Molecular Metabolism最新文献

{"title":"Deletion of miPEP in adipocytes protects against obesity and insulin resistance by boosting muscle metabolism","authors":"Alexis Diaz-Vegas ,&nbsp;Kristen C. Cooke ,&nbsp;Harry B. Cutler ,&nbsp;Belinda Yau ,&nbsp;Stewart W.C. Masson ,&nbsp;Dylan Harney ,&nbsp;Oliver K. Fuller ,&nbsp;Meg Potter ,&nbsp;Søren Madsen ,&nbsp;Niamh R. Craw ,&nbsp;Yiju Zhang ,&nbsp;Cesar L. Moreno ,&nbsp;Melkam A. Kebede ,&nbsp;G. Gregory Neely ,&nbsp;Jacqueline Stöckli ,&nbsp;James G. Burchfield ,&nbsp;David E. James","doi":"10.1016/j.molmet.2024.101983","DOIUrl":"10.1016/j.molmet.2024.101983","url":null,"abstract":"<div><p>Mitochondria facilitate thousands of biochemical reactions, covering a broad spectrum of anabolic and catabolic processes. Here we demonstrate that the adipocyte mitochondrial proteome is markedly altered across multiple models of insulin resistance and reveal a consistent decrease in the level of the mitochondrial processing peptidase miPEP.</p></div><div><h3>Objective</h3><p>To determine the role of miPEP in insulin resistance.</p></div><div><h3>Methods</h3><p>To experimentally test this observation, we generated adipocyte-specific miPEP knockout mice to interrogate its role in the aetiology of insulin resistance.</p></div><div><h3>Results</h3><p>We observed a strong phenotype characterised by enhanced insulin sensitivity and reduced adiposity, despite normal food intake and physical activity. Strikingly, these phenotypes vanished when mice were housed at thermoneutrality, suggesting that metabolic protection conferred by miPEP deletion hinges upon a thermoregulatory process. Tissue specific analysis of miPEP deficient mice revealed an increment in muscle metabolism, and upregulation of the protein FBP2 that is involved in ATP hydrolysis in the gluconeogenic pathway.</p></div><div><h3>Conclusion</h3><p>These findings suggest that miPEP deletion initiates a compensatory increase in skeletal muscle metabolism acting as a protective mechanism against diet-induced obesity and insulin resistance.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"86 ","pages":"Article 101983"},"PeriodicalIF":7.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001145/pdfft?md5=1611a0194364d36b5468c6e2cfbb73bc&pid=1-s2.0-S2212877824001145-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141498447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NCLX controls hepatic mitochondrial Ca2+ extrusion and couples hormone-mediated mitochondrial Ca2+ oscillations with gluconeogenesis","authors":"","doi":"10.1016/j.molmet.2024.101982","DOIUrl":"10.1016/j.molmet.2024.101982","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Objective&lt;/h3&gt;&lt;p&gt;Hepatic Ca&lt;sup&gt;2+&lt;/sup&gt; signaling has been identified as a crucial key factor in driving gluconeogenesis. The involvement of mitochondria in hormone-induced Ca&lt;sup&gt;2+&lt;/sup&gt; signaling and their contribution to metabolic activity remain, however, poorly understood. Moreover, the molecular mechanism governing the mitochondrial Ca&lt;sup&gt;2+&lt;/sup&gt; efflux signaling remains unresolved. This study investigates the role of the Na&lt;sup&gt;+&lt;/sup&gt;/Ca&lt;sup&gt;2+&lt;/sup&gt; exchanger, NCLX, in modulating hepatic mitochondrial Ca&lt;sup&gt;2+&lt;/sup&gt; efflux, and examines its physiological significance in hormonal hepatic Ca&lt;sup&gt;2+&lt;/sup&gt; signaling, gluconeogenesis, and mitochondrial bioenergetics.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;Primary mouse hepatocytes from both an AAV-mediated conditional hepatic-specific and a total mitochondrial Na&lt;sup&gt;+&lt;/sup&gt;/Ca&lt;sup&gt;2+&lt;/sup&gt; exchanger, NCLX, knockout (KO) mouse models were employed for fluorescent monitoring of purinergic and glucagon/vasopressin-dependent mitochondrial and cytosolic hepatic Ca&lt;sup&gt;2+&lt;/sup&gt; responses in cultured hepatocytes. Isolated liver mitochondria and permeabilized primary hepatocytes were used to analyze the ion-dependence of Ca&lt;sup&gt;2+&lt;/sup&gt; efflux. Utilizing the conditional hepatic-specific NCLX KO model, the rate of gluconeogenesis was assessed by first monitoring glucose levels in fasted mice, and subsequently subjecting the mice to a pyruvate tolerance test while monitoring their blood glucose. Additionally, cultured primary hepatocytes from both genotypes were assessed in vitro for glucagon-dependent glucose production and cellular bioenergetics through glucose oxidase assay and Seahorse respirometry, respectively.