Molecular Metabolism最新文献

{"title":"Exercise-induced methylation of the Serhl2 promoter and implication for lipid metabolism in rat skeletal muscle","authors":"Mutsumi Katayama ,&nbsp;Kazuhiro Nomura ,&nbsp;Jonathan M. Mudry ,&nbsp;Alexander V. Chibalin ,&nbsp;Anna Krook ,&nbsp;Juleen R. Zierath","doi":"10.1016/j.molmet.2024.102081","DOIUrl":"10.1016/j.molmet.2024.102081","url":null,"abstract":"<div><h3>Objectives</h3><div>Environmental factors such as physical activity induce epigenetic modifications, with exercise-responsive DNA methylation changes occurring in skeletal muscle. To determine the skeletal muscle DNA methylation signature of endurance swim training, we used whole-genome methylated DNA immunoprecipitation (MeDIP) sequencing.</div></div><div><h3>Methods</h3><div>We utilized endurance-trained rats, cultured L6 myotubes, and human skeletal muscle cells, employing MeDIP sequencing, gene silencing, and palmitate oxidation assays. Additional methods included promoter luciferase assays, fluorescence microscopy, and RNA/DNA analysis to investigate exercise-induced molecular changes.</div></div><div><h3>Results</h3><div>Gene set enrichment analysis (GSEA) of differentially methylated promoter regions identified an enrichment of four gene sets, including those linked to lipid metabolic processes, with hypermethylated or hypomethylated promoter regions in skeletal muscle of exercise-trained rats. Bisulfite sequencing confirmed hypomethylation of CpGs in the <em>Serhl2</em> (Serine Hydrolase Like 2) transcription start site in exercise-trained rats. <em>Serhl2</em> gene expression was upregulated in both exercise-trained rats and an \"exercise-in-a-dish\" model of L6 myotubes subjected to electrical pulse stimulation (EPS). <em>Serhl2</em> promoter activity was regulated by methylation and EPS. A <em>Nr4a</em> binding motif in the <em>Serhl2</em> promoter, when deleted, reduced promoter activity and sensitivity to methylation in L6 myotubes. Silencing <em>Serhl2</em> in L6 myotubes reduced intracellular lipid oxidation and triacylglycerol synthesis in response to EPS.</div></div><div><h3>Conclusions</h3><div>Exercise-training enhances intracellular lipid metabolism and phenotypic changes in skeletal muscle through epigenomic modifications on <em>Serhl2</em>. Hypomethylation of the <em>Serhl2</em> promoter influences <em>Nr4a</em> transcription factor binding, promoter activity, and gene expression, linking exercise-induced epigenomic regulation of <em>Serhl2</em> to lipid oxidation and triacylglycerol synthesis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102081"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807643","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":"Hypoxia-inducible factor 1α is required to establish the larval glycolytic program in Drosophila melanogaster","authors":"Yasaman Heidarian ,&nbsp;Tess D. Fasteen ,&nbsp;Liam Mungcal ,&nbsp;Kasun Buddika ,&nbsp;Nader H. Mahmoudzadeh ,&nbsp;Travis Nemkov ,&nbsp;Angelo D'Alessandro ,&nbsp;Jason M. Tennessen","doi":"10.1016/j.molmet.2025.102106","DOIUrl":"10.1016/j.molmet.2025.102106","url":null,"abstract":"<div><h3>Objectives</h3><div>The rapid growth that occurs during <em>Drosophila</em> larval development requires a dramatic rewiring of central carbon metabolism to support biosynthesis. Larvae achieve this metabolic state, in part, by coordinately up-regulating the expression of genes involved in carbohydrate metabolism. The resulting metabolic program exhibits hallmark characteristics of aerobic glycolysis and establishes a physiological state that supports growth. To date, the only factor known to activate the larval glycolytic program is the <em>Drosophila</em> Estrogen-Related Receptor (dERR). However, dERR is dynamically regulated during the onset of this metabolic switch, indicating that other factors must be involved. Here we examine the possibility that the <em>Drosophila</em> ortholog of Hypoxia inducible factor 1α (Hif1α) is also required to activate the larval glycolytic program.