Molecular Metabolism最新文献

{"title":"Dietary medium-chain fatty acids reduce hepatic fat accumulation via activation of a CREBH-FGF21 axis","authors":"Ye Cao ,&nbsp;Masaya Araki ,&nbsp;Yoshimi Nakagawa ,&nbsp;Luisa Deisen ,&nbsp;Annemarie Lundsgaard ,&nbsp;Josephine M. Kanta ,&nbsp;Stephanie Holm ,&nbsp;Kornelia Johann ,&nbsp;Jens Christian Brings Jacobsen ,&nbsp;Markus Jähnert ,&nbsp;Annette Schürmann ,&nbsp;Bente Kiens ,&nbsp;Christoffer Clemmensen ,&nbsp;Hitoshi Shimano ,&nbsp;Andreas M. Fritzen ,&nbsp;Maximilian Kleinert","doi":"10.1016/j.molmet.2024.101991","DOIUrl":"10.1016/j.molmet.2024.101991","url":null,"abstract":"<div><h3>Objective</h3><p>Dietary medium-chain fatty acids (MCFAs), characterized by chain lengths of 8–12 carbon atoms, have been proposed to have beneficial effects on glucose and lipid metabolism, yet the underlying mechanisms remain elusive. We hypothesized that MCFA intake benefits metabolic health by inducing the release of hormone-like factors.</p></div><div><h3>Methods</h3><p>The effects of chow diet, high-fat diet rich in long-chain fatty acids (LCFA HFD) fed <em>ad libitum</em> or pair-fed to a high-fat diet rich in MCFA (MCFA HFD) on glycemia, hepatic gene expression, circulating fibroblast growth factor 21 (FGF21), and liver fat content in both wildtype and <em>Fgf21</em> knockout mice were investigated. The impact of a single oral dose of an MCFA-rich oil on circulating FGF21 and hepatic <em>Fgf21</em> mRNA expression was assessed. In flag-tagged <em>Crebh</em> knockin mice and liver-specific <em>Crebh</em> knockout mice, fed LCFA HFD or MCFA HFD, active hepatic CREBH and hepatic <em>Fgf21</em> mRNA abundance were determined, respectively.</p></div><div><h3>Results</h3><p>MCFA HFD improves glucose tolerance, enhances glucose clearance into brown adipose tissue, and prevents high-fat diet-induced hepatic steatosis in wildtype mice. These benefits are associated with increased liver expression of CREBH target genes (<em>Apoa4</em> and <em>Apoc2</em>), including <em>Fgf21</em>. Both acute and chronic intake of dietary MCFAs elevate circulating FGF21. Augmented hepatic <em>Fgf21</em> mRNA following MCFA HFD intake is accompanied by higher levels of active hepatic CREBH; and MCFA-induced hepatic <em>Fgf21</em> expression is blocked in mice lacking <em>Crebh</em>. Notably, while feeding male and female <em>Fgf21</em> wildtype mice MCFA HFD results in reduced liver triacylglycerol (TG) levels, this liver TG-lowering effect is blunted in <em>Fgf21</em> knockout mice fed MCFA HFD. The reduction in liver TG levels observed with MCFA HFD was independent of weight loss.</p></div><div><h3>Conclusions</h3><p>Dietary MCFAs reduce liver fat accumulation via activation of a CREBH-FGF21 signaling axis.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"87 ","pages":"Article 101991"},"PeriodicalIF":7.0,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001224/pdfft?md5=52ef2cbb83387512b81a39ae57f11b35&pid=1-s2.0-S2212877824001224-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633955","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":"Experimental colonization with H. hepaticus, S. aureus and R. pneumotropicus does not influence the metabolic response to high-fat diet or incretin-analogues in wildtype SOPF mice","authors":"Margit Wunderlich ,&nbsp;Manuel Miller ,&nbsp;Bärbel Ritter ,&nbsp;Ronan Le Gleut ,&nbsp;Hannah Marchi ,&nbsp;Monir Majzoub-Altweck ,&nbsp;Patrick J. Knerr ,&nbsp;Jonathan D. Douros ,&nbsp;Timo D. Müller ,&nbsp;Markus Brielmeier","doi":"10.1016/j.molmet.2024.101992","DOIUrl":"10.1016/j.molmet.2024.101992","url":null,"abstract":"<div><h3>Objectives</h3><p>We here assessed whether typical pathogens of laboratory mice affect the development of diet-induced obesity and glucose intolerance, and whether colonization affects the efficacy of the GLP-1R agonist liraglutide and of the GLP-1/GIP co-agonist MAR709 to treat obesity and diabetes.