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;Analysis of Ca&lt;sup&gt;2+&lt;/sup&gt; responses in isolated liver mitochondria and cultured primary hepatocytes from NCLX KO versus WT mice showed that NCLX serves as the principal mechanism for mitochondrial calcium extrusion in hepatocytes. We then determined the role of NCLX in glucagon and vasopressin-induced Ca&lt;sup&gt;2+&lt;/sup&gt; oscillations. Consistent with previous studies, glucagon and vasopressin triggered Ca&lt;sup&gt;2+&lt;/sup&gt; oscillations in WT hepatocytes, however, the deletion of NCLX resulted in selective elimination of mitochondrial, but not cytosolic, Ca&lt;sup&gt;2+&lt;/sup&gt; oscillations, underscoring NCLX’s pivotal role in mitochondrial Ca&lt;sup&gt;2+&lt;/sup&gt; regulation. Subsequent &lt;em&gt;in vivo&lt;/em&gt; investigation for hepatic NCLX role in gluconeogenesis revealed that, as opposed to WT mice which maintained normoglycemic blood glucose levels when fasted, conditional hepatic-specific NCLX KO mice exhibited a faster drop in glucose levels, becoming hypoglycemic. Furthermore, KO mice showed deficient conversion of pyruvate to glucose when challenged under fasting conditions. Concurrent in vitro assessments showed impaired glucagon-dependent glucose production and compromised bioenergetics in KO hepatocytes, thereby underscoring NCLX’s significant contribution to hepatic g","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"87 ","pages":"Article 101982"},"PeriodicalIF":7.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001133/pdfft?md5=6b639add38baebbd2358b5662dd32bf2&pid=1-s2.0-S2212877824001133-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141498448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Skeletal muscle BMAL1 is necessary for transcriptional adaptation of local and peripheral tissues in response to endurance exercise training","authors":"Mark R. Viggars ,&nbsp;Hannah E. Berko ,&nbsp;Stuart J. Hesketh ,&nbsp;Christopher A. Wolff ,&nbsp;Miguel A. Gutierrez-Monreal ,&nbsp;Ryan A. Martin ,&nbsp;Isabel G. Jennings ,&nbsp;Zhiguang Huo ,&nbsp;Karyn A. Esser","doi":"10.1016/j.molmet.2024.101980","DOIUrl":"10.1016/j.molmet.2024.101980","url":null,"abstract":"<div><h3>Objective</h3><p>In this investigation, we addressed the contribution of the core circadian clock factor, BMAL1, in skeletal muscle to both acute transcriptional responses to exercise and transcriptional remodeling in response to exercise training. Additionally, we adopted a systems biology approach to investigate how loss of skeletal muscle BMAL1 altered peripheral tissue homeostasis as well as exercise training adaptations in iWAT, liver, heart, and lung of male mice.</p></div><div><h3>Methods</h3><p>Combining inducible skeletal muscle specific BMAL1 knockout mice, physiological testing and standardized exercise protocols, we performed a multi-omic analysis (transcriptomics, chromatin accessibility and metabolomics) to explore loss of muscle BMAL1 on muscle and peripheral tissue responses to exercise.</p></div><div><h3>Results</h3><p>Muscle-specific BMAL1 knockout mice demonstrated a blunted transcriptional response to acute exercise, characterized by the lack of upregulation of well-established exercise responsive transcription factors including <em>Nr4a3</em> and <em>Ppargc1a</em>. Six weeks of exercise training in muscle-specific BMAL1 knockout mice induced significantly greater and divergent transcriptomic and metabolomic changes in muscle. Surprisingly, liver, lung, inguinal white adipose and heart showed divergent exercise training transcriptomes with less than 5% of ‘exercise-training’ responsive genes shared for each tissue between genotypes.