in vitro experiments revealed that LGR6 deletion aggravated, whereas LGR6 overexpression alleviated, ferroptosis and disrupted mitochondrial biogenesis by regulating STAT3/Pgc1a signaling. STAT3 inhibition and Pgc1a activation abrogated LGR6 knockout-induced mitochondrial dysfunction and ferroptosis in diabetic mice. In addition, LGR6 activation by recombinant RSPO3 treatment ameliorated cardiac dysfunction, ferroptosis and mitochondrial dysfunction in diabetic mice.
Conclusions
We identified a previously undescribed signaling pathway of the LGR6-STAT3-Pgc1a axis that plays a critical role in ferroptosis and mitochondrial disorders during diabetic cardiomyopathy and provides an option for treatment of diabetic hearts.
{"title":"Cardiomyocyte LGR6 alleviates ferroptosis in diabetic cardiomyopathy via regulating mitochondrial biogenesis","authors":"Mengmeng Zhao , Zican Shen , Zihui Zheng , Yao Xu , Jishou Zhang , Jianfang Liu , Shanshan Peng , Jun Wan , Juan-Juan Qin , Menglong Wang","doi":"10.1016/j.metabol.2024.155979","DOIUrl":"10.1016/j.metabol.2024.155979","url":null,"abstract":"<div><h3>Aims</h3><p>The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, and conventional drug therapy cannot correct the progression of diabetic cardiomyopathy. We assessed the potential role and therapeutic value of LGR6 (G protein-coupled receptor containing leucine-rich repeats 6) in diabetic cardiomyopathy.</p></div><div><h3>Methods and results</h3><p>Type 2 diabetes models were established using high-fat diet/streptozotocin-induced diabetes in mice. LGR6 knockout mice were generated. Recombinant adeno-associated virus serotype 9 carrying LGR6 under the cardiac troponin T promoter was injected into diabetic mice. Cardiomyocytes incubated with high glucose (HG) were used to imitate diabetic cardiomyopathy in vitro. The molecular mechanism was explored through RNA sequencing and a chromatin immunoprecipitation assay. We found that LGR6 expression was upregulated in diabetic hearts and HL1 cardiomyocytes treated with HG. The LGR6 knockout aggravated, but cardiomyocyte-specific LGR6 overexpression ameliorated, cardiac dysfunction and remodeling in diabetic mice. Mechanistically, in vivo and in vitro experiments revealed that LGR6 deletion aggravated, whereas LGR6 overexpression alleviated, ferroptosis and disrupted mitochondrial biogenesis by regulating STAT3/Pgc1a signaling. STAT3 inhibition and Pgc1a activation abrogated LGR6 knockout-induced mitochondrial dysfunction and ferroptosis in diabetic mice. In addition, LGR6 activation by recombinant RSPO3 treatment ameliorated cardiac dysfunction, ferroptosis and mitochondrial dysfunction in diabetic mice.</p></div><div><h3>Conclusions</h3><p>We identified a previously undescribed signaling pathway of the LGR6-STAT3-Pgc1a axis that plays a critical role in ferroptosis and mitochondrial disorders during diabetic cardiomyopathy and provides an option for treatment of diabetic hearts.</p></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"159 ","pages":"Article 155979"},"PeriodicalIF":10.8,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748578","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}
Estrogen secretion by the ovaries regulates the hypothalamic-pituitary-gonadal axis during the reproductive cycle, influencing gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion, and also plays a role in regulating metabolism. Here, we establish that hypothalamic tanycytes—specialized glia lining the floor and walls of the third ventricle—integrate estrogenic feedback signals from the gonads and couple reproduction with metabolism by relaying this information to orexigenic neuropeptide Y (NPY) neurons.
Methods
Using mouse models, including mice floxed for Esr1 (encoding estrogen receptor alpha, ERα) and those with Cre-dependent expression of designer receptors exclusively activated by designer drugs (DREADDs), along with viral-mediated, pharmacological and indirect calorimetric approaches, we evaluated the role of tanycytes and tanycytic estrogen signaling in pulsatile LH secretion, cFos expression in NPY neurons, estrous cyclicity, body-weight changes and metabolic parameters in adult females.