</div></div><div><h3>Methods</h3><div>CRISPR/Cas9 was used to generate new loss-of-function alleles in the <em>Drosophila</em> gene <em>similar</em> (<em>sima</em>), which encodes the sole fly ortholog of Hif1α. The resulting mutant strains were analyzed using a combination of metabolomics and RNAseq for defects in carbohydrate metabolism.</div></div><div><h3>Results</h3><div>Our studies reveal that <em>sima</em> mutants fail to activate aerobic glycolysis and die during larval development with metabolic phenotypes that mimic those displayed by <em>dERR</em> mutants. Moreover, we demonstrate that dERR and Sima/Hif1α protein accumulation is mutually dependent, as loss of either transcription factor results in decreased abundance of the other protein.</div></div><div><h3>Conclusions</h3><div>These findings demonstrate that Sima/HIF1α is required during embryogenesis to coordinately up-regulate carbohydrate metabolism in preparation for larval growth. Notably, our study also reveals that the Sima/HIF1α-dependent gene expression program shares considerable overlap with that observed in <em>dERR</em> mutant, suggesting that Sima/HIF1α and dERR cooperatively regulate embryonic and larval glycolytic gene expression.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102106"},"PeriodicalIF":7.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080515","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":"Characterization of subcutaneous and visceral de-differentiated fat cells","authors":"Yan Li ,&nbsp;Houyu Zhang ,&nbsp;Carlos F. Ibáñez ,&nbsp;Meng Xie","doi":"10.1016/j.molmet.2025.102105","DOIUrl":"10.1016/j.molmet.2025.102105","url":null,"abstract":"<div><h3>Objective</h3><div>The capacity of mature adipocytes to de-differentiate into fibroblast-like cells has been demonstrated in vitro and a few, rather specific in vivo conditions. A detailed comparison between de-differentiated fat (DFAT) cells and adipose stem and progenitor cells (ASPCs) from different adipose depots is yet to be conducted. Moreover, whether de-differentiation of mature adipocytes from classical subcutaneous and visceral depots occurs under physiological conditions remains unknown.</div></div><div><h3>Methods</h3><div>Here, we used in vitro \"ceiling culture\", single cell/nucleus RNA sequencing, epigenetic anaysis and genetic lineage tracing to address these unknowns.</div></div><div><h3>Results</h3><div>We show that in vitro-derived DFAT cells have lower adipogenic potential and distinct cellular composition compared to ASPCs. In addition, DFAT cells derived from adipocytes of inguinal origin have dramatically higher adipogenic potential than DFAT cells of the epididymal origin, due in part to enhanced NF-KB signaling in the former. We also show that high-fat diet (HFD) feeding enhances DFAT cell colony formation and re-differentiation into adipocytes, while switching from HFD to chow diet (CD) only reverses their re-differentiation. Moreover, HFD deposits epigenetic changes in DFAT cells and ASPCs that are not reversed after returning to CD. Finally, combining genetic lineage tracing and single cell/nucleus RNA sequencing, we demonstrate the existence of DFAT cells in inguinal and epididymal adipose depots in vivo, with transcriptomes resembling late-stage ASPCs.</div></div><div><h3>Conclusions</h3><div>These data uncover the cell type- and depot-specific properties of DFAT cells, as well as their plasticity in response to dietary intervention. This knowledge may shed light on their role in life style change-induced weight loss and regain.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102105"},"PeriodicalIF":7.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066766","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":"Nutrient control of splice site selection contributes to methionine addiction of cancer","authors":"Da-Wei Lin ,&nbsp;Francisco G. Carranza ,&nbsp;Stacey Borrego ,&nbsp;Linda Lauinger ,&nbsp;Lucas Dantas de Paula ,&nbsp;Harika R. Pulipelli ,&nbsp;Anna Andronicos ,&nbsp;Klemens J. Hertel ,&nbsp;Peter Kaiser","doi":"10.1016/j.molmet.2025.102103","DOIUrl":"10.1016/j.molmet.2025.102103","url":null,"abstract":"<div><h3>Objective</h3><div>Many cancer cells depend on exogenous methionine for proliferation, whereas non-tumorigenic cells can divide in media supplemented with the metabolic precursor homocysteine. This phenomenon is known as methionine dependence of cancer or methionine addiction. The underlying mechanisms driving this cancer-specific metabolic addiction are poorly understood. Here we find that methionine dependence is associated with severe dysregulation of pre-mRNA splicing.