</p></div><div><h3>Methods</h3><p>Male C57BL/6J mice were experimentally infected with <em>Helicobacter hepaticus, Rodentibacter pneumotropicus</em> and <em>Staphylococcus aureus</em> and compared to a group of uninfected specific and opportunistic pathogen free (SOPF) mice. The development of diet-induced obesity and glucose intolerance was monitored over a period of 26 weeks. To study the influence of pathogens on drug treatment, mice were then subjected for 6 days daily treatment with either the GLP-1 receptor agonist liraglutide or the GLP-1/GIP co-agonist MAR709.</p></div><div><h3>Results</h3><p>Colonized mice did not differ from SOPF controls regarding HFD-induced body weight gain, food intake, body composition, glycemic control, or responsiveness to treatment with liraglutide or the GLP-1/GIP co-agonist MAR709.</p></div><div><h3>Conclusions</h3><p>We conclude that the occurrence of <em>H. hepaticus</em>, <em>R. pneumotropicus</em> and <em>S. aureus</em> does neither affect the development of diet-induced obesity or type 2 diabetes, nor the efficacy of GLP-1-based drugs to decrease body weight and to improve glucose control in mice.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"87 ","pages":"Article 101992"},"PeriodicalIF":7.0,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001236/pdfft?md5=5eb33fd2a3fbf2eb99e1d3f861ef6797&pid=1-s2.0-S2212877824001236-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633956","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":"Cathepsin D is essential for the degradomic shift of macrophages required to resolve liver fibrosis","authors":"Paloma Ruiz-Blázquez ,&nbsp;María Fernández-Fernández ,&nbsp;Valeria Pistorio ,&nbsp;Celia Martinez-Sanchez ,&nbsp;Michele Costanzo ,&nbsp;Paula Iruzubieta ,&nbsp;Ekaterina Zhuravleva ,&nbsp;Júlia Cacho-Pujol ,&nbsp;Silvia Ariño ,&nbsp;Alejandro Del Castillo-Cruz ,&nbsp;Susana Núñez ,&nbsp;Jesper B. Andersen ,&nbsp;Margherita Ruoppolo ,&nbsp;Javier Crespo ,&nbsp;Carmen García-Ruiz ,&nbsp;Luigi Michele Pavone ,&nbsp;Thomas Reinheckel ,&nbsp;Pau Sancho-Bru ,&nbsp;Mar Coll ,&nbsp;José C. Fernández-Checa ,&nbsp;Anna Moles","doi":"10.1016/j.molmet.2024.101989","DOIUrl":"10.1016/j.molmet.2024.101989","url":null,"abstract":"<div><h3>Background and objectives</h3><p>Fibrosis contributes to 45% of deaths in industrialized nations and is characterized by an abnormal accumulation of extracellular matrix (ECM). There are no specific anti-fibrotic treatments for liver fibrosis, and previous unsuccessful attempts at drug development have focused on preventing ECM deposition. Because liver fibrosis is largely acknowledged to be reversible, regulating fibrosis resolution could offer novel therapeutical options. However, little is known about the mechanisms controlling ECM remodeling during resolution. Changes in proteolytic activity are essential for ECM homeostasis and macrophages are an important source of proteases. Herein, in this study we evaluate the role of macrophage-derived cathepsin D (CtsD) during liver fibrosis.</p></div><div><h3>Methods</h3><p>CtsD expression and associated pathways were characterized in single-cell RNA sequencing and transcriptomic datasets in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD and hepatocyte-CtsD knock-out mice.</p></div><div><h3>Results</h3><p>Analysis of single-cell RNA sequencing datasets demonstrated CtsD was expressed in macrophages and hepatocytes in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD (CtsD^ΔMyel) and hepatocyte-CtsD knock-out mice. CtsD deletion in macrophages, but not in hepatocytes, resulted in enhanced liver fibrosis. Both inflammatory and matrisome proteomic signatures were enriched in fibrotic CtsD^ΔMyel livers. Besides, CtsD^ΔMyel liver macrophages displayed functional, phenotypical and secretomic changes, which resulted in a degradomic phenotypical shift, responsible for the defective proteolytic processing of collagen I <em>in vitro</em> and impaired collagen remodeling during fibrosis resolution <em>in vivo</em>. Finally, CtsD-expressing mononuclear phagocytes of cirrhotic human livers were enriched in lysosomal and ECM degradative signaling pathways.