</p></div><div><h3>Conclusions</h3><p>Our investigation has uncovered the critical role that BMAL1 plays in skeletal muscle as a key regulator of gene expression programs for both acute exercise and training adaptations. In addition, our work has uncovered the significant impact that altered exercise response in muscle and its likely impact on the system plays in the peripheral tissue adaptations to exercise training. Our work also demonstrates that if the muscle adaptations diverge to a more maladaptive state this is linked to increased gene expression signatures of inflammation across many tissues. Understanding the molecular targets and pathways contributing to health vs. maladaptive exercise adaptations will be critical for the next stage of therapeutic design for exercise mimetics.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"86 ","pages":"Article 101980"},"PeriodicalIF":7.0,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221287782400111X/pdfft?md5=88526c8a3dc6bd2e4027ac2abedbec13&pid=1-s2.0-S221287782400111X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Super-enhancer-driven LncRNA PPARα-seRNA exacerbates glucolipid metabolism and diabetic cardiomyopathy via recruiting KDM4B","authors":"Xiaozhu Ma ,&nbsp;Shuai Mei ,&nbsp;Qidamugai Wuyun ,&nbsp;Li Zhou ,&nbsp;Ziyang Cai ,&nbsp;Hu Ding ,&nbsp;Jiangtao Yan","doi":"10.1016/j.molmet.2024.101978","DOIUrl":"10.1016/j.molmet.2024.101978","url":null,"abstract":"<div><h3>Objective</h3><p>Aberrant glucolipid metabolism in the heart is a characteristic factor in diabetic cardiomyopathy (DbCM). Super-enhancers-driven noncoding RNAs (seRNAs) are emerging as powerful regulators in the progression of cardiac diseases. However, the functions of seRNAs in DbCM have not been fully elucidated.</p></div><div><h3>Methods</h3><p>Super enhancers and their associated seRNAs were screened and identified by H3K27ac ChIP-seq data in the Encyclopedia of DNA Elements (ENCODE) dataset. A dual-luciferase reporter assay was performed to analyze the function of super-enhancers on the transcription of peroxisome proliferator-activated receptor α-related seRNA (<em>PPARα-seRNA</em>). A DbCM mouse model was established using db/db leptin receptor-deficient mice. Adeno-associated virus serotype 9-seRNA (AAV9-seRNA) was injected via the tail vein to evaluate the role of seRNA in DbCM. The underlying mechanism was explored through RNA pull-down, RNA and chromatin immunoprecipitation, and chromatin isolation by RNA purification.</p></div><div><h3>Results</h3><p><em>PPARα-seRNA</em> was regulated by super-enhancers and its levels were increased in response to high glucose and palmitic acid stimulation in cardiomyocytes. Functionally, <em>PPARα-seRNA</em> overexpression aggravated lipid deposition, reduced glucose uptake, and repressed energy production. In contrast, <em>PPARα-seRNA</em> knockdown ameliorated metabolic disorder <em>in vitro</em>. <em>In vivo</em>, overexpression of <em>PPARα-seRNA</em> exacerbated cardiac metabolic disorder and deteriorated cardiac dysfunction, myocardial fibrosis, and hypertrophy in DbCM. Mechanistically, <em>PPARα-seRNA</em> bound to the histone demethylase KDM4B (Lysine-specific demethylase 4B) and decreased H3K9me3 levels in the promoter region of PPARα<em>,</em> ultimately enhancing its transcription.</p></div><div><h3>Conclusions</h3><p>Our study revealed the pivotal function of a super-enhancer-driven long noncoding RNA (lncRNA), <em>PPARα-seRNA</em>, in the deterioration of cardiac function and the exacerbation of metabolic abnormalities in diabetic cardiomyopathy, which recruited KDM4B to the promoter region of PPARα and repression of its transcription. This suggests a promising therapeutic strategy for the treatment of DbCM.