</div></div><div><h3>Methods</h3><div>We used triple-negative breast cancer cells and their methionine-independent derivatives R8 to compare RNA expression profiles in methionine and homocysteine growth media. The data set was also analyzed for alternative splicing.</div></div><div><h3>Results</h3><div>When tumorigenic cells were cultured in homocysteine medium, cancer cells failed to efficiently methylate the spliceosomal snRNP component SmD1, which resulted in reduced binding to the Survival-of-Motor-Neuron protein SMN leading to aberrant splicing. These effects were specific for cancer cells as neither Sm protein methylation nor splicing fidelity was affected when non-tumorigenic cells were cultured in homocysteine medium. Sm protein methylation is catalyzed by Protein Arginine Methyl Transferase 5 (Prmt5). Reducing methionine concentrations in the culture medium sensitized cancer cells to Prmt5 inhibition supporting a mechanistic link between methionine dependence of cancer and splicing.</div></div><div><h3>Conclusions</h3><div>Our results link nutritional demands to splicing changes and thereby provide a link between the cancer-specific metabolic phenomenon, described as methionine addiction over 40 years ago, with a defined cellular pathway that contributes to cancer cell proliferation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102103"},"PeriodicalIF":7.0,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040294","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":"High fructose rewires gut glucose sensing via glucagon-like peptide 2 to impair metabolic regulation in mice","authors":"Eya Sellami ,&nbsp;Paulo Henrique Evangelista-Silva ,&nbsp;Caio Jordão Teixeira ,&nbsp;Khoudia Diop ,&nbsp;Patricia Mitchell ,&nbsp;Fernando Forato Anhê","doi":"10.1016/j.molmet.2025.102101","DOIUrl":"10.1016/j.molmet.2025.102101","url":null,"abstract":"<div><h3>Objective</h3><div>Increased fructose consumption contributes to type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanisms are ill-defined. Gut nutrient sensing involves enterohormones like Glucagon-like peptide (Glp)2, which regulates the absorptive capacity of luminal nutrients. While glucose is the primary dietary energy source absorbed in the gut, it is unknown whether excess fructose alters gut glucose sensing to impair blood glucose regulation and liver homeostasis.</div></div><div><h3>Methods</h3><div>Mice were fed diets where carbohydrates were either entirely glucose (70 %Kcal) or glucose partially replaced with fructose (8.5 %Kcal). Glp2 receptor (Glp2r) was inhibited with Glp2 (3-33) injections. Glucose tolerance, insulin sensitivity, and gut glucose absorption were concomitantly assessed, and enteric sugar transporters and absorptive surface were quantified by RT-qPCR and histological analysis, respectively.</div></div><div><h3>Results</h3><div>High fructose feeding led to impairment of blood glucose disposal, ectopic fat accumulation in the liver, and hepatic (but not muscle or adipose tissue) insulin resistance independent of changes in fat mass. This was accompanied by increased gut glucose absorption, which preceded glucose intolerance and liver steatosis. Fructose upregulated glucose transporters and enlarged the gut surface, but these effects were prevented by Glp2r inhibition. Blocking Glp2r prevented fructose-induced impairments in glucose disposal and hepatic lipid handling.</div></div><div><h3>Conclusion</h3><div>Excess fructose impairs blood glucose and liver homeostasis by rewiring gut glucose sensing and exacerbating gut glucose absorption. Our findings are positioned to inform novel early diagnostic tools and treatments tailored to counter high fructose-induced metabolic derangements predisposing to T2D and MASLD.