Metabolism: clinical and experimental最新文献

{"title":"GDF-15 improves the predictive capacity of steatotic liver disease non-invasive tests for incident morbidity and mortality risk for cardio-renal-metabolic diseases and malignancies","authors":"Michail Kokkorakis ,&nbsp;Pytrik Folkertsma ,&nbsp;José Castela Forte ,&nbsp;Bruce H.R. Wolffenbuttel ,&nbsp;Sipko van Dam ,&nbsp;Christos S. Mantzoros","doi":"10.1016/j.metabol.2024.156047","DOIUrl":"10.1016/j.metabol.2024.156047","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>Noninvasive tools (NITs) are currently used to stratify the risk of having or developing hepatic steatosis or fibrosis. Their performance and a proteomic-enabled improvement in forecasting long-term cardio-renal-metabolic morbidity, malignancies, as well as cause-specific and all-cause mortality, are lacking. Therefore, the performance of established NITs needs to be investigated in identifying cardio-renal-metabolic morbidity, malignancies, cause-specific and overall mortality and improve their performance with novel, proteomic-enabled NITs, including growth differentiation factor 15 (GDF-15), allowing multipurpose utilization.</div></div><div><h3>Methods</h3><div>502,359 UK Biobank participants free of the study outcomes at baseline with a 14-year median follow-up were grouped into three categories: a) general population, b) potentially metabolic dysfunction-associated steatotic liver disease (MASLD) population, c) individuals with type 2 diabetes mellitus. The investigated NITs include Aspartate aminotransferase to Platelet Ratio Index (APRI), Fibrosis 4 Index (FIB-4), Fatty Liver Index (FLI), Hepatic Steatosis Index (HSI), Lipid Accumulation Product (LAP), and metabolic dysfunction–associated fibrosis (MAF-5) score.</div></div><div><h3>Results</h3><div>Adding GDF-15 to the existing NITs led to significantly increased prognostic performance compared to the traditional NITs in almost all instances, reaching substantially high C-indices, ranging between 0.601 and 0.808, with an overall &gt;0.2 improvement in C-index. Overall, with the GDF-15 enhanced NITs, up to more than seven times fewer individuals need to be screened to identify more incident cases of adverse outcomes compared to the traditional NITs. The cumulative incidence of all outcomes, based on the continuous value percentiles of NITs, is increasing exponentially in the upper quintile of the GDF-15 enhanced NITs.</div></div><div><h3>Conclusions</h3><div>The herein-developed GDF-15 enhanced indices demonstrate higher screening effectiveness and significantly improved prognostic abilities, which are reduced to practice through an easy-to-use web-based calculator tool (<span><span>https://clinicalpredictor.shinyapps.io/multimorbidity-mortality-risk/</span><svg><path></path></svg></span>).</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156047"},"PeriodicalIF":10.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470016","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}

{"title":"The role of IL-1 family cytokines in diabetic cardiomyopathy","authors":"Qi Wu ,&nbsp;Yan Zeng ,&nbsp;Kang Geng ,&nbsp;Man Guo ,&nbsp;Fang-yuan Teng ,&nbsp;Pi-jun Yan ,&nbsp;Yi Lei ,&nbsp;Yang Long ,&nbsp;Zong-zhe Jiang ,&nbsp;Betty Yuen-Kwan Law ,&nbsp;Yong Xu","doi":"10.1016/j.metabol.2024.156083","DOIUrl":"10.1016/j.metabol.2024.156083","url":null,"abstract":"<div><div>Diabetic cardiomyopathy (DCM) is the primary cause of heart failure in patients with diabetes and is characterised by contractile dysfunction and left ventricular hypertrophy. The complex pathological and physiological mechanisms underlying DCM have contributed to a limited number of available treatment options. A substantial body of evidence has established that DCM is a low-grade inflammatory cardiovascular disorder, with the interleukin-1 (IL-1) family of cytokines playing crucial roles in initiating inflammatory responses and shaping innate and adaptive immunity. In this review, we aim to provide an overview of the underlying mechanisms of the IL-1 family and their relevance in DCM of various aetiologies. Furthermore, we highlighted potential therapeutic targets within the IL-1 family for the management of DCM.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156083"},"PeriodicalIF":10.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739812","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}