</p></div><div><h3>Conclusions</h3><p>Our work describes for the first-time CtsD-driven lysosomal activity as a central hub for restorative macrophage function during fibrosis resolution and opens new avenues to explore their degradome landscape to inform drug development.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"87 ","pages":"Article 101989"},"PeriodicalIF":7.0,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001200/pdfft?md5=195eb12d948ef506074c6bad3375be3b&pid=1-s2.0-S2212877824001200-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633954","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":"RIPK1 is dispensable for cell death regulation in β-cells during hyperglycemia","authors":"Önay Veli ,&nbsp;Öykü Kaya ,&nbsp;Ana Beatriz Varanda ,&nbsp;Ximena Hildebrandt ,&nbsp;Peng Xiao ,&nbsp;Yann Estornes ,&nbsp;Matea Poggenberg ,&nbsp;Yuan Wang ,&nbsp;Manolis Pasparakis ,&nbsp;Mathieu J.M. Bertrand ,&nbsp;Henning Walczak ,&nbsp;Alessandro Annibaldi ,&nbsp;Alessandra K. Cardozo ,&nbsp;Nieves Peltzer","doi":"10.1016/j.molmet.2024.101988","DOIUrl":"10.1016/j.molmet.2024.101988","url":null,"abstract":"<div><h3>Objective</h3><p>Receptor-interacting protein kinase 1 (RIPK1) orchestrates the decision between cell survival and cell death in response to tumor necrosis factor (TNF) and other cytokines. Whereas the scaffolding function of RIPK1 is crucial to prevent TNF-induced apoptosis and necroptosis, its kinase activity is required for necroptosis and partially for apoptosis. Although TNF is a proinflammatory cytokine associated with β-cell loss in diabetes, the mechanism by which TNF induces β-cell demise remains unclear.</p></div><div><h3>Methods</h3><p>Here, we dissected the contribution of RIPK1 scaffold versus kinase functions to β-cell death regulation using mice lacking RIPK1 specifically in β-cells (<em>Ripk1</em>^{<em>β-KO</em>} mice) or expressing a kinase-dead version of RIPK1 (<em>Ripk1</em>^{<em>D138N</em>} mice), respectively. These mice were challenged with streptozotocin, a model of autoimmune diabetes. Moreover, <em>Ripk1</em>^{<em>β-KO</em>} mice were further challenged with a high-fat diet to induce hyperglycemia. For mechanistic studies, pancreatic islets were subjected to various killing and sensitising agents.</p></div><div><h3>Results</h3><p>Inhibition of RIPK1 kinase activity (<em>Ripk1</em>^{<em>D138N</em>} mice) did not affect the onset and progression of hyperglycemia in a type 1 diabetes model. Moreover, the absence of RIPK1 expression in β-cells did not affect normoglycemia under basal conditions or hyperglycemia under diabetic challenges. <em>Ex vivo</em>, primary pancreatic islets are not sensitised to TNF-induced apoptosis and necroptosis in the absence of RIPK1. Intriguingly, we found that pancreatic islets display high levels of the antiapoptotic cellular FLICE-inhibitory protein (cFLIP) and low levels of apoptosis (Caspase-8) and necroptosis (RIPK3) components. Cycloheximide treatment, which led to a reduction in cFLIP levels, rendered primary islets sensitive to TNF-induced cell death which was fully blocked by caspase inhibition.</p></div><div><h3>Conclusions</h3><p>Unlike in many other cell types (e.g., epithelial, and immune), RIPK1 is not required for cell death regulation in β-cells under physiological conditions or diabetic challenges. Moreover, <em>in vivo</em> and <em>in vitro</em> evidence suggest that pancreatic β-cells do not undergo necroptosis but mainly caspase-dependent death in response to TNF. Last, our results show that β-cells have a distinct mode of regulation of TNF-cytotoxicity that is independent of RIPK1 and that may be highly dependent on cFLIP.