Molecular Metabolism最新文献

{"title":"Nuclear receptor co-factor TBL1X/TBL1XR1 T cell activity protects against atherosclerosis","authors":"Sahika Cingir Koker ,&nbsp;Amit Mhamane ,&nbsp;Julia Geppert ,&nbsp;George Shakir ,&nbsp;Raquel Guillamat-Prats ,&nbsp;Bingni Chen ,&nbsp;Pernilla Katra ,&nbsp;Martina Geiger ,&nbsp;Foivos-Filippos Tsokanos ,&nbsp;Gretchen Wolff ,&nbsp;Julia Szendrödi ,&nbsp;Maria Rohm ,&nbsp;Carolin Daniel ,&nbsp;Lars Maegdefessel ,&nbsp;Sabine Steffens ,&nbsp;Stephan Herzig","doi":"10.1016/j.molmet.2026.102318","DOIUrl":"10.1016/j.molmet.2026.102318","url":null,"abstract":"<div><div>Atherosclerosis is a long-term complication of obesity and diabetes and as such a key driver of vascular dysfunction and eventually mortality in affected patients. Both aberrant lipid metabolism and inflammatory reactions promote atherosclerotic plaque development in the vessel wall by triggering a cascade of cellular events involving multiple cell types, including smooth muscle cells, monocytic macrophages, and lymphocytes. Despite its eminent impact on human health, molecular drivers of cellular dysfunction in atherosclerosis remain poorly defined and therapeutic options are scarce.</div><div>Here we show by single-cell RNA sequencing that the expression of the nuclear receptor co-factors, TBL1X and TBL1XR1, was particularly prominent in the CD4⁺ T cell population of human carotid artery plaques. Indeed, genetic double deletion of TBL1X/TBL1XR1 in CD4⁺ T cells led to a substantial shift from naïve CD44^lowCD62L^hi cells to CD44^hiCD62L^low effector and Foxp3⁺ Tregs. CD4⁺ TBL1X/TBL1XR1 KO cells exhibited enhanced cytokine production capacity upon ionomycin/PMA stimulation, correlating with the induction of pro-inflammatory and cytokine-producing transcriptional pathways in these cells. Consistently, transplantation of bone marrow from CD4⁺-specific TBL1X/TBL1XR1 knock out mice into LDLR KO recipients doubled the development of atherosclerotic plaques in the aortic arch compared with wild-type bone marrow transplanted littermates. As TBL1X/TBL1XR1 expression levels were diminished in carotid arteries from patients with advanced unstable plaques compared to stable plaques or healthy controls, these data suggest that aberrant inhibition of TBL1X/TBL1XR1 in CD4⁺ T cells may contribute to the development of atherosclerosis in humans. Restoration of TBL1X/TBL1XR1 functionality may thus serve as a novel, druggable strategy for preventing or limiting atherosclerosis progression.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102318"},"PeriodicalIF":6.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990100","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":"Branched chain amino acids prime metabolic inflammation","authors":"Nandini K. Doshi ,&nbsp;Tristan Pesaresi ,&nbsp;Trishya Pagadala ,&nbsp;William Dion ,&nbsp;Yang Zhang ,&nbsp;Natalie L. David ,&nbsp;Tânia Amorim ,&nbsp;Wenjia Wang ,&nbsp;G.V. Naveen Kumar ,&nbsp;Bokai Zhu ,&nbsp;Silvia Liu ,&nbsp;Parth Patwari ,&nbsp;Pouneh K. Fazeli ,&nbsp;Matthew L. Steinhauser","doi":"10.1016/j.molmet.2025.102308","DOIUrl":"10.1016/j.molmet.2025.102308","url":null,"abstract":"<div><div>Sterile inflammation is associated with a broad range of metabolic stressors including both dietary excess and prolonged fasting. In a 10-day human fasting study, we previously identified a surge in the circulating inflammatory biomarker, C-reactive protein (CRP), which we leveraged in the current study to identify novel metabolic inflammatory correlates. With a variety of longitudinal metabolic variables as input, including metabolomics, we identified branched chain amino acids (BCAA) as the top candidate inflammatory correlate. We then used <em>in vitro</em> myeloid/macrophage culture and <em>in vivo</em> murine models to test BCAA as a determinant of inflammatory signaling. Short-term exposure to BCAA alone had modest effects on a variety of immune readouts; however, when coupled with a second stimulus, such as exposure to endotoxin or when administered to diet-induced obese mice, members of the JAK/STAT/cytokine signaling pathways were augmented on the transcriptional level by concurrent BCAA administration in multiple tissues, including visceral adipose and liver. The modifying effect of BCAA on inflammatory stressors translated into increased levels of circulating inflammatory cytokines. Collectively, these data position BCAA as an immune priming factor, a potential mechanism underlying the well-established association between circulating BCAA and diverse diseases of aging.