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"86 ","pages":"Article 101978"},"PeriodicalIF":7.0,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001091/pdfft?md5=bbd7fc74961fa2b6134576c5e0b5ff6a&pid=1-s2.0-S2212877824001091-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of somatostatin enhances the long-term metabolic outcomes of sleeve gastrectomy in mice","authors":"Doron Kleiman ,&nbsp;Yhara Arad ,&nbsp;Shira Azulai ,&nbsp;Aaron Baker ,&nbsp;Michael Bergel ,&nbsp;Amit Elad ,&nbsp;Arnon Haran ,&nbsp;Liron Hefetz ,&nbsp;Hadar Israeli ,&nbsp;Mika Littor ,&nbsp;Anna Permyakova ,&nbsp;Itia Samuel ,&nbsp;Joseph Tam ,&nbsp;Rachel Ben-Haroush Schyr ,&nbsp;Danny Ben-Zvi","doi":"10.1016/j.molmet.2024.101979","DOIUrl":"10.1016/j.molmet.2024.101979","url":null,"abstract":"<div><h3>Objective</h3><p>Bariatric surgery is an effective treatment to obesity, leading to weight loss and improvement in glycemia, that is characterized by hypersecretion of gastrointestinal hormones. However, weight regain and relapse of hyperglycemia are not uncommon. We set to identify mechanisms that can enhance gastrointestinal hormonal secretion following surgery to sustain weight loss.</p></div><div><h3>Methods</h3><p>We investigated the effect of somatostatin (Sst) inhibition on the outcomes of bariatric surgery using a mouse model of sleeve gastrectomy (SG).</p></div><div><h3>Results</h3><p>Sst knockout (sst-ko) mice fed with a calorie-rich diet gained weight normally and had a mild favorable metabolic phenotype compared to heterozygous sibling controls, including elevated plasma levels of GLP-1. Mathematical modeling of the feedback inhibition between Sst and GLP-1 showed that Sst exerts its maximal effect on GLP-1 under conditions of high hormonal stimulation, such as following SG. Obese sst-ko mice that underwent SG had higher levels of GLP-1 compared with heterozygous SG-operated controls. The SG-sst-ko mice regained less weight than controls and maintained lower glycemia months after surgery. Obese wild-type mice that underwent SG and were treated daily with a Sst receptor inhibitor for two months had higher GLP-1 levels, regained less weight, and improved metabolic profile compared to saline-treated SG-operated controls, and compared to inhibitor or saline-treated sham-operated obese mice.</p></div><div><h3>Conclusions</h3><p>Our results suggest that inhibition of Sst signaling enhances the long-term favorable metabolic outcomes of bariatric surgery.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"86 ","pages":"Article 101979"},"PeriodicalIF":7.0,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001108/pdfft?md5=ea10dd6d430fd4ceed38d38d2535f9c6&pid=1-s2.0-S2212877824001108-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver matrin-3 protects mice against hepatic steatosis and stress response via constitutive androstane receptor","authors":"Xiao Cheng ,&nbsp;Vijaya Bhaskar Baki ,&nbsp;Matthew Moran ,&nbsp;Baolong Liu ,&nbsp;Jiujiu Yu ,&nbsp;Miaoyun Zhao ,&nbsp;Qingsheng Li ,&nbsp;Jean-Jack Riethoven ,&nbsp;Channabasavaiah B. Gurumurth ,&nbsp;Edward N. Harris ,&nbsp;Xinghui Sun","doi":"10.1016/j.molmet.2024.101977","DOIUrl":"10.1016/j.molmet.2024.101977","url":null,"abstract":"<div><h3>Objective</h3><p>The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise with the increasing obesity epidemic. Rezdiffra as an activator of a thyroid hormone receptor-beta is the only Food and Drug Administration approved therapy. As such, there is a critical need to improve our understanding of gene expression regulation and signaling transduction in MASLD to develop new therapies. Matrin-3 is a DNA- and RNA-binding protein involved in the pathogenesis of human diseases. Here we examined its previously uncharacterized role in limiting hepatic steatosis and stress response via the constitutive androstane receptor (CAR).</p></div><div><h3>Methods</h3><p>Matrin-3 floxed and liver-specific knockout mice were fed either a chow diet or 60 kcal% high-fat diet (HFD) for up to 16 weeks. The mice were euthanized for different analysis including liver histology, lipid levels, and gene expression. Bulk RNA-seq, bulk ATAC-seq, and single-nucleus Multiome were used to examine changes of transcriptome and chromatin accessibility in the liver. Integrative bioinformatics analysis of our data and publicly available datasets and different biochemical assays were performed to identify underlying the molecular mechanisms mediating matrin-3's effects. Liver-tropic adeno-associated virus was used to restore the expression of CAR for lipid, acute phase genes, and histological analysis.