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102101"},"PeriodicalIF":7.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040260","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":"Novel translational mouse models of metabolic dysfunction-associated steatotic liver disease comparable to human MASLD with severe obesity","authors":"Katharina L. Hupa-Breier ,&nbsp;Heiko Schenk ,&nbsp;Alejandro Campos-Murguia ,&nbsp;Freya Wellhöner ,&nbsp;Benjamin Heidrich ,&nbsp;Janine Dywicki ,&nbsp;Björn Hartleben ,&nbsp;Clara Böker ,&nbsp;Julian Mall ,&nbsp;Christoph Terkamp ,&nbsp;Ludwig Wilkens ,&nbsp;Friedrich Becker ,&nbsp;Karl Lenhard Rudolph ,&nbsp;Michael Peter Manns ,&nbsp;Young-Seon Mederacke ,&nbsp;Silke Marhenke ,&nbsp;Hanna Redeker ,&nbsp;Maren Lieber ,&nbsp;Konstantinos Iordanidis ,&nbsp;Richard Taubert ,&nbsp;Elmar Jaeckel","doi":"10.1016/j.molmet.2025.102104","DOIUrl":"10.1016/j.molmet.2025.102104","url":null,"abstract":"<div><h3>Objective</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease, especially in patients with severe obesity. However, current mouse models for MASLD do not reflect the polygenetic background nor the metabolic changes in this population. Therefore, we investigated two novel mouse models of MASLD with a polygenetic background for the metabolic syndrome.</div></div><div><h3>Methods</h3><div>TALLYHO/JngJ mice and NONcNZO10/LtJ mice were fed a high-fat- high-carbohydrate (HF-HC) diet with a surplus of cholesterol diet. A second group of TH mice was additional treated with empagliflozin.</div></div><div><h3>Results</h3><div>After sixteen weeks of feeding, both strains developed metabolic syndrome with severe obesity and histological manifestation of steatohepatitis, which was associated with significantly increased intrahepatic CD8⁺cells, CD4⁺cells and Tregs, contributing to a significant increase in pro-inflammatory and pro-fibrotic gene activation as well as ER stress and oxidative stress. In comparison with the human transcriptomic signature, we could demonstrate a good metabolic similarity, especially for the TH mouse model. Furthermore, TH mice also developed signs of kidney injury as an extrahepatic comorbidity of MASLD. Additional treatment with empagliflozin in TH mice attenuates hepatic steatosis and improves histological manifestation of MASH.</div></div><div><h3>Conclusions</h3><div>Overall, we have developed two promising new mouse models that are suitable for preclinical studies of MASLD as they recapitulate most of the key features of MASLD.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102104"},"PeriodicalIF":7.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040291","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":"Transcriptomic signatures of cold acclimated adipocytes reveal CXCL12 as a Brown autocrine and paracrine chemokine","authors":"Marina Agueda-Oyarzabal ,&nbsp;Marie S. Isidor ,&nbsp;Kaja Plucińska ,&nbsp;Lars R. Ingerslev ,&nbsp;Oksana Dmytriyeva ,&nbsp;Patricia S.S. Petersen ,&nbsp;Sara Laftih ,&nbsp;Axel B. Pontoppidan ,&nbsp;Jo B. Henningsen ,&nbsp;Kaja Rupar ,&nbsp;Erin L. Brown ,&nbsp;Thue W. Schwartz ,&nbsp;Romain Barrès ,&nbsp;Zachary Gerhart-Hines ,&nbsp;Camilla C. Schéele ,&nbsp;Brice Emanuelli","doi":"10.1016/j.molmet.2025.102102","DOIUrl":"10.1016/j.molmet.2025.102102","url":null,"abstract":"<div><div>Besides its thermogenic capacity, brown adipose tissue (BAT) performs important secretory functions that regulate metabolism. However, the BAT microenvironment and factors involved in BAT homeostasis and adaptation to cold remain poorly characterized. We therefore aimed to study brown adipocyte-derived secreted factors that may be involved in adipocyte function and/or may orchestrate intercellular communications. For this, mRNA levels in mature adipocytes from mouse adipose depots were assessed using RNA sequencing upon chronic cold acclimation, and bioinformatic analysis was used to identify secreted factors. Among 858 cold-sensitive transcripts in BAT adipocytes were 210 secreted factor-encoding genes, and <em>Cxcl12</em> was the top brown adipocyte-enriched