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102308"},"PeriodicalIF":6.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775023","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":"Effect of free fatty acids on TGF-β1 mediated fibrogenesis in hepatic stellate cells","authors":"William De Nardo ,&nbsp;Jacqueline Bayliss ,&nbsp;Sheik Nadeem Elahee Doomun ,&nbsp;Olivia Lee ,&nbsp;Paula M. Miotto ,&nbsp;Natasha D. Suriani ,&nbsp;Shuai Nie ,&nbsp;Michael Leeming ,&nbsp;Diego A. Miranda ,&nbsp;David P. De Souza ,&nbsp;Matthew J. Watt","doi":"10.1016/j.molmet.2025.102309","DOIUrl":"10.1016/j.molmet.2025.102309","url":null,"abstract":"<div><h3>Abstract/objective</h3><div>Metabolic associated steatotic liver disease (MASLD) is the most prevalent liver disorder and a major risk factor for hepatic fibrosis. Activated hepatic stellate cells (HSCs) are the primary source of collagen production in the liver, contributing to fibrosis. However, the mechanisms by which HSCs reprogram their metabolism to support sustained collagen production, particularly in a lipid-rich environment such as MASLD, remain inadequately understood. In this study, we investigated the effect of extracellular fatty acids on HSC substrate metabolism, HSC activation, and collagen synthesis.</div></div><div><h3>Methods</h3><div>Immortalized human HSCs (LX-2 cells) were cultured with or without transforming growth factor-beta 1 (TGF-β1) and varying concentrations of palmitate or oleate. Cellular lipid composition was assessed by mass spectrometry lipidomics. Fatty acid metabolism was assessed using radiometric techniques and isotopic labelling experiments using ¹³C-glucose or ¹³C-palmitate. HSC activation was assessed by measuring <em>ACTA2, TGFB1, and COL1A1</em> mRNA levels and collagen secretion by ELISA.</div></div><div><h3>Results</h3><div>TGF-β1 reduced the abundance of many lipid types in LX-2 cells. Exogenous palmitate did not increase HSC activation, as determined by <em>ACTA2, TGFB1, COL1A1</em> mRNA levels. Palmitate potentiated TGF-β1 induced collagen secretion but not in the presence of oleate. Palmitate reduced glucose incorporation into glycine in activated HSCs and induced a reciprocal increase in palmitate incorporation into glycine, most likely via carbons derived from TCA cycle intermediates. Pharmacological inhibition of fatty acid uptake reduced TGF-β1-mediated collagen secretion.</div></div><div><h3>Conclusions</h3><div>These results suggest that in activated HSCs, palmitate oxidation is reduced and that TCA cycle intermediates derived from palmitate are used as carbon sources for amino acid production that supports collagen synthesis and secretion.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102309"},"PeriodicalIF":6.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794426","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":"Targeting DHODH reveals a metabolic vulnerability in AR-positive and AR-negative prostate cancer cells via pyrimidine synthesis and metabolic crosstalk with the TCA and urea cycles","authors":"Maxime Labroy ,&nbsp;Marc-Oliver Paré ,&nbsp;Line Berthiaume ,&nbsp;Mélissa Thomas ,&nbsp;Cynthia Jobin ,&nbsp;Alain Veilleux ,&nbsp;Martin Pelletier ,&nbsp;Frédéric Pouliot ,&nbsp;Jean-Yves Masson ,&nbsp;Étienne Audet-Walsh","doi":"10.1016/j.molmet.2025.102316","DOIUrl":"10.1016/j.molmet.2025.102316","url":null,"abstract":"<div><div>Following recurrence, the cornerstone clinical therapy to treat prostate cancer (PCa) is to inhibit the androgen receptor (AR) signaling. While AR inhibition is initially successful, tumors will eventually develop