Molecular Metabolism最新文献

{"title":"Amygdala aromatase controls food intake, reward, and thermoregulation","authors":"Ivana Maric ,&nbsp;Jennifer E. Richard ,&nbsp;Lilly Taing ,&nbsp;Suyeun Byun ,&nbsp;Lorena Lopez-Ferreras ,&nbsp;Yifan Qiu ,&nbsp;Karolina P. Skibicka","doi":"10.1016/j.molmet.2025.102202","DOIUrl":"10.1016/j.molmet.2025.102202","url":null,"abstract":"<div><h3>Objective</h3><div>Estrogens play a pivotal role in energy balance control, by acting on its CNS receptors. It is generally assumed that the gonads are the main source of estradiol for these receptors. However, aromatase, the sole enzyme responsible for estradiol synthesis, is also present in the brain, and its role in energy balance remains largely unexplored.</div></div><div><h3>Methods and Results</h3><div>We identified high aromatase expression in the neurons of rat amygdala and investigated whether brain-derived estradiol, particularly within the amygdala, plays a role in energy balance and food reward control. Both whole brain chronic pharmacological inhibition of aromatase with a clinically utilized inhibitor, Letrozole, and a virogenetic approach to manipulate aromatase specifically in the amygdala were used in adult male and female rats, in conjunction with an array of measurements assessing feeding behavior and thermoregulation. Our results show that inhibition of brain aromatase results in increased food intake and body weight gain in females, but reduced food intake in males. This was driven by opposing effects on food preference for a high-fat diet. Amygdala aromatase knockdown was sufficient to increase feeding and body weight in lean and obese females, with increased visceral adiposity; effects not observed in males. Even in the absence of ovarian steroids, which already results in obesity, loss of amygdala aromatase further exacerbated weight gain and hyperphagia on an obesogenic diet. In females, hyperphagia was driven by increased meal size and increased food-motivated behavior, with increased preference for fat-rich but not sucrose-rich foods. Loss of amygdala aromatase also led to disrupted thermoregulation, with increased temperature in males but reduced in females, linked to alteration in brown adipose tissue thermogenesis.</div></div><div><h3>Conclusions</h3><div>Collectively, our data reveal that estradiol synthesis in the brain is necessary for body weight and feeding behavior control, as well as thermoregulation, in a sex specific manner. Our findings may have translational and clinical relevance, as aromatase inhibitors are widely used in the clinic, and aromatase has recently been found in the human amygdala.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102202"},"PeriodicalIF":7.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diverse actions of 15 structurally unrelated mitochondrial uncouplers in cells and mice","authors":"Divya P. Shah ,&nbsp;Calum S. Vancuylenburg ,&nbsp;Ellen M. Olzomer ,&nbsp;Sing-Young Chen ,&nbsp;Robert J. Grams ,&nbsp;Martina Beretta ,&nbsp;Frances L. Byrne ,&nbsp;Webster L. Santos ,&nbsp;Kyle L. Hoehn","doi":"10.1016/j.molmet.2025.102204","DOIUrl":"10.1016/j.molmet.2025.102204","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Objective&lt;/h3&gt;&lt;div&gt;Mitochondrial uncouplers are used as chemical tools to study mitochondrial function &lt;em&gt;in vitro&lt;/em&gt; and &lt;em&gt;in vivo&lt;/em&gt;, and some molecules are in development for the treatment of metabolic diseases. One problem in the field is that any molecule that increases proton transport into the mitochondrial matrix independent of ATP production can be classified as an uncoupler regardless of off-target activities. Therefore, there are dozens of classes of molecules that exhibit a wide spectrum of phenotypes. Herein we directly compared 15 mitochondrial uncouplers side-by-side in a well-defined cell system to better understand their &lt;em&gt;in vitro&lt;/em&gt; dose response profiles and the top molecules with suitable pharmacology and safety profiles were compared in &lt;em&gt;db/db&lt;/em&gt; mice.