Molecular Metabolism最新文献

{"title":"Esrra regulates Rplp1-mediated translation of lysosome proteins suppressed in metabolic dysfunction-associated steatohepatitis and reversed by alternate day fasting","authors":"Madhulika Tripathi ,&nbsp;Karine Gauthier ,&nbsp;Reddemma Sandireddy ,&nbsp;Jin Zhou ,&nbsp;Priyanka Guptta ,&nbsp;Suganya Sakthivel ,&nbsp;Wei Wen Teo ,&nbsp;Yadanar Than Naing ,&nbsp;Kabilesh Arul ,&nbsp;Keziah Tikno ,&nbsp;Sung-Hee Park ,&nbsp;Yajun Wu ,&nbsp;Lijin Wang ,&nbsp;Boon-Huat Bay ,&nbsp;Lei Sun ,&nbsp;Vincent Giguere ,&nbsp;Pierce K.H. Chow ,&nbsp;Sujoy Ghosh ,&nbsp;Donald P. McDonnell ,&nbsp;Paul M. Yen ,&nbsp;Brijesh K. Singh","doi":"10.1016/j.molmet.2024.101997","DOIUrl":"10.1016/j.molmet.2024.101997","url":null,"abstract":"<div><h3>Objective</h3><p>Currently, little is known about the mechanism(s) regulating global and specific protein translation during metabolic dysfunction-associated steatohepatitis (MASH; previously known as non-alcoholic steatohepatitis, NASH).</p></div><div><h3>Methods</h3><p>Unbiased label-free quantitative proteome, puromycin-labelling and polysome profiling were used to understand protein translation activity <em>in vitro</em> and <em>in vivo</em>.</p></div><div><h3>Results</h3><p>We observed a global decrease in protein translation during lipotoxicity in human primary hepatocytes, mouse hepatic AML12 cells, and livers from a dietary mouse model of MASH. Interestingly, proteomic analysis showed that Rplp1, which regulates ribosome and translation pathways, was one of the most downregulated proteins. Moreover, decreased Esrra expression and binding to the Rplp1 promoter, diminished Rplp1 gene expression during lipotoxicity. This, in turn, reduced global protein translation and Esrra/Rplp1-dependent translation of lysosome (Lamp2, Ctsd) and autophagy (sqstm1, Map1lc3b) proteins. Of note, Esrra did not increase its binding to these gene promoters or their gene transcription, confirming its regulation of their translation during lipotoxicity. Notably, hepatic Esrra-Rplp1-dependent translation of lysosomal and autophagy proteins also was impaired in MASH patients and liver-specific <em>Esrra</em> knockout mice. Remarkably, alternate day fasting induced Esrra-Rplp1-dependent expression of lysosomal proteins, restored autophagy, and reduced lipotoxicity, inflammation, and fibrosis in hepatic cell culture and <em>in vivo</em> models of MASH.</p></div><div><h3>Conclusions</h3><p>Esrra regulation of Rplp1-mediated translation of lysosome/autolysosome proteins was downregulated during MASH. Alternate day fasting activated this novel pathway and improved MASH, suggesting that Esrra and Rplp1 may serve as therapeutic targets for MASH. Our findings also provided the first example of a nuclear hormone receptor, Esrra, to not only regulate transcription but also protein translation, via induction of Rplp1.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"87 ","pages":"Article 101997"},"PeriodicalIF":7.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001285/pdfft?md5=81df0324e8a5b092148f5e4c0dd213eb&pid=1-s2.0-S2212877824001285-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141734634","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 plasticity in a Pde6bSTOP/STOP retinitis pigmentosa mouse model following rescue","authors":"Monika Ayten ,&nbsp;Nundehui Díaz-Lezama ,&nbsp;Hanaa Ghanawi ,&nbsp;Felia C. Haffelder ,&nbsp;Jacqueline Kajtna ,&nbsp;Tobias Straub ,&nbsp;Marco Borso ,&nbsp;Axel Imhof ,&nbsp;Stefanie M. Hauck ,&nbsp;Susanne F. Koch","doi":"10.1016/j.molmet.2024.101994","DOIUrl":"10.1016/j.molmet.2024.101994","url":null,"abstract":"<div><h3>Objective</h3><p>Retinitis pigmentosa (RP) is a hereditary retinal disease characterized by progressive photoreceptor degeneration, leading to vision loss. The best hope for a cure for RP lies in gene therapy. However, given that RP patients are most often diagnosed in the midst of ongoing photoreceptor degeneration, it is unknown how the retinal proteome changes as RP disease progresses, and which changes can be prevented, halted, or reversed by gene therapy.</p></div><div><h3>Methods</h3><p>Here, we used a <em>Pde6b</em>-deficient RP gene therapy mouse model and performed untargeted proteomic analysis to identify changes in protein expression during degeneration and after treatment.