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"87 ","pages":"Article 101988"},"PeriodicalIF":7.0,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001194/pdfft?md5=369f13a6e3e4a1b99fd266339f1df0c9&pid=1-s2.0-S2212877824001194-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616811","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":"Comprehensive alpha, beta, and delta cell transcriptomics reveal an association of cellular aging with MHC class I upregulation","authors":"W. Staels ,&nbsp;C. Berthault ,&nbsp;S. Bourgeois ,&nbsp;V. Laville ,&nbsp;C. Lourenço ,&nbsp;N. De Leu ,&nbsp;R. Scharfmann","doi":"10.1016/j.molmet.2024.101990","DOIUrl":"10.1016/j.molmet.2024.101990","url":null,"abstract":"<div><h3>Objectives</h3><p>This study aimed to evaluate the efficacy of a purification method developed for isolating alpha, beta, and delta cells from pancreatic islets of adult mice, extending its application to islets from newborn and aged mice. Furthermore, it sought to examine transcriptome dynamics in mouse pancreatic endocrine islet cells throughout postnatal development and to validate age-related alterations within these cell populations.</p></div><div><h3>Methods</h3><p>We leveraged the high surface expression of CD71 on beta cells and CD24 on delta cells to FACS-purify alpha, beta, and delta cells from newborn (1-week-old), adult (12-week-old), and old (18-month-old) mice. Bulk RNA sequencing was conducted on these purified cell populations, and subsequent bioinformatic analyses included differential gene expression, overrepresentation, and intersection analysis.</p></div><div><h3>Results</h3><p>Alpha, beta, and delta cells from newborn and aged mice were successfully FACS-purified using the same method employed for adult mice. Our analysis of the age-related transcriptional changes in alpha, beta, and delta cell populations revealed a decrease in cell cycling and an increase in neuron-like features processes during the transition from newborn to adult mice. Progressing from adult to old mice, we identified an inflammatory gene signature related to aging (inflammaging) encompassing an increase in β-2 microglobulin and major histocompatibility complex (MHC) Class I expression.</p></div><div><h3>Conclusions</h3><p>Our study demonstrates the effectiveness of our cell sorting technique in purifying endocrine subsets from mouse islets at different ages. We provide a valuable resource for better understanding endocrine pancreas aging and identified an inflammaging gene signature with increased β-2 microglobulin and MHC Class I expression as a common hallmark of old alpha, beta, and delta cells, with potential implications for immune response regulation and age-related diabetes.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"87 ","pages":"Article 101990"},"PeriodicalIF":7.0,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001212/pdfft?md5=e0f1edd38415e3ea35a9b982fc29c13e&pid=1-s2.0-S2212877824001212-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620486","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":"Alpha-melanocyte-stimulating hormone contributes to an anti-inflammatory response to lipopolysaccharide","authors":"","doi":"10.1016/j.molmet.2024.101986","DOIUrl":"10.1016/j.molmet.2024.101986","url":null,"abstract":"<div><h3>Objective</h3><p>During infection, metabolism and immunity react dynamically to promote survival through mechanisms that remain unclear. Pro-opiomelanocortin (POMC) cleavage products are produced and released in the brain and in the pituitary gland. One POMC cleavage product, alpha-melanocyte-stimulating hormone (α-MSH), is known to regulate food intake and energy expenditure and has anti-inflammatory effects. However, it is not known whether α-MSH is required to regulate physiological anti-inflammatory responses. We recently developed a novel mouse model with a targeted mutation in <em>Pomc</em> (<em>Pomc</em>^tm1/tm1 mice) to block production of all α-MSH forms which are required to regulate metabolism. To test whether endogenous α-MSH is required to regulate immune responses, we compared acute bacterial lipopolysaccharide (LPS)-induced inflammation between <em>Pomc</em>^tm1/tm1 and wild-type <em>Pomc</em>^wt/wt mice.