</p></div><div><h3>Results</h3><p>Matrin-3 expression is induced in the steatotic livers of mice. Liver-specific matrin-3 deletion exacerbated HFD-induced steatosis, acute phase response, and inflammation in the liver of female mice. The transcriptome and chromatin accessibility were re-programmed in the liver of these mice with signatures indicating that CAR signaling is dysregulated. Mechanistically, matrin-3 interacts with CAR mRNA, and matrin-3 deficiency promotes CAR mRNA degradation. Consequently, matrin-3 deletion impaired CAR signaling by reducing CAR expression. Matrin-3 levels positively correlate with CAR expression in human livers. Ces2a and Il1r1 were identified as new target genes of CAR. Interestingly, we found that CAR discords with the expression of its target genes including Cyp2b10 and Ces2a in response to HFD, indicating CAR signaling is dysregulated by HFD despite increased CAR expression. Dysregulated CAR signaling upon matrin-3 deficiency reduced Ces2a and de-repressed Il1r1 expression. CAR restoration partially abrogated the dysregulated gene expression, exacerbated hepatic steatosis, acute phase response, and inflammation in liver-specific matrin-3 knockout mice fed a HFD.</p></div><div><h3>Conclusions</h3><p>Our findings demonstrate that matrin-3 is a key upstream regulator maintaining CAR signaling upon metabolic stress, and the matrin-3-CAR axis limits hepatic steatosis and stress response signaling that may give insights for therapeutic intervention.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"86 ","pages":"Article 101977"},"PeriodicalIF":7.0,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221287782400108X/pdfft?md5=b77dc703bcace9c98e32940e143eecce&pid=1-s2.0-S221287782400108X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sphingosine kinase 2 and p62 regulation are determinants of sexual dimorphism in hepatocellular carcinoma","authors":"Christopher D. Green ,&nbsp;Ryan D.R. Brown ,&nbsp;Baasanjav Uranbileg ,&nbsp;Cynthia Weigel ,&nbsp;Sumit Saha ,&nbsp;Makoto Kurano ,&nbsp;Yutaka Yatomi ,&nbsp;Sarah Spiegel","doi":"10.1016/j.molmet.2024.101971","DOIUrl":"10.1016/j.molmet.2024.101971","url":null,"abstract":"<div><h3>Objective</h3><p>Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality, and its incidence is increasing due to endemic obesity. HCC is sexually dimorphic in both humans and rodents with higher incidence in males, although the mechanisms contributing to these correlations remain unclear. Here, we examined the role of sphingosine kinase 2 (SphK2), the enzyme that regulates the balance of bioactive sphingolipid metabolites, sphingosine-1-phosphate (S1P) and ceramide, in gender specific MASH-driven HCC.</p></div><div><h3>Methods</h3><p>Male and female mice were fed a high fat diet with sugar water, a clinically relevant model that recapitulates MASH-driven HCC in humans followed by physiological, biochemical cellular and molecular analyses. In addition, correlations with increased risk of HCC recurrence were determined in patients.</p></div><div><h3>Results</h3><p>Here, we report that deletion of SphK2 protects both male and female mice from Western diet-induced weight gain and metabolic dysfunction without affecting hepatic lipid accumulation or fibrosis. However, SphK2 deficiency decreases chronic diet-induced hepatocyte proliferation in males but increases it in females. Remarkably, SphK2 deficiency reverses the sexual dimorphism of HCC, as SphK2^−/− male mice are protected whereas the females develop liver cancer. Only in male mice, chronic western diet induced accumulation of the autophagy receptor p62 and its downstream mediators, the antioxidant response target NQO1, and the oncogene c-Myc. SphK2 deletion repressed these known drivers of HCC development. Moreover, high p62 expression correlates with poor survival in male HCC patients but not in females. In hepatocytes, lipotoxicity-induced p62 accumulation is regulated by sex hormones and prevented by SphK2 deletion. Importantly, high SphK2 expression in male but not female HCC patients is associated with a more aggressive HCC differentiation status and increased risk of cancer recurrence.