treatment resistance and evolve into lethal castration-resistant PCa. To discover new anti-metabolic treatments for PCa, a high-throughput anti-metabolic drug screening was performed in PC3 cells, an AR-negative PCa cell line. This screening identified the dihydroorotate dehydrogenase (DHODH) enzyme as a metabolic vulnerability, using both AR-positive and AR-negative models, including the neuroendocrine cell line LASCPC-01 and patient-derived organoids. DHODH is required for <em>de novo</em> pyrimidine synthesis and is the sole mitochondrial enzyme of this pathway. Using extracellular flux assays and targeted metabolomics, DHODH inhibition was shown to impair the pyrimidine synthesis pathway, as expected, along with a significant reprogramming of mitochondrial metabolism, with a massive increase in fumarate (&gt;10-fold). Using ¹³C₆-glucose, it was shown that following DHODH inhibition, PCa cells redirect carbons from glucose toward biosynthetic pathways rather than the TCA cycle. In parallel, using ¹³C₅-glutamine, it was shown that PCa cells use this amino acid to fuel a reverse TCA cycle. Finally, ¹³C₁-aspartate and ¹⁵N₁-glutamine highlighted the connection between pyrimidine synthesis and the urea cycle, redirecting pyrimidine synthesis intermediates toward the urea cycle as a stress response mechanism upon DHODH inhibition. Consequently, combination therapies targeting DHODH and glutamine metabolism were synergistic in impairing PCa cell proliferation. Altogether, these results highlight DHODH as a metabolic vulnerability of AR-positive and AR-negative PCa cells by regulating central carbon and nitrogen metabolism.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102316"},"PeriodicalIF":6.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934061","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":"TRPM7 kinase regulates α-cell proliferation and glucagon production in mice","authors":"Severin Boulassel ,&nbsp;Pascale C.F. Schreier ,&nbsp;Andreas Beck ,&nbsp;Hyeri Choi ,&nbsp;Anna M. Melyshi ,&nbsp;Peter S. Reinach ,&nbsp;Megan Duraj ,&nbsp;Mikhail Vinogradov ,&nbsp;Bibiazhar Suleimen ,&nbsp;Johanna Berger ,&nbsp;Katharina Jacob ,&nbsp;Andreas Breit ,&nbsp;Susanna Zierler ,&nbsp;Ingrid Boekhoff ,&nbsp;Thomas Gudermann ,&nbsp;Noushafarin Khajavi","doi":"10.1016/j.molmet.2026.102317","DOIUrl":"10.1016/j.molmet.2026.102317","url":null,"abstract":"<div><h3>Objectives</h3><div>Glucagon is essential for maintaining glucose homeostasis, yet the molecular mechanisms governing α-cell function remain incompletely understood. Transient receptor potential melastatin 7 (TRPM7) is a ubiquitously expressed ion channel with an intrinsic kinase domain, which regulates the mammalian target of rapamycin (mTOR) signaling in various cell types. Given the central role of mTOR in α-cell regulation, this study investigates how TRPM7 influences α-cell biology and examines whether its function is modulated through interaction with the mTOR signaling pathway.</div></div><div><h3>Methods</h3><div>Islets were isolated from wild-type (WT) mice and mice lacking TRPM7 kinase activity (<em>Trpm7</em>^<em>R/R</em>). Functional analyses included Bio-Plex assays, RNA sequencing, glucagon ELISA, qRT-PCR, Western blotting, immunocytochemistry, and patch-clamp recordings. αTC1c9 cells were used as a murine α-cell model. NS8593, a small synthetic compound, was used as a potent TRPM7 inhibitor.</div></div><div><h3>Results</h3><div><em>Ex vivo</em> analysis revealed impaired mTOR signaling in <em>Trpm7</em>^<em>R/R</em> islets. <em>Trpm7</em>^<em>R/R</em> islets secreted less glucagon in response to various secretagogues compared to WT controls. This reduction was partially caused by diminished glucagon content due to downregulation of key transcriptional regulators of glucagon biosynthesis, including <em>Gcg</em> and <em>Mafb</em>. Morphological analysis identified reduced proliferation and enhanced apoptosis of <em>Trpm7</em>^<em>R/R</em> α-cells. Similarly, pharmacological inhibition of TRPM7 impaired mTOR signaling, suppressed α -cell identity, and α-cell proliferation in both WT islets and αTC1c9 cells.