</p></div><div><h3>Methods</h3><p>We challenged 10- to 14-week-old male <em>Pomc</em>^tm1/tm1 and <em>Pomc</em>^wt/wt mice with single i.p. injections of either saline or low-dose LPS (100 μg/kg) and monitored immune and metabolic responses. We used telemetry to measure core body temperature (T_b), ELISA to measure circulating cytokines, corticosterone and α-MSH, and metabolic chambers to measure body weight, food intake, activity, and respiration. We also developed a mass spectrometry method to measure three forms of α-MSH produced in the mouse hypothalamus and pituitary gland.</p></div><div><h3>Results</h3><p>LPS induced an exaggerated immune response in <em>Pomc</em>^tm1/tm1 compared to <em>Pomc</em>^wt/wt mice. Both groups of mice were hypoactive and hypothermic following LPS administration, but <em>Pomc</em>^tm1/tm1 mice were significantly more hypothermic compared to control mice injected with LPS. <em>Pomc</em>^tm1/tm1 mice also had reduced oxygen consumption and impaired metabolic responses to LPS compared to controls. <em>Pomc</em>^tm1/tm1 mice had increased levels of key proinflammatory cytokines at 2 h and 4 h post LPS injection compared to <em>Pomc</em>^wt/wt mice. Lastly, <em>Pomc</em>^wt/wt mice injected with LPS compared to saline had increased total α-MSH in circulation 2 h post injection.</p></div><div><h3>Conclusions</h3><p>Our data indicate endogenous α-MSH contributes to the inflammatory immune responses triggered by low-dose LPS administration and suggest that targeting the melanocortin system could be a potential therapeutic for the treatment of sepsis or inflammatory disease.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"87 ","pages":"Article 101986"},"PeriodicalIF":7.0,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001170/pdfft?md5=3006292fce857c6768c726734e6dfc6d&pid=1-s2.0-S2212877824001170-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141590780","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":"Hepatic glucokinase regulatory protein and carbohydrate response element binding protein attenuation reduce de novo lipogenesis but do not mitigate intrahepatic triglyceride accumulation in Aldob deficiency","authors":"Amée M. Buziau ,&nbsp;Maaike H. Oosterveer ,&nbsp;Kristiaan Wouters ,&nbsp;Trijnie Bos ,&nbsp;Dean R. Tolan ,&nbsp;Loranne Agius ,&nbsp;Brian E. Ford ,&nbsp;David Cassiman ,&nbsp;Coen D.A. Stehouwer ,&nbsp;Casper G. Schalkwijk ,&nbsp;Martijn C.G.J. Brouwers","doi":"10.1016/j.molmet.2024.101984","DOIUrl":"10.1016/j.molmet.2024.101984","url":null,"abstract":"<div><h3>Objective</h3><p>Stable isotope studies have shown that hepatic <em>de novo</em> lipogenesis (DNL) plays an important role in the pathogenesis of intrahepatic lipid (IHL) deposition. Furthermore, previous research has demonstrated that fructose 1-phosphate (F1P) not only serves as a substrate for DNL, but also acts as a signalling metabolite that stimulates DNL from glucose. The aim of this study was to elucidate the mediators of F1P-stimulated DNL, with special focus on two key regulators of intrahepatic glucose metabolism, i.e., glucokinase regulatory protein (GKRP) and carbohydrate response element binding protein (ChREBP).</p></div><div><h3>Methods</h3><p>Aldolase B deficient mice (<em>Aldob</em>^{<em>−/−</em>}), characterized by hepatocellular F1P accumulation, enhanced DNL, and hepatic steatosis, were either crossed with GKRP deficient mice (<em>Gckr</em>^{<em>−/−</em>}) or treated with short hairpin RNAs directed against hepatic ChREBP.