cytokine. <em>Cxcl1</em>2 mRNA expression analysis by RT-qPCR and fluorescence in situ hybridization specified <em>Cxcl12</em> distribution in various cell types, and indicated its enrichment in cold-acclimated brown adipocytes. We found that CXCL12 secretion from BAT was increased after chronic cold, yet its level in plasma remained unchanged, suggesting a local/paracrine function. <em>Cxcl12</em> knockdown in mature brown adipocytes impaired thermogenesis, as assessed by norepinephrine (NE)-induced glycerol release and mitochondrial respiration. However, knockdown of <em>Cxcl12</em> did not impact β-adrenergic signaling, suggesting that CXCL12 regulates adipocyte function downstream of the β-adrenergic pathway. Moreover, we provide evidence for CXCL12 to exert intercellular cross-talk via its capacity to promote macrophage chemotaxis and neurite outgrowth. Collectively, our results indicate that CXCL12 is a brown adipocyte-enriched, cold-induced secreted factor involved in adipocyte function and the BAT microenvironment communication network.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102102"},"PeriodicalIF":7.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028889","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":"Timing of exercise differentially impacts adipose tissue gain in male adolescent rats","authors":"Y. Kutsenko ,&nbsp;L.P. Iñiguez ,&nbsp;A. Barreda ,&nbsp;L. Pardo-Marín ,&nbsp;A. Toval ,&nbsp;D. Garrigos ,&nbsp;M. Martínez-Morga ,&nbsp;S. Pujante ,&nbsp;B. Ribeiro Do-Couto ,&nbsp;K.Y. Tseng ,&nbsp;J.J. Cerón ,&nbsp;M. Garaulet ,&nbsp;M.B. Wisniewska ,&nbsp;M. Irimia ,&nbsp;J.L. Ferran","doi":"10.1016/j.molmet.2025.102100","DOIUrl":"10.1016/j.molmet.2025.102100","url":null,"abstract":"<div><h3>Objective</h3><div>Circadian rhythms of metabolic, hormonal, and behavioral fluctuations and their alterations can impact health. An important gap in knowledge in the field is whether the time of the day of exercise and the age of onset of exercise exert distinct effects at the level of whole-body adipose tissue and body composition. The goal of the present study was to determine how exercise at different times of the day during adolescence impacts the adipose tissue transcriptome and content in a rodent model.</div></div><div><h3>Methods</h3><div>Rats were subjected to one of four conditions during their adolescence: early active phase control or exercise (EAC or EAE; ZT13), and late active phase control or exercise (LAC or LAE; ZT23). The effects of exercise timing were assessed at the level of subcutaneous and visceral adipose tissue transcriptome, body composition, hypothalamic expression of orexigenic and anorexigenic genes, blood serum markers and 24-hour core body temperature patterns.</div></div><div><h3>Results</h3><div>We found that late active phase exercise (ZT23) greatly upregulated pathways of lipid synthesis, glycolysis and NADH shuttles in LAE rats, compared to LAC or EAE. Conversely, LAE rats showed notably lower content of adipose tissue. In addition, LAE rats showed signs of impaired FGF21-adiponectin axis compared to other groups.</div></div><div><h3>Conclusions</h3><div>Finally, LAE rats showed higher post-exercise core body temperature compared to other groups. Our results thus indicate that our exercise protocol induced an unusual effect characterized by enhanced lipid synthesis but reduced adipose tissue content in late active phase but not early active phase exercise during adolescence.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102100"},"PeriodicalIF":7.0,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008438","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":"Endothelial autophagy-related gene 7 contributes to high fat diet-induced obesity","authors":"Guang Ren ,&nbsp;Sushant Bhatnagar ,&nbsp;Martin E. Young ,&nbsp;Timmy Lee ,&nbsp;Jeong-a Kim","doi":"10.1016/j.molmet.2025.102099","DOIUrl":"10.1016/j.molmet.2025.102099","url":null,"abstract":"<div><h3>Objective</h3><div>Obesity-associated metabolic dysfunction is a major public health concern worldwide. Endothelial dysfunction is a hallmark of metabolic dysfunction, and endothelial cells affect metabolic functions. Because autophagy-related gene 7 (ATG7) is involved in various cellular physiology, we investigated the roles of endothelial cell-ATG7 (EC-ATG7) on high-fat diet-induced obesity and its related metabolic dysfunction.