{"title":"PCSK9 in metabolism and diseases","authors":"Amir Ajoolabady ,&nbsp;Domenico Pratico ,&nbsp;Mohsen Mazidi ,&nbsp;Ian G. Davies ,&nbsp;Gregory Y.H. Lip ,&nbsp;Nabil Seidah ,&nbsp;Peter Libby ,&nbsp;Guido Kroemer ,&nbsp;Jun Ren","doi":"10.1016/j.metabol.2024.156064","DOIUrl":"10.1016/j.metabol.2024.156064","url":null,"abstract":"<div><div>PCSK9 is a serine protease that regulates plasma levels of low-density lipoprotein (LDL) and cholesterol by mediating the endolysosomal degradation of LDL receptor (LDLR) in the liver. When PCSK9 functions unchecked, it leads to increased degradation of LDLR, resulting in elevated circulatory levels of LDL and cholesterol. This dysregulation contributes to lipid and cholesterol metabolism abnormalities, foam cell formation, and the development of various diseases, including cardiovascular disease (CVD), viral infections, cancer, and sepsis. Emerging clinical and experimental evidence highlights an imperative role for PCSK9 in metabolic anomalies such as hypercholesterolemia and hyperlipidemia, as well as inflammation, and disturbances in mitochondrial homeostasis. Moreover, metabolic hormones – including insulin, glucagon, adipokines, natriuretic peptides, and sex steroids - regulate the expression and circulatory levels of PCSK9, thus influencing cardiovascular and metabolic functions. In this comprehensive review, we aim to elucidate the regulatory role of PCSK9 in lipid and cholesterol metabolism, pathophysiology of diseases such as CVD, infections, cancer, and sepsis, as well as its pharmaceutical and non-pharmaceutical targeting for therapeutic management of these conditions.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156064"},"PeriodicalIF":10.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639261","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}

{"title":"Association between the Life's essential 8 health behaviors score and all-cause mortality in patients with metabolic dysfunction-associated steatotic liver disease","authors":"Yan Han ,&nbsp;Jing Tang ,&nbsp;Na Wu ,&nbsp;Zhao Li ,&nbsp;Hong Ren ,&nbsp;Peng Hu ,&nbsp;Zhiwei Chen","doi":"10.1016/j.metabol.2024.156096","DOIUrl":"10.1016/j.metabol.2024.156096","url":null,"abstract":"<div><h3>Background</h3><div>The association between Life's Essential 8 (LE8) score and all-cause mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unknown.</div></div><div><h3>Methods</h3><div>This population-based prospective cohort study analyzed data of participants aged 20–79 years in the National Health and Nutrition Examination Survey from 2005 to 2018, with linked mortality information until 2019. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for the association between different cardiovascular health (CVH) scores and all-cause mortality in participants with MASLD.</div></div><div><h3>Results</h3><div>Among 11,988 participants, 4109 (34.3 %) were diagnosed with MASLD. During the median 7.8 years of follow-up, 912 deaths were recorded. Unexpectedly, the total LE8 CVH score was not associated with all-cause mortality in patients with MASLD (all <em>P</em> &gt; .05). However, individuals with MASLD with moderate and poor LE8 health behaviors scores exhibited an increased risk of all-cause mortality (moderate: HR, 1.51; 95 % CI, 1.05–2.17; poor: HR, 2.32; 95 % CI, 1.64–3.30), particularly among patients with advanced fibrosis (moderate: HR, 1.77; 95 % CI, 1.07–2.92; poor: HR, 2.43; 95 % CI, 1.23–4.78). Population-attributable fraction estimates suggest that 35.0 % of all-cause mortality attributed to poor or moderate health behaviors scores could be avoided if ideal CVH metrics were achieved in all patients with MASLD.</div></div><div><h3>Conclusion</h3><div>These findings demonstrate a significant association between the LE8 health behaviors score and all-cause mortality in patients with MASLD, highlighting the usefulness of this score in optimizing risk management strategies for MASLD in future clinical practice.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156096"},"PeriodicalIF":10.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770352","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}