</p></div><div><h3>Results</h3><p><em>Aldob</em>^{<em>−/−</em>} mice showed higher rates of <em>de novo</em> palmitate synthesis from glucose when compared to wildtype mice (p &lt; 0.001). <em>Gckr</em> knockout reduced <em>de novo</em> palmitate synthesis in <em>Aldob</em>^{<em>−/−</em>} mice (p = 0.017), without affecting the hepatic mRNA expression of enzymes involved in DNL. In contrast, hepatic ChREBP knockdown normalized the hepatic mRNA expression levels of enzymes involved in DNL and reduced fractional DNL in <em>Aldob</em>^{<em>−/−</em>} mice (p &lt; 0.05). Of interest, despite downregulation of DNL in response to <em>Gckr</em> and ChREBP attenuation, no reduction in intrahepatic triglyceride levels was observed.</p></div><div><h3>Conclusions</h3><p>Both GKRP and ChREBP mediate F1P-stimulated DNL in aldolase B deficient mice. Further studies are needed to unravel the role of GKRP and hepatic ChREBP in regulating IHL accumulation in aldolase B deficiency.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"87 ","pages":"Article 101984"},"PeriodicalIF":7.0,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001157/pdfft?md5=8bca3a7ecd1cb67473ae86fb175ea89b&pid=1-s2.0-S2212877824001157-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141555230","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":"A review on cell-free RNA profiling: Insights into metabolic diseases and predictive value for bariatric surgery outcomes","authors":"","doi":"10.1016/j.molmet.2024.101987","DOIUrl":"10.1016/j.molmet.2024.101987","url":null,"abstract":"<div><h3>Background</h3><p>The advent of liquid biopsies presents a novel, minimally invasive methodology for the detection of disease biomarkers, offering a significant advantage over traditional biopsy techniques. Particularly, the analysis of cell-free RNA (cfRNA) has garnered interest due to its dynamic expression profiles and the capability to study various RNA species, including messenger RNA (mRNA) and long non-coding RNA (lncRNA). These attributes position cfRNA as a versatile biomarker with broad potential applications in clinical research and diagnostics.</p></div><div><h3>Scope of Review</h3><p>This review delves into the utility of cfRNA biomarkers as prognostic tools for obesity-related comorbidities, such as diabetes, dyslipidemia, and non-alcoholic fatty liver disease.</p></div><div><h3>Major conclusions</h3><p>We evaluate the efficacy of cfRNA in forecasting metabolic outcomes associated with obesity and in identifying patients likely to experience favorable clinical outcomes following bariatric surgery. Additionally, this review synthesizes evidence from studies examining circulating cfRNA across different physiological and pathological states, with a focus on its role in diabetes, including disease progression monitoring and treatment efficacy assessment. Through this exploration, we underscore the emerging relevance of cfRNA signatures in the context of obesity and its comorbidities, setting the stage for future investigative efforts in this rapidly advancing domain.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"87 ","pages":"Article 101987"},"PeriodicalIF":7.0,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001182/pdfft?md5=8001366ca96c3600442da3197969c432&pid=1-s2.0-S2212877824001182-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141559178","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":"Long-term metabolic effects of non-nutritive sweeteners","authors":"","doi":"10.1016/j.molmet.2024.101985","DOIUrl":"10.1016/j.molmet.2024.101985","url":null,"abstract":"<div><h3>Objective</h3><p>Excessive consumption of added sugars has been linked to the rise in obesity and associated metabolic abnormalities. Non-nutritive sweeteners (NNSs) offer a potential solution to reduce sugar intake, yet their metabolic safety remains debated. This study aimed to systematically assess the long-term metabolic effects of commonly used NNSs under both normal and obesogenic conditions.