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Fifteen mitochondrial uncouplers were characterised &lt;em&gt;in vitro&lt;/em&gt; in CHO–K1 cells. The top five candidates were selected for further characterisation in male &lt;em&gt;db/db&lt;/em&gt; mice based on their &lt;em&gt;in vitro&lt;/em&gt; dose response and/or tolerability. We tested two doses of each mitochondrial uncoupler in mice and benchmarked their efficacy to a lifestyle intervention of 35% calorie restriction as well as to lean &lt;em&gt;db/+&lt;/em&gt; metabolically healthy mice. Eleven groups of mice were fed &lt;em&gt;ad libitum&lt;/em&gt; either; 1) chow (control), 2) chow with 0.15% BAM15 (w/w), 3) chow with 0.2% BAM15 (w/w), 4) chow with 0.1% NEN (w/w), 5) chow with 0.25% NEN (w/w), 6) chow with 0.01% OPC-163493 (w/w), 7) chow with 0.02% OPC-63493 (w/w), 8) chow with 0.015% ES9 (w/w), 9) chow with 0.03% ES9 (w/w), 10) chow with 0.2% NTZ (w/w), and 11) chow with 0.4% NTZ (w/w). Another group of mice was fed chow to receive ∼65% of the average daily food intake of control mice as a model of calorie restriction (CR). Mice were metabolically phenotyped over 4 weeks of treatment with assessment of key readouts including body weight, HbA1c, blood glucose and glucose tolerance tests. At termination, key tissues were collected and plasma was analysed for markers of toxicity.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Few mitochondrial uncouplers behaved similarly &lt;em&gt;in vitro&lt;/em&gt;, with 11 molecules impairing maximal mitochondrial capacity. &lt;em&gt;In vivo&lt;/em&gt;, BAM15 dose-dependently improved body weight and metabolic parameters in &lt;em&gt;db/db&lt;/em&gt; mice, with 0.2% BAM15 treatment yielding statistically significant improvements in body weight, fat pad weight, glucose tolerance, blood glucose, HbA1c, liver weight and triglyceride content. The next-best treatment was 0.03% ES9 which significantly improved glucose tolerance, blood glucose levels, and HbA1c, but increased body weight, liver size and steatosis relative to &lt;em&gt;db/db&lt;/em&gt; controls.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Mitochondrial uncouplers BAM15 and ES9 had the greatest dose tolerance range &lt;em&gt;in vitro&lt;/em&gt;, while BAM15 had the best overall effects on body weight, glucose control and liver steatosis in","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102204"},"PeriodicalIF":7.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beta-hydroxybutyrate counteracts the deleterious effects of a saturated high-fat diet on synaptic AMPAR receptors and cognitive performance","authors":"Rocío Rojas ,&nbsp;Christian Griñán-Ferré ,&nbsp;Aida Castellanos ,&nbsp;Ernesto Griego ,&nbsp;Marc Martínez ,&nbsp;Juan de Dios Navarro-López ,&nbsp;Lydia Jiménez-Díaz ,&nbsp;José Rodríguez-Álvarez ,&nbsp;David Soto del Cerro ,&nbsp;Pablo E. Castillo ,&nbsp;Mercè Pallàs ,&nbsp;Núria Casals ,&nbsp;Rut Fadó","doi":"10.1016/j.molmet.2025.102207","DOIUrl":"10.1016/j.molmet.2025.102207","url":null,"abstract":"<div><div>The ketogenic diet —high in fat and low in carbohydrates— and intermittent fasting have gained popularity not only for weight management but also for their potential to delay cognitive decline associated with neurodegenerative diseases and aging. However, adherence to these diets remains low due to their restrictive nature and undesirable side effects. Both dietary approaches stimulate hepatic production of ketone bodies, primarily β-hydroxybutyrate (BHB), which serves as an alternative energy source for neurons. Here, we investigated whether BHB supplementation could mitigate AMPA receptor trafficking impairments, synaptic dysfunction, and cognitive decline induced by metabolic challenges such as a saturated fat-rich diet. Our results show that, in cultured primary cortical neurons, exposure to palmitic acid decreases surface levels of glutamate GluA1-containing AMPA receptors, whereas unsaturated fatty acids and BHB increase these levels. Furthermore, physiological concentrations of BHB (1–2 mM) countered the adverse effects of palmitic acid on synaptic GluA1 and GluA2 levels in hippocampal neurons, restoring AMPA receptor-mediated synaptic transmission. In hippocampal slices, BHB also reversed palmitate-induced impairments in excitability and synaptic plasticity (long-term potentiation; LTP). Additionally, daily intragastric administration of BHB (100 mg/kg/day for two months) prevented deficits in recognition and spatial memory induced by a saturated fat-rich diet (49% of calories from fat) in mice. In summary, our findings underscore the significant impact of fatty acids and ketone bodies on AMPA receptor abundance, synaptic function, and neuroplasticity, shedding light on the potential use of BHB as a dietary supplement to counteract cognitive impairments linked to metabolic diseases.