{"title":"Effects of coding variants in the glucokinase regulatory protein gene on hepatic glucose and triglyceride metabolism suggest a gene regulatory function of glucokinase","authors":"Sara Langer ,&nbsp;David Jagdhuhn ,&nbsp;Rica Waterstradt ,&nbsp;Jessica Gromoll ,&nbsp;Michael Müller ,&nbsp;Matthew G. Rees ,&nbsp;Anna L. Gloyn ,&nbsp;Simone Baltrusch","doi":"10.1016/j.metabol.2025.156150","DOIUrl":"10.1016/j.metabol.2025.156150","url":null,"abstract":"<div><h3>Background</h3><div>Regulation of glucose metabolism after a meal is the major task of hepatic glucokinase (GCK). Inhibition and nuclear retention of glucokinase during fasting is achieved by glucokinase regulatory protein (GKRP). Compounds disrupting the GCK-GKRP interaction alter glucose but not triglyceride levels, whilst GKRP coding alleles lower glucose but elevate triglycerides. The aim of this study was to identify yet unknown functions of GKRP by examining human variants both rare (p.Q234P, p.H438Y) and common (p.P446L).</div></div><div><h3>Methods</h3><div>Fluorescently labelled human GKRP variant and GCK proteins were expressed in hepatoma cells or primary mouse hepatocytes to investigate the subcellular localization of both proteins, cellular glucose uptake, and triglyceride levels. Mutational effects on GKRP protein structure were analyzed with PyMOL. Nuclear-to-cytoplasmic distribution of the GCK-GKRP complex was modeled in MATLAB.</div></div><div><h3>Results</h3><div>Nuclear localization of the GKRP variants was decreased compared to wild-type. Only H438Y-GKRP still evoked WT-like GCK nuclear accumulation. Nuclear localization of Q234P-GKRP was most impaired and depended on the presence of GCK, which, supported by structural analyses, could stabilize its conformation. Nonetheless, inhibition of glucose uptake was least impaired with Q234P-GKRP. Triglyceride contents related to the glucose uptake of hepatoma cells were disproportionately high for cells expressing wild-type or H438Y-GKRP, the two variants that induced higher nuclear sequestration of GCK.</div></div><div><h3>Conclusions</h3><div>Our results, supported by a modeling approach, suggest that GKRP-mediated nuclear localization of GCK has a function in liver metabolism beyond GCK inhibition and sequestration. This needs further elucidation given that GKRP disruptors have been proposed for antihyperglycemic therapy.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"166 ","pages":"Article 156150"},"PeriodicalIF":10.8,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080300","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}

{"title":"Combined loss of glyoxalase 1 and aldehyde dehydrogenase 3a1 amplifies dicarbonyl stress, impairs proteasome activity resulting in hyperglycemia and activated retinal angiogenesis","authors":"Shu Li ,&nbsp;Hao Li ,&nbsp;Katrin Bennewitz ,&nbsp;Gernot Poschet ,&nbsp;Michael Buettner ,&nbsp;Ingrid Hausser ,&nbsp;Julia Szendroedi ,&nbsp;Peter Paul Nawroth ,&nbsp;Jens Kroll","doi":"10.1016/j.metabol.2025.156149","DOIUrl":"10.1016/j.metabol.2025.156149","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>Any energy consumption results in the generation of highly reactive dicarbonyls and the need to prevent excessive dicarbonyls accumulation through the activity of several interdependent detoxification enzymes. Glyoxalase 1 (GLO1) knockout zebrafish showed only moderately elevated methylglyoxal (MG) levels, but increased Aldehyde Dehydrogenases (ALDH) activity and increased <em>aldh3a1</em> expression. Elevated levels of 4-hydroxynonenal (4-HNE) but no MG increase were observed in ALDH3A1KO. The question of whether ALDH3A1 prevents MG formation as a compensatory mechanism in the absence of GLO1 remained unclear.</div></div><div><h3>Methods</h3><div>To investigate whether ALDH3A1 detoxifies MG as a compensatory mechanism in the absence of GLO1, the GLO1/ALDH3A1 double knockout (DKO) zebrafish was first generated. Various metabolites including advanced glycation end products (AGEs), as well as glucose metabolism and hyaloid vasculature were analyzed in GLO1KO, ALDH3A1KO and GLO1/ALDH3A1DKO zebrafish.</div></div><div><h3>Results</h3><div>In the absence of GLO1 and ALDH3A1, MG-H1 levels were increased. MG-H1 accumulation led to a severe deterioration of proteasome function, resulting in impaired glucose homeostasis and consequently amplified angiogenic activation of the hyaloid and retinal vasculature. Rescue of these pathological processes could be observed by using L-carnosine, and proteasome activator betulinic acid.