Molecular Metabolism最新文献

{"title":"Hepatic stellate cell-specific Kcnma1 deletion mitigates metabolic dysfunction-associated steatotic liver disease progression via upregulating Amphiregulin secretion","authors":"Yunhan Zou ,&nbsp;Jiaoxiang Wu ,&nbsp;Sheng Cheng ,&nbsp;Daqing Cheng ,&nbsp;Taoying Chen ,&nbsp;Xirong Guo ,&nbsp;Li Tang ,&nbsp;Xianbin Su ,&nbsp;Man Zhang ,&nbsp;Xin Zhang ,&nbsp;Ying Liu ,&nbsp;Jin Zhang ,&nbsp;Qun Bao ,&nbsp;Shangwei Hou ,&nbsp;Peng Sun ,&nbsp;Yong Li ,&nbsp;Bo Han","doi":"10.1016/j.molmet.2025.102164","DOIUrl":"10.1016/j.molmet.2025.102164","url":null,"abstract":"<div><h3>Objective</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health concern, with limited effective treatments. KCNMA1 potassium channel has been implicated in the pathogenesis of various metabolic diseases. However, whether and how KCNMA1 regulates MASLD have been elusive.</div></div><div><h3>Methods</h3><div>Global, hepatic stellate cells (HSCs)-specific, and hepatocyte-specific <em>Kcnma1</em> knockout mice were fed either a standard chow or a high-fat diet (HFD). Serum and liver tissues were collected and analyzed by biochemical assay, histology, qPCR and western blotting. HSCs conditioned medium (CM) treatment hepatocytes experiment model and three-dimensional (3D) hepatocytes-HSCs spheroids were employed to study lipid accumulation in hepatocytes. A Cytokine Antibody Array was used to analyze the cytokine profile.</div></div><div><h3>Results</h3><div>Our study demonstrated that global <em>Kcnma1</em> deletion prevented diet-induced hepatic steatosis and improved insulin sensitivity. Further analyses using HSC-specific and hepatocyte-specific <em>Kcnma1</em> knockout MASLD mouse models revealed that the protective effect against hepatic steatosis was predominantly mediated by <em>Kcnma1</em> deletion in HSCs, rather than in hepatocytes. CM transfer experiment and 3D spheroid studies show <em>Kcnma1</em> deletion effectively prevents lipid accumulation in hepatocytes. Mechanically, <em>Kcnma1</em>-deficient HSCs secrete Amphiregulin (AREG) to regulate lipid metabolism in hepatocytes via epidermal growth factor receptor (EGFR) signaling. Of clinical significance, AREG levels were notably reduced in the liver tissue of MASLD patients, while injection of recombinant AREG protein significantly ameliorated MASLD in mice.</div></div><div><h3>Conclusions</h3><div>Our study uncovers a novel mechanism in which <em>Kcnma1</em> deletion in HSCs enhances AREG secretion, thereby reducing lipid accumulation in hepatocytes through the AREG/EGFR signaling, ultimately inhibiting the progression of MASLD.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"97 ","pages":"Article 102164"},"PeriodicalIF":7.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143946885","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":"Off-target depletion of plasma tryptophan by allosteric inhibitors of BCKDK","authors":"Caitlyn E. Bowman ,&nbsp;Michael D. Neinast ,&nbsp;Ryo Kawakami ,&nbsp;Nicholas Forelli ,&nbsp;Cholsoon Jang ,&nbsp;Jiten Patel ,&nbsp;Megan C. Blair ,&nbsp;Michael C. Noji ,&nbsp;Emily T. Mirek ,&nbsp;William O. Jonsson ,&nbsp;Qingwei Chu ,&nbsp;Lauren Merlo ,&nbsp;Laura Mandik-Nayak ,&nbsp;Tracy G. Anthony ,&nbsp;Joshua D. Rabinowitz ,&nbsp;Zolt Arany","doi":"10.1016/j.molmet.2025.102165","DOIUrl":"10.1016/j.molmet.2025.102165","url":null,"abstract":"<div><div>The activation of branched chain amino acid (BCAA) catabolism has garnered interest as a potential therapeutic approach to improve insulin sensitivity, enhance recovery from heart failure, and blunt tumor growth. Evidence for this interest relies in part on BT2, a small molecule that promotes BCAA oxidation and is protective in mouse models of these pathologies. BT2 and other analogs allosterically inhibit branched chain ketoacid dehydrogenase kinase (BCKDK) to promote BCAA oxidation, which is presumed to underlie the salutary effects of BT2. Potential “off-target” effects of BT2 have not been considered, however. We therefore tested for metabolic off-target effects of BT2 in <em>Bckdk</em>^−/− animals. As expected, BT2 failed to activate BCAA oxidation in these animals. Surprisingly, however, BT2 strongly reduced plasma tryptophan levels and promoted catabolism of tryptophan to kynurenine in both control and <em>Bckdk</em>^−/− mice. Mechanistic studies revealed that none of the principal tryptophan catabolic or kynurenine-producing/consuming enzymes (TDO, IDO1, IDO2, or KATs) were required for BT2-mediated lowering of plasma tryptophan. Instead, using equilibrium dialysis assays and mice lacking albumin, we show that BT2 avidly binds plasma albumin and displaces tryptophan, releasing it for catabolism. These data confirm that BT2 activates BCAA oxidation via inhibition of BCKDK but also reveal a robust off-target effect on tryptophan metabolism via displacement from serum albumin. The data highlight a potential confounding effect for pharmaceutical compounds that compete for binding with albumin-bound tryptophan.