</p></div><div><h3>Conclusions</h3><p>This work identifies SphK2 as a potential regulator of HCC sexual dimorphism and suggests SphK2 inhibitors now in clinical trials could have opposing, gender-specific effects in patients.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"86 ","pages":"Article 101971"},"PeriodicalIF":7.0,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001029/pdfft?md5=2a1ec55c7d5849dc7d2af6fd26836662&pid=1-s2.0-S2212877824001029-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Muscle weakness and mitochondrial stress occur before severe metastasis in a novel mouse model of ovarian cancer cachexia","authors":"Luca J. Delfinis ,&nbsp;Leslie M. Ogilvie ,&nbsp;Shahrzad Khajehzadehshoushtar ,&nbsp;Shivam Gandhi ,&nbsp;Madison C. Garibotti ,&nbsp;Arshdeep K. Thuhan ,&nbsp;Kathy Matuszewska ,&nbsp;Madison Pereira ,&nbsp;Ronald G. Jones III ,&nbsp;Arthur J. Cheng ,&nbsp;Thomas J. Hawke ,&nbsp;Nicholas P. Greene ,&nbsp;Kevin A. Murach ,&nbsp;Jeremy A. Simpson ,&nbsp;Jim Petrik ,&nbsp;Christopher G.R. Perry","doi":"10.1016/j.molmet.2024.101976","DOIUrl":"10.1016/j.molmet.2024.101976","url":null,"abstract":"<div><h3>Objectives</h3><p>A high proportion of women with advanced epithelial ovarian cancer (EOC) experience weakness and cachexia. This relationship is associated with increased morbidity and mortality. EOC is the most lethal gynecological cancer, yet no preclinical cachexia model has demonstrated the combined hallmark features of metastasis, ascites development, muscle loss and weakness in adult immunocompetent mice.</p></div><div><h3>Methods</h3><p>Here, we evaluated a new model of ovarian cancer-induced cachexia with the advantages of inducing cancer in adult immunocompetent C57BL/6J mice through orthotopic injections of EOC cells in the ovarian bursa. We characterized the development of metastasis, ascites, muscle atrophy, muscle weakness, markers of inflammation, and mitochondrial stress in the tibialis anterior (TA) and diaphragm ∼45, ∼75 and ∼90 days after EOC injection.</p></div><div><h3>Results</h3><p>Primary ovarian tumour sizes were progressively larger at each time point while severe metastasis, ascites development, and reductions in body, fat and muscle weights occurred by 90 Days. There were no changes in certain inflammatory (TNFα), atrogene (MURF1 and Atrogin) or GDF15 markers within both muscles whereas IL-6 was increased at 45 and 90 Day groups in the diaphragm. TA weakness in 45 Day preceded atrophy and metastasis that were observed later (75 and 90 Day, respectively). The diaphragm demonstrated both weakness and atrophy in 45 Day. In both muscles, this pre-severe-metastatic muscle weakness corresponded with considerable reprogramming of gene pathways related to mitochondrial bioenergetics as well as reduced functional measures of mitochondrial pyruvate oxidation and creatine-dependent ADP/ATP cycling as well as increased reactive oxygen species emission (hydrogen peroxide). Remarkably, muscle force per unit mass at 90 days was partially restored in the TA despite the presence of atrophy and severe metastasis. In contrast, the diaphragm demonstrated progressive weakness. At this advanced stage, mitochondrial pyruvate oxidation in both muscles exceeded control mice suggesting an apparent metabolic super-compensation corresponding with restored indices of creatine-dependent adenylate cycling.