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102207"},"PeriodicalIF":7.0,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel NPY2R agonist BI 1820237 provides synergistic anti-obesity efficacy when combined with the GCGR/GLP-1R dual agonist survodutide","authors":"Robert Augustin ,&nbsp;Anouk Oldenburger ,&nbsp;Tamara Baader-Pagler ,&nbsp;Tina Zimmermann ,&nbsp;Jens Borghardt ,&nbsp;Jacob Hecksher-Sørensen ,&nbsp;Angela Baljuls ,&nbsp;Wolfgang Reindl ,&nbsp;Bartlomiej Krawczyk ,&nbsp;Eric Martel ,&nbsp;Albert Brennauer ,&nbsp;Stefan Peters ,&nbsp;Achim Grube ,&nbsp;Lise Biehl Rudkjaer ,&nbsp;Peter Haebel","doi":"10.1016/j.molmet.2025.102205","DOIUrl":"10.1016/j.molmet.2025.102205","url":null,"abstract":"<div><h3>Objective</h3><div>Nutrient-stimulated gut hormone peptide YY3–36 (PYY3–36) selectively activates the neuropeptide Y2 receptor (NPY2R) and reduces energy intake in humans. We describe the discovery and pharmacology of the long-acting NPY2R agonist BI 1820237 and its potential bodyweight-lowering efficacy alone and in combination with the glucagon receptor (GCGR)/glucagon-like peptide-1 receptor (GLP-1R) dual agonist survodutide.</div></div><div><h3>Methods &amp; Results</h3><div>BI 1820237 dose-dependently reduced food intake and gastric emptying in lean mice. Significant bodyweight reductions were not observed with BI 1820237 alone in diet-induced obese mice, however combination with survodutide led to bodyweight reduction of 22% which was significantly (<em>p</em> &lt; 0.01) greater than the 17% bodyweight reduction with survodutide alone. Regression-based interaction analysis demonstrated that BI 1820237 increased the efficacy of survodutide by 265% at an ED50 of 11.7 nmol/kg over a range of dose combinations.</div></div><div><h3>Conclusion</h3><div>Synergistic NPY2R and GCGR/GLP-1R agonism provides an attractive mode of action for clinically relevant weight loss in patients with obesity.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102205"},"PeriodicalIF":7.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endurance training promotes chromatin closure and timely repression of the post-exercise immediate early stress response","authors":"Laura M. de Smalen,&nbsp;Volkan Adak,&nbsp;Aurel B. Leuchtmann ,&nbsp;Konstantin Schneider-Heieck ,&nbsp;Stefan A. Steurer,&nbsp;Christoph Handschin","doi":"10.1016/j.molmet.2025.102206","DOIUrl":"10.1016/j.molmet.2025.102206","url":null,"abstract":"<div><h3>Objectives</h3><div>Endurance training is known to elicit numerous changes in skeletal muscle to enhance performance and function. Many of these adaptations are controlled by the modulation of transcriptional programs in myonuclei. While previous studies have explored alterations in DNA methylation and histone modifications in response to exercise, the specific changes in chromatin restructuring and accessibility, a prerequisite for transcription, are still poorly understood.</div></div><div><h3>Methods</h3><div>A multi-omics analysis was performed: ATAC-sequencing was used to map chromatin accessibility in myonuclei isolated from endurance-trained and untrained mice at multiple time points (0 h, 6 h, and 72 h) post-exercise. Gene expression was assessed via RNA-sequencing, and motif activity analysis identified regulatory factors involved in exercise-induced chromatin remodeling and transcriptomic response.</div></div><div><h3>Results</h3><div>Endurance training amplified rapid chromatin closing immediately after exercise, with trained muscle exhibiting a more pronounced loss of chromatin accessibility at 0 h and 6 h post-exercise compared to untrained muscle. These chromatin accessibility changes persisted longer in trained muscle, with significant retention until 72 h post-exercise. Immediate early transcription factors, such as Fos and Jun, showed a training state-dependent shift in activation dynamics. Similarly, specific modulation of genes involved in metabolism, insulin response and angiogenesis was observed.</div></div><div><h3>Conclusions</h3><div>Endurance training triggers rapid and persistent chromatin remodeling in muscle, contributing to the transcriptional response to exercise. Our findings suggest that training induces long-lasting epigenetic changes, potentially underpinning muscle memory and improved physiological resilience. These new insights into the molecular mechanisms of muscle adaptation help to understand the training response, and might become relevant in disease prevention.