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"97 ","pages":"Article 102165"},"PeriodicalIF":7.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018460","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":"Abundance of a metabolically active subpopulation in dedifferentiated adipocytes inversely correlates with body mass index","authors":"Jonathan Trujillo-Viera ,&nbsp;Mona C. Wittmann ,&nbsp;Daniel Lam ,&nbsp;Yang Shen ,&nbsp;Adhideb Ghosh ,&nbsp;Falko Noé ,&nbsp;Anne Hoffmann ,&nbsp;Coralie Viollet ,&nbsp;Alec Dick ,&nbsp;Matthias Blüher ,&nbsp;Jiawei Zhong ,&nbsp;Lucas Massier ,&nbsp;Christian Wolfrum ,&nbsp;Holger Klein ,&nbsp;Heike Neubauer ,&nbsp;Bradford Hamilton","doi":"10.1016/j.molmet.2025.102161","DOIUrl":"10.1016/j.molmet.2025.102161","url":null,"abstract":"<div><h3>Objective</h3><div>The cellular composition and functionality of adipose tissue are key determinants of metabolic diseases associated with adipose tissue dysregulation, such as obesity. We hypothesized that distinct subpopulations with unique gene expression profiles and functional characteristics exist within human adipocytes.</div></div><div><h3>Methods</h3><div>Dedifferentiated adipocytes (DFAT), obtained by ceiling culture of human adipocytes, were analyzed using single-cell RNA sequencing (10x Genomics). Clustering analysis identified one subpopulation with a particular gene signature containing muscle cell genes which was further characterized by bulk-sequencing and analyzed alongside different cohorts of human adipose tissue.</div></div><div><h3>Results</h3><div>This subpopulation, named cluster 7 (C7), was isolated by FACS using two specific surface markers: cluster of differentiation 36 (CD36) and melanoma cell adhesion molecule (MCAM/CD146). Upon differentiation into adipocytes, the FACS-isolated CD36+/CD146+ cells (C7∗) showed an increased oxygen consumption rate compared to CD36-/CD146-cells (control cells) and non-sorted cells. Bulk RNA-sequencing revealed important pathways regulated in the differentiated C7∗ subpopulation that may contribute to its increased metabolic activity. Furthermore, the relative abundance of this specific cluster varied across eleven different human donors, demonstrating an inverse correlation between the proportion of C7∗ cells and the body mass index (BMI) of the respective donor. Importantly, a subset of genes regulated within this subpopulation also correlates with clinically relevant metabolic parameters, including weight, BMI, glycated hemoglobin, and plasma insulin, when analyzed alongside the gene expression of a large cohort of human subcutaneous adipose tissue (1759 donors).</div></div><div><h3>Conclusion</h3><div>Our results not only characterize DFAT cells derived from human adipose tissue, but also identify a specific subpopulation with increased energy expenditure that may play a role in body weight control. Future efforts to identify possible therapeutic targets or to promote the enrichment or activation of these energy-burning cells in adipose tissue might be useful in the field of cardiometabolic diseases.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"97 ","pages":"Article 102161"},"PeriodicalIF":7.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971636","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 mediates SREBP-1c-driven hepatic lipogenesis and steatosis in response to zero-fat high-sucrose diet","authors":"Mattias Bergentall ,&nbsp;Valentina Tremaroli ,&nbsp;Chuqing Sun ,&nbsp;Marcus Henricsson ,&nbsp;Muhammad Tanweer Khan ,&nbsp;Louise Mannerås Holm ,&nbsp;Lisa Olsson ,&nbsp;Per-Olof Bergh ,&nbsp;Antonio Molinaro ,&nbsp;Adil Mardinoglu ,&nbsp;Robert Caesar ,&nbsp;Max Nieuwdorp ,&nbsp;Fredrik Bäckhed","doi":"10.1016/j.molmet.2025.102162","DOIUrl":"10.1016/j.molmet.2025.102162","url":null,"abstract":"<div><h3>Objectives</h3><div>Sucrose-rich diets promote hepatic <em>de novo</em> lipogenesis (DNL) and steatosis through interactions with the gut microbiota. However, the role of sugar-microbiota dynamics in the absence of dietary fat remains unclear. This study aimed to investigate the effects of a high-sucrose, zero-fat diet (ZFD) on hepatic steatosis and host metabolism in conventionally raised (CONVR) and germ-free (GF) mice.</div></div><div><h3>Methods</h3><div>CONVR and GF mice were fed a ZFD, and hepatic lipid accumulation, gene expression, and metabolite levels were analyzed. DNL activity was assessed by measuring malonyl-CoA levels, expression of key DNL enzymes, and activation of the transcription factor SREBP-1c. Metabolomic analyses of portal vein plasma identified microbiota-derived metabolites linked to hepatic steatosis. To further examine the role of SREBP-1c, its hepatic expression was knocked down using antisense oligonucleotides in CONVR ZFD-fed mice.