</div></div><div><h3>Conclusions</h3><div>Loss of TRPM7 kinase function impairs mTOR signaling, leading to reduced α-cell proliferation and glucagon secretion. Our findings show that the TRPM7 kinase/mTOR signaling pathway axis is a critical regulator of α-cell function in mice.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102317"},"PeriodicalIF":6.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952517","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":"Vagal sensory neurons encode internal protein status to guide eating","authors":"M. Yang ,&nbsp;A. de Araujo ,&nbsp;J. Shakir ,&nbsp;I. Braga ,&nbsp;R. Mendez-Hernandez ,&nbsp;G.S.S. Tofani ,&nbsp;A. Bali ,&nbsp;J. de Lartigue ,&nbsp;H. Song ,&nbsp;J.E. McCutcheon ,&nbsp;C.D. Morrison ,&nbsp;G. de Lartigue","doi":"10.1016/j.molmet.2025.102303","DOIUrl":"10.1016/j.molmet.2025.102303","url":null,"abstract":"<div><div>Animals adaptively adjust nutrient intake based on internal physiological need. Although protein deficiency elicits robust behavioral and endocrine responses, the sensory mechanisms that detect dietary protein and guide selective feeding remain incompletely understood. Here, we identify a population of vagal sensory neurons that respond selectively to intragastric protein and are required for adaptive regulation of protein intake. Using activity-dependent genetic labeling and in vivo calcium imaging, we show that these neurons are activated by dietary protein, exhibit enhanced responses in protein-restricted states, and are distinct from previously characterized calorie-sensing populations. Selective ablation of protein-responsive vagal sensory neurons disrupts the ability to adapt eating behavior to internal protein need, blunts motivation to work for protein rewards, and prevents behavioral updating following protein repletion. These neurons also mediate protein-specific satiety, limiting further protein intake without affecting carbohydrate consumption. Notably, protein preference is suppressed under mild caloric restriction, indicating that caloric and amino acid needs are hierarchically organized and likely monitored by separate interoceptive systems. Our findings reveal a novel vagal circuit that integrates internal protein status with nutrient-specific cues to guide adaptive protein appetite and maintain amino acid homeostasis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102303"},"PeriodicalIF":6.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781567","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":"Impaired hepatic metabolism in Hereditary Fructose Intolerance confers fructose-independent risk for steatosis and hypertriglyceridemia","authors":"Melissa A. Fulham ,&nbsp;John D. Griffin ,&nbsp;Sylvie Perez ,&nbsp;Zhongyuan Sun ,&nbsp;Natalie A. Daurio ,&nbsp;Gang Xing ,&nbsp;Michelle F. Clasquin ,&nbsp;Melissa R. Miller ,&nbsp;Craig L. Hyde ,&nbsp;Scott P. Kelly ,&nbsp;Magalie Boucher ,&nbsp;Rachel Poskanzer ,&nbsp;Ramya Gamini ,&nbsp;Evanthia Pashos ,&nbsp;Ying Zhang ,&nbsp;Elaine Kuang ,&nbsp;Josh Fienman ,&nbsp;Kendra K. Bence ,&nbsp;Gregory J. Tesz","doi":"10.1016/j.molmet.2025.102310","DOIUrl":"10.1016/j.molmet.2025.102310","url":null,"abstract":"<div><h3>Objectives</h3><div>Hereditary fructose intolerance (HFI), caused by Aldolase B deficiency, is a rare genetic disorder where fructose exposure leads to severe metabolic pathologies including Type-2 diabetes and liver steatosis. Despite adhering to fructose-free diets, some individuals still present with disease. Using a rat model of HFI we demonstrate that fructose independent pathologies exist and identify the molecular pathways driving disease.</div></div><div><h3>Methods</h3><div><em>Aldob</em> was deleted in Sprague Dawley rats using CRIPSR/Cas9 (AldoB-KO). Phenotypic, metabolomic and transcriptomic studies were conducted to identify mechanisms promoting fructose-independent pathologies. Potential molecular causes were tested using pharmacologic inhibitors and ASOs.