</p></div><div><h3>Conclusions</h3><p>This mouse model demonstrates the concurrent development of cachexia and metastasis that occurs in women with EOC. The model provides physiologically relevant advantages of inducing tumour development within the ovarian bursa in immunocompetent adult mice. Moreover, the model reveals that muscle weakness in both TA and diaphragm precedes severe metastasis while weakness also precedes atrophy in the TA. An underlying mitochondrial bioenergetic stress corresponded with this early weakness. Collectively, these discoveries can direct new research towards the development of therapies that target pre-atrophy and pre-severe-metastatic weakness during EOC in addition to therapies targeting cachexia.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"86 ","pages":"Article 101976"},"PeriodicalIF":7.0,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001078/pdfft?md5=c0d8d7541833da254a52f99ca274ba80&pid=1-s2.0-S2212877824001078-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypothalamic AgRP neurons regulate the hyperphagia of lactation","authors":"Kerem Catalbas ,&nbsp;Tanya Pattnaik ,&nbsp;Samuel Congdon ,&nbsp;Christina Nelson ,&nbsp;Lara C. Villano ,&nbsp;Patrick Sweeney","doi":"10.1016/j.molmet.2024.101975","DOIUrl":"10.1016/j.molmet.2024.101975","url":null,"abstract":"<div><h3>Objective</h3><p>The lactational period is associated with profound hyperphagia to accommodate the energy demands of nursing. These changes are important for the long-term metabolic health of the mother and children as altered feeding during lactation increases the risk of mothers and offspring developing metabolic disorders later in life. However, the specific behavioral mechanisms and neural circuitry mediating the hyperphagia of lactation are incompletely understood.</p></div><div><h3>Methods</h3><p>Here, we utilized home cage feeding devices to characterize the dynamics of feeding behavior in lactating mice. A combination of pharmacological and behavioral assays were utilized to determine how lactation alters meal structure, circadian aspects of feeding, hedonic feeding, and sensitivity to hunger and satiety signals in lactating mice. Finally, we utilized chemogenetic, immunohistochemical, and <em>in vivo</em> imaging approaches to characterize the role of hypothalamic agouti-related peptide (AgRP) neurons in lactational-hyperphagia.</p></div><div><h3>Results</h3><p>The lactational period is associated with increased meal size, altered circadian patterns of feeding, reduced sensitivity to gut-brain satiety signals, and enhanced sensitivity to negative energy balance. Hypothalamic AgRP neurons display increased sensitivity to negative energy balance and altered <em>in vivo</em> activity during the lactational state. Further, using <em>in vivo</em> imaging approaches we demonstrate that AgRP neurons are directly activated by lactation. Chemogenetic inhibition of AgRP neurons acutely reduces feeding in lactating mice, demonstrating an important role for these neurons in lactational-hyperphagia.</p></div><div><h3>Conclusions</h3><p>Together, these results show that lactation collectively alters multiple components of feeding behavior and position AgRP neurons as an important cellular substrate mediating the hyperphagia of lactation.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"86 ","pages":"Article 101975"},"PeriodicalIF":7.0,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001066/pdfft?md5=c4cda39552da33ed6b9e889ae1e6b8ab&pid=1-s2.0-S2212877824001066-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Effect of astaxanthin in type-2 diabetes -induced APPxhQC transgenic and NTG mice” [MOLMET 85 (2024) 1–16]","authors":"Joshua Adekunle Babalola ,&nbsp;Anika Stracke ,&nbsp;Tina Loeffler ,&nbsp;Irene Schilcher ,&nbsp;Spyridon Sideromenos ,&nbsp;Stefanie Flunkert ,&nbsp;Joerg Neddens ,&nbsp;Ake Lignell ,&nbsp;Manuela Prokesch ,&nbsp;Ute Panzenboeck ,&nbsp;Herbert Strobl ,&nbsp;Jelena Tadic ,&nbsp;Gerd Leitinger ,&nbsp;Achim Lass ,&nbsp;Birgit Hutter-Paier ,&nbsp;Gerald Hoefler","doi":"10.1016/j.molmet.2024.101972","DOIUrl":"10.1016/j.molmet.2024.101972","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"86 ","pages":"Article 101972"},"PeriodicalIF":7.0,"publicationDate":"2024-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001030/pdfft?md5=c6a54d99be99dfec473b6b60ab8245c7&pid=1-s2.0-S2212877824001030-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}