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102206"},"PeriodicalIF":7.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kynurenic acid derived from mesentery regulates mesenteritis and colitis via inducing white adipose browning in Crohn’s disease","authors":"Yongheng Wang ,&nbsp;Ritian Lin ,&nbsp;Fangtao Wang ,&nbsp;Huijun Fu ,&nbsp;Xia Wang ,&nbsp;Fengshan Jin ,&nbsp;Qiao Wang ,&nbsp;Weigang Shu","doi":"10.1016/j.molmet.2025.102203","DOIUrl":"10.1016/j.molmet.2025.102203","url":null,"abstract":"<div><h3>Objective</h3><div>Hypertrophied mesenteric adipose tissue (MAT) wrapped around the inflamed intestine, also known as creeping fat (CrF), is a classic pathological characteristic of Crohn’s disease (CD). Recent studies revealed that the abnormal mesentery in CD exhibits a white-to-beige transformation (known as white adipose browning), which may be a compensatory mechanism for disease attenuation. However, its underlying causes and mechanisms remain unknown.</div></div><div><h3>Methods</h3><div>The beige MAT samples from patients with CD and normal white MAT samples from patients without CD were collected, and targeted metabolome analysis was performed. Interleukin-10 gene knockout <em>(IL-10</em>^−/−<em>)</em> and 2,4,6-trinitrobenzenesulphonic acid solution (TNBS)-induced colitis mice were used to evaluate the effects of kynurenic acid (KYNA) on mesenteritis and colitis. Mesenteric explants and adipocytes were collected and cultured to assess the effects of KYNA on adipose tissue browning and macrophage inflammation.</div></div><div><h3>Results</h3><div>Targeted metabolomic sequencing revealed that KYNA exhibited the highest level of upregulation in the beige MAT of CD, which was tightly correlated with the browning marker UCP-1, inflammatory factors, and adipokines. <em>In vivo</em> experiments demonstrated that KYNA triggered the white-to-beige transformation of MAT in <em>IL-10</em>^−/− and TNBS-induced colitis mice, which further alleviated mesenteritis and colitis. Additionally, mesenteric explants and adipocytes displayed a browning phenotype with KYNA co-incubation, and their supernatants significantly induced M2 macrophage polarization and inhibited inflammation. Mechanistically, KYNA induced MAT browning and regulated disease procession of CD via GPR35-ERK1/2-PGC-1α signaling pathway.</div></div><div><h3>Conclusions</h3><div>This study provides novel insights into the browning transformation of the mesentery in CD and suggests a potential approach for clinical therapy.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102203"},"PeriodicalIF":7.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complete loss of PAX4 causes transient neonatal diabetes in humans","authors":"James Russ-Silsby ,&nbsp;Yunkyeong Lee ,&nbsp;Varsha Rajesh ,&nbsp;Mahsa Amoli ,&nbsp;Nasser Ali Mirhosseini ,&nbsp;Tushar Godbole ,&nbsp;Matthew B. Johnson ,&nbsp;D. Evelyn Ibarra ,&nbsp;Han Sun ,&nbsp;Nicole A.J. Krentz ,&nbsp;Matthew N. Wakeling ,&nbsp;Sarah E. Flanagan ,&nbsp;Andrew T. Hattersley ,&nbsp;Anna L. Gloyn ,&nbsp;Elisa De Franco","doi":"10.1016/j.molmet.2025.102201","DOIUrl":"10.1016/j.molmet.2025.102201","url":null,"abstract":"<div><h3>Objective</h3><div>Gene discovery studies in individuals with diabetes diagnosed within 6 months of life (neonatal diabetes, NDM) can provide unique insights into the development and function of human pancreatic beta-cells.</div></div><div><h3>Methods</h3><div>We performed genome sequencing in a cohort of 43 consanguineous individuals with NDM in whom all the known genetic causes had previously been excluded. We used quantitative PCR and RNA-sequencing in CRISPR-edited human induced pluripotent stem cells (iPSCs), and CUT&amp;RUN-sequencing in EndoC-βH1 cells to investigate the effect of <em>PAX4</em> loss on human pancreatic development.</div></div><div><h3>Results</h3><div>We describe the identification of homozygous <em>PAX4</em> loss-of-function variants in 2 individuals with transient NDM: a p.(Arg126∗) stop-gain variant and a c.-352_104del deletion affecting the first 4 <em>PAX4</em> exons. We confirmed the p.(Arg126∗) variant causes nonsense mediated decay in CRISPR-edited iPSC-derived pancreatic endoderm cells. Integrated analysis of CUT&amp;RUN-sequencing in EndoC-βH1 cells and RNA-sequencing in <em>PAX4</em>-depleted islet stem cell models identified genes directly regulated by PAX4 involved in both pancreatic islet development and glucose-stimulated insulin secretion.