</div></div><div><h3>Conclusion</h3><div>The present data, together with previous studies, suggest that ALDH3A1 and GLO1 are important detoxification enzymes that prevent the deleterious effects of MG-H1 accumulation on proteasome function, glucose homeostasis and vascular function.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"165 ","pages":"Article 156149"},"PeriodicalIF":10.8,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring receptors for pro-resolving and non-pro-resolving mediators as therapeutic targets for sarcopenia","authors":"Tiantian Wang ,&nbsp;Sihan Chen ,&nbsp;Dong Zhou ,&nbsp;Zhen Hong","doi":"10.1016/j.metabol.2025.156148","DOIUrl":"10.1016/j.metabol.2025.156148","url":null,"abstract":"<div><div>Sarcopenia is defined by a reduction in both muscle strength and mass. Sarcopenia may be an inevitable component of the aging process, but it may also be accelerated by comorbidities and metabolic derangements. The underlying mechanisms contributing to these pathological changes remain poorly understood. We propose that chronic inflammation-mediated networks and metabolic defects that exacerbate muscle dysfunction are critical factors in sarcopenia and related diseases. Consequently, utilizing specialized pro-resolving mediators (SPMs) that function through specific G-protein coupled receptors (GPCRs) may offer effective therapeutic options for these disorders. However, challenges such as a limited understanding of SPM/receptor signaling pathways, rapid inactivation of SPMs, and the complexities of SPM synthesis impede their practical application. In this context, stable small-molecule SPM mimetics and receptor agonists present promising alternatives. Moreover, the aged adipose-skeletal axis may contribute to this process. Activating non-SPM GPCRs on adipocytes, immune cells, and muscle cells under conditions of systemic, chronic, low-grade inflammation (SCLGI) could help alleviate inflammation and metabolic dysfunction. Recent preclinical studies indicate that both SPM GPCRs and non-SPM GPCRs can mitigate symptoms of aging-related diseases such as obesity and diabetes, which are driven by chronic inflammation and metabolic disturbances. These findings suggest that targeting these receptors could provide a novel strategy for addressing various chronic inflammatory conditions, including sarcopenia.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"165 ","pages":"Article 156148"},"PeriodicalIF":10.8,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disrupted metabolic flux balance between pyruvate dehydrogenase and pyruvate carboxylase in human fatty liver","authors":"Jae Mo Park ,&nbsp;Sung-Han Lin ,&nbsp;Jeannie D. Baxter ,&nbsp;Crystal E. Harrison ,&nbsp;Jennine Leary ,&nbsp;Corey Mozingo ,&nbsp;Jeff Liticker ,&nbsp;Craig R. Malloy ,&nbsp;Eunsook S. Jin","doi":"10.1016/j.metabol.2025.156151","DOIUrl":"10.1016/j.metabol.2025.156151","url":null,"abstract":"<div><div>Hepatic metabolism involving pyruvate carboxylase (PC) and pyruvate dehydrogenase (PDH) may be abnormal in fatty livers. In this study, [¹³C]bicarbonate production from [1-¹³C₁]pyruvate in the liver and glycerol glyceroneogenesis were examined in relation to hepatic fat content using hyperpolarized [1-¹³C₁]pyruvate and oral [U-¹³C₃]glycerol. After an overnight fast, 15 subjects with a range of hepatic fat content received hyperpolarized [1-¹³C₁]pyruvate intravenously to assess its conversion to [1-¹³C₁]lactate and [¹³C]bicarbonate in the liver. They also received oral [U-¹³C₃]glycerol, followed by venous blood sampling to examine glucose and the glycerol backbone of the triglycerides released primarily from the liver. From hyperpolarized [1-¹³C₁]pyruvate, participants with high intrahepatic fat fraction produced higher [1-¹³C₁]lactate and lower [¹³C]bicarbonate than those with low liver fat. The fraction of plasma triglycerides derived from oral [U-¹³C₃]glycerol via the TCA cycle was similar between groups. The fraction of plasma [5,6-¹³C₂]glucose, which reflects PC flux, decreased in subjects with fatty liver. In contrast, the fraction of [4,5-¹³C₂]glucose + [6-¹³C₁]glucose, which can be produced via either PC or PDH, was comparable between groups. The study results suggest a shift in pyruvate metabolism in fatty liver, with a decreased metabolic flux ratio of PC/PDH. The methodology in this study provides insights into fatty liver metabolism of human subjects inaccessible previously and is applicable to advanced liver diseases such as cirrhosis and hepatomas.