</div></div><div><h3>Methods</h3><div>We generated an endothelial-specific <em>Atg7</em> knock-out mouse by breeding <em>Atg7</em>^flox/flox mouse with the <em>Chd5-Cre</em> mouse, and investigated the metabolic phenotypes associated with high-fat diet (HFD)-induced obesity. Body weight, food intake, glucose tolerance, insulin sensitivity, and liver fat accumulation were measured in endothelial <em>Atg7</em> deficient (<em>Atg7</em>^ΔEnd) and control mice (<em>Atg7</em>^f/f). Adipose tissue inflammation was assessed by measuring the expression of pro-inflammatory genes. Furthermore, we performed indirect calorimetry and examined the insulin signaling pathway molecules.</div></div><div><h3>Results</h3><div>We found that deletion of EC-<em>Atg7</em> ameliorated HFD-induced weight gain, fatty liver, and adipocyte hypertrophy and inflammatory response in adipose tissue, and improved insulin sensitivity without changing glucose tolerance. These metabolic effects seem to be due to the reduced food intake because there were no differences in energy expenditure, energy excretion to feces, and physical activity. Interestingly, the deletion of EC-<em>Atg7</em> protected from HFD-induced vascular rarefaction, and the knock-down of <em>Atg7</em> in endothelial cells protected from fatty acid-induced cell death.</div></div><div><h3>Conclusions</h3><div>Our results suggest that EC-<em>Atg7</em> deletion ameliorates HFD-induced obesity and its related metabolic dysfunction, such as insulin resistance and fatty liver by attenuating appetite and vascular rarefaction. The EC-<em>Atg7</em> deletion may protect the endothelial cells from lipotoxicity and impaired angiogenesis, which preserves the endothelial function in metabolic tissues. These findings may have implications for developing new therapeutic strategies for preventing and treating obesity and its associated health risks.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102099"},"PeriodicalIF":7.0,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008437","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":"Regulation of energy balance by leptin as an adiposity signal and modulator of the reward system","authors":"Roshanak Asgari ,&nbsp;Maria Caceres-Valdiviezo ,&nbsp;Sally Wu ,&nbsp;Laurie Hamel ,&nbsp;Bailey E. Humber ,&nbsp;Sri Mahavir Agarwal ,&nbsp;Paul J. Fletcher ,&nbsp;Stephanie Fulton ,&nbsp;Margaret K. Hahn ,&nbsp;Sandra Pereira","doi":"10.1016/j.molmet.2024.102078","DOIUrl":"10.1016/j.molmet.2024.102078","url":null,"abstract":"<div><h3>Background</h3><div>Leptin is an adipose tissue-derived hormone that plays a crucial role in body weight, appetite, and behaviour regulation. Leptin controls energy balance as an indicator of adiposity levels and as a modulator of the reward system, which is associated with liking palatable foods. Obesity is characterized by expanded adipose tissue mass and consequently, elevated concentrations of leptin in blood. Leptin's therapeutic potential for most forms of obesity is hampered by leptin resistance and a narrow dose–response window.</div></div><div><h3>Scope of Review</h3><div>This review describes the current knowledge of the brain regions and intracellular pathways through which leptin promotes negative energy balance and restrains neural circuits affecting food reward. We also describe mechanisms that hinder these biological responses in obesity and highlight potential therapeutic interventions.</div></div><div><h3>Major Conclusions</h3><div>Additional research is necessary to understand how pathways engaged by leptin in different brain regions are interconnected in the control of energy balance.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"91 ","pages":"Article 102078"},"PeriodicalIF":7.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770159","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}