</p></div><div><h3>Results</h3><p>We demonstrated that <em>Pde6b</em> gene restoration led to a novel form of homeostatic plasticity in rod phototransduction which functionally compensates for the decreased number of rods. By profiling protein levels of metabolic genes and measuring metabolites, we observed an upregulation of proteins associated with oxidative phosphorylation in mutant and treated photoreceptors.</p></div><div><h3>Conclusion</h3><p>In conclusion, the metabolic demands of the retina differ in our <em>Pde6b</em>-deficient RP mouse model and are not rescued by gene therapy treatment. These findings provide novel insights into features of both RP disease progression and long-term rescue with gene therapy.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 101994"},"PeriodicalIF":7.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221287782400125X/pdfft?md5=6010579f47431b45363c3e5b7663bbf8&pid=1-s2.0-S221287782400125X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141734645","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":"The homeodomain transcription factor Six3 regulates hypothalamic Pomc expression and its absence from POMC neurons induces hyperphagia and mild obesity in male mice","authors":"Hui Yu ,&nbsp;Angelika Chiang ,&nbsp;Marcelo Rubinstein ,&nbsp;Malcolm J. Low","doi":"10.1016/j.molmet.2024.101993","DOIUrl":"10.1016/j.molmet.2024.101993","url":null,"abstract":"<div><h3>Objective</h3><p>Proopiomelanocortin (POMC) neurons release potent anorexigenic neuropeptides, which suppress food intake and enhance energy expenditure via melanocortin receptors. Although the importance of central melanocortin in physiological regulation is well established, the underlying genetic mechanisms that define the functional identity of melanocortin neurons and maintain hypothalamic <em>Pomc</em> expression remain to be fully determined. In this study, we investigate the functional significance of <em>Six3,</em> a transcriptional regulator notably expressed in embryonic and adult mouse POMC neurons, in the regulation of hypothalamic <em>Pomc</em> expression and downstream physiological consequences.</p></div><div><h3>Methods</h3><p>We first evaluated the expression of <em>Six3</em> in the developing and adult hypothalamus by double fluorescence <em>in situ</em> hybridization. Next, we assessed POMC immunoreactivity in mutant mice selectively lacking <em>Six3</em> from <em>Pomc</em>-expressing neurons and quantified <em>Pomc</em> mRNA levels in a tamoxifen-inducible <em>Six3</em> knockout mouse model activated at embryonic E9.5 days. We also determined glucose and insulin sensitivity, daily food intake, body composition and body weight in adult male and female mice lacking <em>Six3</em> specifically from POMC neurons. Lastly, we assessed the physiological consequences of ablating <em>Six3</em> from POMC neurons in adult mice.</p></div><div><h3>Results</h3><p><em>Six3</em> and <em>Pomc</em> were co-expressed in mouse hypothalamic neurons during development and adulthood. Mouse embryos deficient in <em>Six3</em> showed reduced <em>Pomc</em> expression in the developing hypothalamus. Targeted deletion of <em>Six3</em> specifically from POMC neurons resulted in decreased hypothalamic <em>Pomc</em> expression, increased daily food intake, enhanced glucose sensitivity and mild obesity in male but not in female mice. Finally, conditional removal of <em>Six3</em> from POMC neurons in adult mice led to a reduction in hypothalamic POMC immunoreactivity with no significant effects in body weight or food intake.</p></div><div><h3>Conclusions</h3><p>Altogether, our results demonstrate that <em>Six3</em> plays an essential role in the early establishment of POMC neuron identity and the maintenance of physiological levels of hypothalamic <em>Pomc</em> expression. In addition, our study demonstrates that the functional significance of <em>Six3</em> expression in POMC neurons is sexually dimorphic and age-dependent.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"87 ","pages":"Article 101993"},"PeriodicalIF":7.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001248/pdfft?md5=e1f7da9c342a933d0153229da82b53ed&pid=1-s2.0-S2212877824001248-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141697099","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":"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}