</p></div><div><h3>Methods</h3><p>To ensure consistent sweetness level and controlling for the acceptable daily intake (ADI), eight weeks old C57BL/6 male mice were administered with acesulfame K (ace K, 535.25 mg/L), aspartame (411.75 mg/L), sucralose (179.5 mg/L), saccharin (80 mg/L), or steviol glycoside (Reb M, 536.25 mg/L) in the drinking water, on the background of either regular or high-fat diets (in high fat diet 60% of calories from fat). Water or fructose-sweetened water (82.3.gr/L), were used as controls. Anthropometric and metabolic parameters, as well as microbiome composition, were analyzed following 20-weeks of exposure.</p></div><div><h3>Results</h3><p>Under a regular chow diet, chronic NNS consumption did not significantly affect body weight, fat mass, or glucose metabolism as compared to water consumption, with aspartame demonstrating decreased glucose tolerance. In diet-induced obesity, NNS exposure did not increase body weight or alter food intake. Exposure to sucralose and Reb M led to improved insulin sensitivity and decreased weight gain. Reb M specifically was associated with increased prevalence of colonic Lachnospiracea bacteria.</p></div><div><h3>Conclusions</h3><p>Long-term consumption of commonly used NNSs does not induce adverse metabolic effects, with Reb M demonstrating a mild improvement in metabolic abnormalities. These findings provide valuable insights into the metabolic impact of different NNSs, aiding in the development of strategies to combat obesity and related metabolic disorders.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 101985"},"PeriodicalIF":7.0,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001169/pdfft?md5=b68ef69cbbfb4825a1f748263f1295ad&pid=1-s2.0-S2212877824001169-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141559179","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":"Metabolic profiling of single cells by exploiting NADH and FAD fluorescence via flow cytometry","authors":"Ariful Haque Abir ,&nbsp;Leonie Weckwerth ,&nbsp;Artur Wilhelm ,&nbsp;Jana Thomas ,&nbsp;Clara M. Reichardt ,&nbsp;Luis Munoz ,&nbsp;Simon Völkl ,&nbsp;Uwe Appelt ,&nbsp;Markus Mroz ,&nbsp;Raluca Niesner ,&nbsp;Anja Hauser ,&nbsp;Rebecca Sophie Fischer ,&nbsp;Katharina Pracht ,&nbsp;Hans-Martin Jäck ,&nbsp;Georg Schett ,&nbsp;Gerhard Krönke ,&nbsp;Dirk Mielenz","doi":"10.1016/j.molmet.2024.101981","DOIUrl":"10.1016/j.molmet.2024.101981","url":null,"abstract":"<div><h3>Objective</h3><p>The metabolism of different cells within the same microenvironment can differ and dictate physiological or pathological adaptions. Current single-cell analysis methods of metabolism are not label-free.</p></div><div><h3>Methods</h3><p>The study introduces a label-free, live-cell analysis method assessing endogenous fluorescence of NAD(P)H and FAD in surface-stained cells by flow cytometry.</p></div><div><h3>Results</h3><p>OxPhos inhibition, mitochondrial uncoupling, glucose exposure, genetic inactivation of glucose uptake and mitochondrial respiration alter the optical redox ratios of FAD and NAD(P)H as measured by flow cytometry. Those alterations correlate strongly with measurements obtained by extracellular flux analysis. Consequently, metabolically distinct live B-cell populations can be resolved, showing that human memory B-cells from peripheral blood exhibit a higher glycolytic flexibility than naïve B cells. Moreover, the comparison of blood-derived B- and T-lymphocytes from healthy donors and rheumatoid arthritis patients unleashes rheumatoid arthritis-associated metabolic traits in human naïve and memory B-lymphocytes.</p></div><div><h3>Conclusions</h3><p>Taken together, these data show that the optical redox ratio can depict metabolic differences in distinct cell populations by flow cytometry.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"87 ","pages":"Article 101981"},"PeriodicalIF":7.0,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001121/pdfft?md5=a69515c79cbc338d51484fc6523af629&pid=1-s2.0-S2212877824001121-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141545039","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}