</div></div><div><h3>Conclusion</h3><div>We report the first human cases of complete loss of <em>PAX4</em>, establishing it as a novel cause of NDM and highlighting its role in human beta cell development. Both probands had transient NDM which remitted in early infancy but relapsed at the ages of 2.4 and 6.7 years, demonstrating that in contrast to mouse models, PAX4 is not essential for the development of human pancreatic beta-cells.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102201"},"PeriodicalIF":7.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inactivity-induced NR4A3 downregulation in human skeletal muscle affects glucose metabolism and translation: Insights from in vitro analysis","authors":"Jonathon A.B. Smith ,&nbsp;Brendan M. Gabriel ,&nbsp;Aidan J. Brady ,&nbsp;Ahmed M. Abdelmoez ,&nbsp;Mladen Savikj ,&nbsp;Shane C. Wright ,&nbsp;Stefania Koutsilieri ,&nbsp;Romain Barrès ,&nbsp;Volker M. Lauschke ,&nbsp;Anna Krook ,&nbsp;Juleen R. Zierath ,&nbsp;Nicolas J. Pillon","doi":"10.1016/j.molmet.2025.102200","DOIUrl":"10.1016/j.molmet.2025.102200","url":null,"abstract":"<div><h3>Objective</h3><div>Physical activity promotes health, whereas inactivity is associated with metabolic impairment. The transcription factor nuclear receptor subfamily 4 group A member 3 (NR4A3) is a pleiotropic regulator of skeletal muscle exercise adaptation and metabolism. However, the consequence of lower NR4A3 expression remains largely unexplored. We investigated the impact of NR4A3 downregulation on human skeletal muscle metabolism.</div></div><div><h3>Methods</h3><div>Published transcriptomic datasets from human bed rest and limb immobilisation studies were curated to meta-analyse the effect of physical inactivity on skeletal muscle <em>NR4A3</em> levels. In primary human skeletal myotubes, siRNA and lentivirus were used to silence and overexpress <em>NR4A3</em>, respectively. Basal and stimulated (insulin ± leucine) signal transduction was determined by immunoblot analysis. Effects on glucose, fatty acid, and protein metabolism were measured using radiolabelled substrate assays. Lactate production was assessed in culture supernatant by colourimetry. Cell morphology was analysed by immunocytochemistry and gene expression was quantified by RT-qPCR.</div></div><div><h3>Results</h3><div>Physical inactivity decreased skeletal muscle <em>NR4A3</em> (−27%), concomitant with pathways related to mitochondrial function, cytoskeleton organization, chromatin regulation, protein synthesis and degradation. Silencing of <em>NR4A3</em> reduced glucose oxidation (−18%) and increased lactate production (+23%) <em>in vitro</em>. This coincided with greater signalling downstream of AMPK and elevated rates of basal (+26%) and FCCP-stimulated (+55%) fatty acid oxidation. NR4A3 downregulation lowered protein synthesis (−25%), and impaired mTORC1 signalling and ribosomal transcription. Alternatively, overexpression of the canonical NR4A3 protein isoform (+290%) augmented translation and total cellular protein content, which protected myotubes against dexamethasone-induced atrophy. Moreover, partial restoration of <em>NR4A3</em> levels rescued glucose oxidation in <em>NR4A</em><em>3</em>-silenced muscle cells and restored phosphorylation of mTORC1 substrates. NR4A3 depletion reduced myotube area (−48%) and further altered protein and gene expression of key contractile elements in skeletal muscle.</div></div><div><h3>Conclusions</h3><div>Our study connects reduced NR4A3 expression with physical inactivity and indicates that NR4A3 downregulation in human skeletal muscle has adverse effects on glucose metabolism and protein synthesis. Thus, decrements in NR4A3 abundance could be causal in the deleterious health consequences resulting from sedentary lifestyles and targeting NR4A3 may offer new avenues for combating conditions such as disuse muscle atrophy.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102200"},"PeriodicalIF":7.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dorsal raphe nucleus MC4R-GABAergic neurons regulate feeding and anxiety","authors":"Satoshi Yamagata ,&nbsp;Francesca Copperi ,&nbsp;Gavin Thomas White ,&nbsp;Jung Dae Kim ,&nbsp;Sabrina Diano","doi":"10.1016/j.molmet.2025.102199","DOIUrl":"10.1016/j.molmet.2025.102199","url":null,"abstract":"<div><h3>Objective</h3><div>The melanocortin receptor 4 (MC4R) plays a key role in the CNS regulation of metabolism. In addition to its role within the hypothalamus, other brain areas, including the dorsal raphe nucleus (DRN), express MC4R. However, the identity and role of these neurons in metabolism regulation are not fully understood. We performed studies to address these questions.