Results
In ovariectomized mice, chemogenetic activation of tanycytes significantly reduced LH pulsatile release, mimicking the effects of direct NPY neuron activation. In intact mice, tanycytes were crucial for the estrogen-mediated control of GnRH/LH release, with tanycytic ERα activation suppressing fasting-induced NPY neuron activation. Selective knockout of Esr1 in tanycytes altered estrous cyclicity and fertility in female mice and affected estrogen's ability to inhibit refeeding in fasting mice. The absence of ERα signaling in tanycytes increased Npy transcripts and body weight in intact mice and prevented the estrogen-mediated decrease in food intake as well as increase in energy expenditure and fatty acid oxidation in ovariectomized mice.
Conclusions
Our findings underscore the pivotal role of tanycytes in the neuroendocrine coupling of reproduction and metabolism, with potential implications for its age-related deregulation after menopause.
Significance statement
Our investigation reveals that tanycytes, specialized glial cells in the brain, are key interpreters of estrogen signals for orexigenic NPY neurons in the hypothalamus. Disrupting tanycytic estrogen receptors not only alters fertility in female mice but also impairs the ability of estrogens to suppress appetite. This work thus sheds light on the critical role played by tanycytes in bridging the hormonal regulation of cyclic reproductive function and appetite/feeding behavior. This understanding may have potential implications for age-related metabolic deregulation after menopause.
{"title":"Estrogen receptor-α signaling in tanycytes lies at the crossroads of fertility and metabolism","authors":"Daniela Fernandois , Mariam Rusidzé , Helge Mueller-Fielitz , Florent Sauve , Eleonora Deligia , Mauro S.B. Silva , Florence Evrard , Aurelio Franco-García , Daniele Mazur , Ines Martinez-Corral , Nathalie Jouy , S. Rasika , Claude-Alain Maurage , Paolo Giacobini , Ruben Nogueiras , Benedicte Dehouck , Markus Schwaninger , Francoise Lenfant , Vincent Prevot","doi":"10.1016/j.metabol.2024.155976","DOIUrl":"10.1016/j.metabol.2024.155976","url":null,"abstract":"<div><h3>Background</h3><p>Estrogen secretion by the ovaries regulates the hypothalamic-pituitary-gonadal axis during the reproductive cycle, influencing gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion, and also plays a role in regulating metabolism. Here, we establish that hypothalamic tanycytes—specialized glia lining the floor and walls of the third ventricle—integrate estrogenic feedback signals from the gonads and couple reproduction with metabolism by relaying this information to orexigenic neuropeptide Y (NPY) neurons.</p></div><div><h3>Methods</h3><p>Using mouse models, including mice floxed for <em>Esr1</em> (encoding estrogen receptor alpha, ERα) and those with Cre-dependent expression of designer receptors exclusively activated by designer drugs (DREADDs), along with viral-mediated, pharmacological and indirect calorimetric approaches, we evaluated the role of tanycytes and tanycytic estrogen signaling in pulsatile LH secretion, cFos expression in NPY neurons, estrous cyclicity, body-weight changes and metabolic parameters in adult females.</p></div><div><h3>Results</h3><p>In ovariectomized mice, chemogenetic activation of tanycytes significantly reduced LH pulsatile release, mimicking the effects of direct NPY neuron activation. In intact mice, tanycytes were crucial for the estrogen-mediated control of GnRH/LH release, with tanycytic ERα activation suppressing fasting-induced NPY neuron activation. Selective knockout of <em>Esr1</em> in tanycytes altered estrous cyclicity and fertility in female mice and affected estrogen's ability to inhibit refeeding in fasting mice. The absence of ERα signaling in tanycytes increased <em>Npy</em> transcripts and body weight in intact mice and prevented the estrogen-mediated decrease in food intake as well as increase in energy expenditure and fatty acid oxidation in ovariectomized mice.</p></div><div><h3>Conclusions</h3><p>Our findings underscore the pivotal role of tanycytes in the neuroendocrine coupling of reproduction and metabolism, with potential implications for its age-related deregulation after menopause.</p></div><div><h3>Significance statement</h3><p>Our investigation reveals that tanycytes, specialized glial cells in the brain, are key interpreters of estrogen signals for orexigenic NPY neurons in the hypothalamus. Disrupting tanycytic estrogen receptors not only alters fertility in female mice but also impairs the ability of estrogens to suppress appetite. This work thus sheds light on the critical role played by tanycytes in bridging the hormonal regulation of cyclic reproductive function and appetite/feeding behavior. This understanding may have potential implications for age-related metabolic deregulation after menopause.</p></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"158 ","pages":"Article 155976"},"PeriodicalIF":10.8,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0026049524002038/pdfft?md5=d2545dea26684f2163b988792a4ac788&pid=1-s2.0-S0026049524002038-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633937","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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