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"165 ","pages":"Article 156151"},"PeriodicalIF":10.8,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolites-mediated posttranslational modifications in cardiac metabolic remodeling: Implications for disease pathology and therapeutic potential","authors":"Lifei Guo ,&nbsp;Yuting Du ,&nbsp;Heng Li ,&nbsp;Ting He ,&nbsp;Li Yao ,&nbsp;Guodong Yang ,&nbsp;Xuekang Yang","doi":"10.1016/j.metabol.2025.156144","DOIUrl":"10.1016/j.metabol.2025.156144","url":null,"abstract":"<div><div>The nonenergy – producing functions of metabolism are attracting increasing attention, as metabolic changes are involved in discrete pathways modulating enzyme activity and gene expression. Substantial evidence suggests that myocardial metabolic remodeling occurring during diabetic cardiomyopathy, heart failure, and cardiac pathological stress (e.g., myocardial ischemia, pressure overload) contributes to the progression of pathology. Within the rewired metabolic network, metabolic intermediates and end-products can directly alter protein function and/or regulate epigenetic modifications by providing acyl groups for posttranslational modifications, thereby affecting the overall cardiac stress response and providing a direct link between cellular metabolism and cardiac pathology. This review provides a comprehensive overview of the functional diversity and mechanistic roles of several types of metabolite-mediated histone and nonhistone acylation, namely O-GlcNAcylation, lactylation, crotonylation, β-hydroxybutyrylation, and succinylation, as well as fatty acid-mediated modifications, in regulating physiological processes and contributing to the progression of heart disease. Furthermore, it explores the potential of these modifications as therapeutic targets for disease intervention.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"165 ","pages":"Article 156144"},"PeriodicalIF":10.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FSH exacerbates bone loss by promoting osteoclast energy metabolism through the CREB-MDH2-NAD+ axis","authors":"Jingqiu Chen ,&nbsp;Yilin Liao ,&nbsp;Yue Sheng,&nbsp;Hantao Yao,&nbsp;Ting Li,&nbsp;Zhenru He,&nbsp;Weng Wan Yue Ye,&nbsp;Mengjie Yin,&nbsp;Huilin Tang,&nbsp;Yaoyu Zhao,&nbsp;Peiqi Zhang,&nbsp;Yuting Wang,&nbsp;Xiazhou Fu,&nbsp;Yaoting Ji","doi":"10.1016/j.metabol.2025.156147","DOIUrl":"10.1016/j.metabol.2025.156147","url":null,"abstract":"<div><h3>Aims</h3><div>Osteoclast energy metabolism is a promising target for treating diseases characterized by high osteoclast activity, such as osteoporosis. However, the regulatory factors involved in osteoclast bioenergetic processes are still in the early stages of being fully understood. This study reveals the effects of follicle-stimulating hormone (FSH) on osteoclast energy metabolism.</div></div><div><h3>Methods</h3><div>The <em>Lyz2</em>-Cre-Flox model selectively deletes FSH receptor (FSHR) from osteoclast precursor cells to generate <em>Fshr</em>^<em>f/f</em><em>; Lyz2-Cre</em> (<em>Fshr</em>^f/f; Cre) mice. Bone quality was assessed using micro-computed tomography, histomorphometric analysis, and dual-fluorescence labeling. The in vitro assays measured oxygen consumption rate, extracellular acidification rate, pyruvate content, and mitochondrial membrane potential to determine metabolic flux. RNA-seq, LC-MS, dual-luciferase reporter assays, and chromatin immunoprecipitation (ChIP) assays were used to elucidate the underlying mechanisms.</div></div><div><h3>Results</h3><div>FSHR deficiency in osteoclasts protected bone from resorption under normal and ovariectomized conditions. FSHR-deficient osteoclasts have reduced nicotinamide adenine dinucleotide (NAD⁺) levels, impairing osteoclast activity and energy metabolism. Mechanistically, FSH influenced NAD⁺ levels via the CREB/MDH2 axis. Treatment with FSH monoclonal antibodies rescued bone loss in OVX mice and reduced bone marrow NAD⁺ levels.</div></div><div><h3>Conclusions</h3><div>Targeting FSH may be a promising metabolic modulation strategy for treating osteoporosis and other diseases associated with high osteoclast activity.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"165 ","pages":"Article 156147"},"PeriodicalIF":10.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}