</div></div><div><h3>Methods</h3><div>We generated <em>Mc4r-cre;Vgat-FlpO</em> and <em>Mc4r-cre;Vglut2-FlpO</em> mice to determine the contribution of these MC4R neuronal populations in DRN. We then chemogenetically activated or inhibited the GABAergic and glutamatergic populations of MC4R. Finally, we selectively deleted MC4R from these two neuronal populations and studied the impact on whole-body metabolism.</div></div><div><h3>Results</h3><div>We found that about 60% of DRN MC4R neurons are GABAergic (Vgat), while only about 20% are glutamatergic (Vglut2). Most of the projections onto DRN neurons originated from the arcuate nucleus (ARC)-POMC neurons, and only a small input from the nucleus of the solitary tract (NTS)-POMC neurons was identified. Significant projections of DRN MC4R/Vgat neurons were observed in the paraventricular nucleus of the hypothalamus (PVN). Chemogenetic activation or inhibition of MC4R/Vgat neurons increased or inhibited food intake, respectively. No effects were observed when the same approach was used in MC4R/Vglut2 neurons. Furthermore, only chemogenetic manipulation of the MC4R/Vgat neurons affected anxiety-like behavior, which was associated with changes in serotonin staining in the DRN. Finally, MC4R-selective deletion in Vgat but not Vglut2 neurons affected whole-body metabolism.</div></div><div><h3>Conclusions</h3><div>These findings suggest that DRN MC4R/Vgat neurons receiving projections from the ARC POMC neurons and projecting to the hypothalamic PVN play a role in metabolism regulation. In addition, this same DRN neuronal subpopulation affects anxiety-like behavior by modulating DRN serotonin neurons.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102199"},"PeriodicalIF":7.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An epigenome atlas of mouse adipocytes","authors":"Laura C. Hinte ,&nbsp;Adhideb Ghosh ,&nbsp;Daniel Castellano-Castillo ,&nbsp;Christian Wolfrum ,&nbsp;Ferdinand von Meyenn","doi":"10.1016/j.molmet.2025.102197","DOIUrl":"10.1016/j.molmet.2025.102197","url":null,"abstract":"<div><h3>Objective</h3><div>Epigenetic modifications including histone post translational modifications can influence gene expression in adipocytes, potentially contributing to metabolic dysfunctions, obesity, and insulin resistance. Despite recent advances in the characterization of the mouse adipocyte epigenome, epigenetic characterization of adipocytes <em>in vivo</em> has been challenging, particularly across different adipose depots and of several epigenetic modifications.</div></div><div><h3>Methods</h3><div>Here, we use specific reporter mice labelling brown, beige and white adipocytes, diphtheria toxin-mediated ablation of beige adipocytes, and Cleavage Under Targets and Tagmentation (CUT&amp;Tag) to generate paired single mouse datasets of five histone marks. We perform an integrative multi-omics factor analysis (MOFA) of H3K4me3, H3K27me3, H3K4me1, H3K27ac and H3K9me3 in brown, white and beige adipocytes from three distinct mouse adipose tissue depots obtained during cold exposure and thermoneutrality.</div></div><div><h3>Results</h3><div>Our analysis reveals that enhancers distinguish adipocytes by their tissue of origin, with H3K4me1 deposition differentiating between beige and brown adipocytes. Beige adipocytes poised promoters associated to thermogenic genes during warming. Diphtheria toxin-mediated ablation of beige adipocytes shows that non-beigeing white adipocytes in inguinal adipose tissue and beige adipocytes are not inherently epigenetically different suggesting that they share a common developmental progenitor.</div></div><div><h3>Conclusions</h3><div>These paired multimodal data comprise an extensive resource (<span><span>https://github.com/vonMeyennLab/mAT_CE_Atlas</span><svg><path></path></svg></span>) for the further exploration of the mouse adipocyte epigenome which will enable discovery of regulatory elements governing adipocyte identity and gene regulation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102197"},"PeriodicalIF":7.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}