</div></div><div><h3>Results</h3><div>Deletion of <em>Aldob</em> caused hepatic steatosis, fibrosis and stunted growth in rats weaned on low fructose chow recapitulating human HFI. On fructose-free chow, AldoB-KO rats were phenotypically normal. However, upon fasting, male and female AldoB-KO rats developed hepatic steatosis and hyperlipidemia due to impaired fatty acid oxidation (FAOx) and elevated de novo lipogenesis (DNL). Transcriptional and metabolomic profiling revealed increased hepatic Carbohydrate Response Element Binding Protein (ChREBP) activation in AldoB-KO rats due to glycolytic metabolite accumulation caused by impaired gluconeogenesis. Treatment with Acetyl-CoA Carboxylase (ACC) and Diacylglycerol Acyl Transferase 2 (DGAT2) inhibitors reduced hepatic lipids and plasma triglycerides in AldoB-KO rats. Finally, using electronic health records we observed increased metabolic dysfunction-associated steatohepatitis (MASH) diagnosis in individuals with HFI.</div></div><div><h3>Conclusions</h3><div><em>Aldob</em> deletion caused fructose-independent hyperlipidemia and steatosis upon fasting in rats. Individuals with HFI may have risk for hepatic disease and hyperlipidemia even upon fructose abstinence suggesting additional therapies may be needed to mitigate disease.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102310"},"PeriodicalIF":6.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805074","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":"Diet and temperature interactively impact brown adipose tissue gene regulation controlled by DNA methylation","authors":"Tobias Hagemann ,&nbsp;Anne Hoffmann ,&nbsp;Kerstin Rohde-Zimmermann ,&nbsp;Helen Broghammer ,&nbsp;Lucas Massier ,&nbsp;Peter Kovacs ,&nbsp;Michael Stumvoll ,&nbsp;Matthias Blüher ,&nbsp;John T. Heiker ,&nbsp;Juliane Weiner","doi":"10.1016/j.molmet.2025.102315","DOIUrl":"10.1016/j.molmet.2025.102315","url":null,"abstract":"<div><h3>Background</h3><div>Controlling brown adipose tissue (BAT) plasticity offers potential for novel obesity therapies. DNA methylation is closely linked to thermogenic and metabolic pathways and thereby influences BAT function. How metabolic state and cold exposure interact to shape methylation-dependent BAT gene regulation was investigated.</div></div><div><h3>Methods</h3><div>Five-week-old mice were fed either chow for 11 weeks (lean) or high-fat diet for 22 weeks to induce obesity (DIO), after which cold exposure was applied for seven days. BAT transcriptomes (RNAseq) and methylomes (RRBS) were generated, and differentially methylated and expressed genes (DMEGs) showing metabolic state–dependent cold responses were identified. Pathway enrichment, epigenetic regulator screening, and transcription factor (TF) motif analyses were performed. DNA methylation was experimentally modulated <em>in vitro</em> to validate selected gene expression responses.</div></div><div><h3>Results</h3><div>A total of 1,364 differentially expressed genes (DEGs) were uniquely affected by the interaction of metabolic state and cold, with most downregulated in DIO mice. Sixty-five DMEGs (4 % of DEGs) showed metabolic state–specific responses to cold. In DIO mice, DMEGs were enriched in pathways associated with mitochondrial dysfunction, altered lipid metabolism, neuroendocrine signaling, and stress responses. Several epigenetic regulators, including <em>Tet2, Dnmt3a,</em> and <em>Apobec1</em>, exhibited metabolic state- and cold-dependent expression, and TF-motif analyses highlighted roles for AhrArnt and Foxn1. In vitro assays confirmed that DNA methylation influences expression of thermogenic genes.</div></div><div><h3>Conclusion</h3><div>These findings provide the first evidence that the epigenetic cold response of BAT differs by metabolic condition. BAT remodeling is shaped by coordinated transcriptional and epigenetic mechanisms integrating environmental and metabolic cues.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102315"},"PeriodicalIF":6.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896141","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":"Deciphering tissue-specific protein regulation for insights into cardiometabolic disease","authors":"April E. Hartley ,&nbsp;Katyayani Sukhavasi ,&nbsp;Sile Hu ,&nbsp;Matthew Traylor ,&nbsp;Mar Gonzalez-Ramirez ,&nbsp;Kristian Ebbesen Hanghøj ,&nbsp;Husain Talukdar ,&nbsp;Arno Ruusalepp ,&nbsp;Ellen Björkegren ,&nbsp;Johan LM. Björkegren ,&nbsp;Joanna MM. Howson ,&nbsp;Yalda Jamshidi","doi":"10.1016/j.molmet.2025.102314","DOIUrl":"10.1016/j.molmet.2025.102314","url":null,"abstract":"<div><div>Understanding tissue-specific mechanisms of protein regulation gives crucial insights into cardiometabolic disease and informs drug discovery. Most proteomic studies have primarily concentrated on plasma, overlooking tissue-specific effects. Utilizing Olink technology, we assessed relative protein levels across plasma and tissue (aortic wall, mammary artery, liver, and skeletal muscle) from the STARNET cohort: 284 individuals with a high prevalence of coronary artery disease (CAD). We identified 608 <em>cis</em> protein quantitative trait loci (pQTLs), primarily in plasma, reflecting greater protein variability. Of 190 proteins with <em>cis</em>-pQTLs in non-plasma tissues, 50% also had plasma pQTLs, validating Olink technology in these tissues while reinforcing the relevance of plasma data for understanding protein regulation. To identify potential mechanistic pathways linking genetic variants to clinical traits, we performed Bayesian colocalization and Mendelian randomization. These analyses revealed shared genetic regulation between tissues at the gene expression and protein level, and key cardiometabolic traits including low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides. Notably, analyses provide further support to SORT1 and PSRC1 gene and protein expression having liver-specific influences on CAD risk and lipid profiles. We also observed distinct genetic regulation of gene expression and protein within the same tissues, underscoring the value of tissue proteomics for therapeutic insights.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102314"},"PeriodicalIF":6.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850202","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":"Gut microbiota shape diurnal rhythms of amino acid metabolism in the mouse prefrontal cortex","authors":"Gabriel S.S. Tofani ,&nbsp;John F. Cryan","doi":"10.1016/j.molmet.2026.102319","DOIUrl":"10.1016/j.molmet.2026.102319","url":null,"abstract":"<div><h3>Objectives</h3><div>The gut microbiota plays a key role in maintaining brain health and homeostasis. Previous studies have demonstrated that metabolites in the brain respond to alterations in gut microbial composition. In this study we aimed to explore how depletion of the gut microbiota is associated with alterations in the diurnal rhythmicity of metabolites in the brain.</div></div><div><h3>Methods</h3><div>We used antibiotic-induced microbial depletion in mice to examine the impact of the gut microbiota on the rhythmicity of metabolites in the prefrontal cortex. Metabolite profiles were assessed across multiple timepoints using untargeted metabolomics.</div></div><div><h3>Results</h3><div>Microbial depletion was associated with alterations in the rhythmic profile of metabolites in the prefrontal cortex, with amino acids showing a robust inversion of their normal rhythm. These alterations were specific to the prefrontal cortex, with hippocampus and amygdala showing minimal changes. This altered gut microbial environment was associated with potential consequences for neurotransmitter production, including glutamate and serotonin.</div></div><div><h3>Conclusions</h3><div>These findings provide further evidence that the gut microbiota shapes rhythmic diurnal processes in the brain. Future studies are warranted to investigate how such microbial effects influence actual neurotransmitter levels and behavioral phenotypes associated with the prefrontal cortex.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102319"},"PeriodicalIF":6.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145985072","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}