</div></div><div><h3>Results</h3><div>The gut microbiota was essential for sucrose-induced DNL and hepatic steatosis. In CONVR ZFD-fed mice, hepatic fat accumulation increased alongside elevated expression of genes encoding DNL enzymes, higher malonyl-CoA levels, and upregulation of SREBP-1c. Regardless of microbiota status, ZFD induced fatty acid elongase and desaturase gene expression and increased hepatic monounsaturated fatty acids. Metabolomic analyses identified microbiota-derived metabolites associated with hepatic steatosis. SREBP-1c knockdown in CONVR ZFD-fed mice reduced hepatic steatosis and suppressed fatty acid synthase expression.</div></div><div><h3>Conclusions</h3><div>Sucrose-microbiota interactions and SREBP-1c are required for DNL and hepatic steatosis in the absence of dietary fat. These findings provide new insights into the complex interplay between diet, gut microbiota, and metabolic regulation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"97 ","pages":"Article 102162"},"PeriodicalIF":7.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971837","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":"Pervasive glycative stress links metabolic imbalance and muscle atrophy in early-onset Parkinson's disease","authors":"Natalia Prudente de Mello ,&nbsp;Michelle Tamara Berger ,&nbsp;Kim A. Lagerborg ,&nbsp;Yingfei Yan ,&nbsp;Jennifer Wettmarshausen ,&nbsp;Susanne Keipert ,&nbsp;Leopold Weidner ,&nbsp;Janina Tokarz ,&nbsp;Gabriele Möller ,&nbsp;Stefano Ciciliot ,&nbsp;Safal Walia ,&nbsp;Yiming Cheng ,&nbsp;Margarita Chudenkova ,&nbsp;Anna Artati ,&nbsp;Daniela Vogt Weisenhorn ,&nbsp;Wolfgang Wurst ,&nbsp;Jerzy Adamski ,&nbsp;Roland Nilsson ,&nbsp;Giovanni Cossu ,&nbsp;Agnita Boon ,&nbsp;Kenneth Allen Dyar","doi":"10.1016/j.molmet.2025.102163","DOIUrl":"10.1016/j.molmet.2025.102163","url":null,"abstract":"<div><h3>Objective</h3><div>Parkinson’s disease (PD) is recognized as a systemic condition, with clinical features potentially modifiable by dietary intervention. Diets high in saturated fats and refined sugars significantly increase PD risk and exacerbate motor and non-motor symptoms, yet precise metabolic mechanisms are unclear. Our objective here was to investigate the interplay between diet and PD-associated phenotypes from a metabolic perspective.</div></div><div><h3>Methods</h3><div>We explored PARK7 KO mice under chronic glycative stress induced by prolonged high-fat high-sucrose (HFHS) diet. We investigated metabolic consequences by combining classical metabolic phenotyping (body composition, glucose tolerance, indirect calorimetry, functional assays of isolated mitochondria) with metabolomics profiling of biospecimens from mice and PD patients.</div></div><div><h3>Results</h3><div>We found this obesogenic diet drives loss of fat and muscle mass in early-onset PD mice, with a selective vulnerability of glycolytic myofibers. We show that PD mice and early-onset familial PD patients are under pervasive glycative stress with pathological accumulation of advanced glycation end products (AGEs), including N-α-glycerinylarginine (α-GR) and N-α-glycerinyllysine (α-GK), two previously unknown glycerinyl-AGE markers.</div></div><div><h3>Conclusions</h3><div>Our results offer the first proof for a direct link between diet, accumulation of AGEs and genetics of PD. We also expand the repertoire of clinically-relevant glycative stress biomarkers to potentially define at-risk patients before neurological or metabolic symptoms arise, and/or to monitor disease onset, progression, and effects of interventions.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"97 ","pages":"Article 102163"},"PeriodicalIF":7.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971670","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":"14-3-3ζ allows for adipogenesis by modulating chromatin accessibility during the early stages of adipocyte differentiation","authors":"Sabri A. Rial ,&nbsp;Zhipeng You ,&nbsp;Alexis Vivoli ,&nbsp;Fédéric Paré ,&nbsp;Daphné Sean ,&nbsp;Amal AlKhoury ,&nbsp;Geneviève Lavoie ,&nbsp;Mete Civelek ,&nbsp;Aida Martinez-Sanchez ,&nbsp;Philippe P. Roux ,&nbsp;Thomas M. Durcan ,&nbsp;Gareth E. Lim","doi":"10.1016/j.molmet.2025.102159","DOIUrl":"10.1016/j.molmet.2025.102159","url":null,"abstract":"<div><h3>Objective</h3><div>We previously established the scaffold protein 14-3-3ζ as a critical regulator of adipogenesis and adiposity, but whether 14-3-3ζ exerted its regulatory functions in mature adipocytes or in adipose progenitor cells (APCs) remained unclear.</div></div><div><h3>Methods</h3><div>To decipher which cell type accounted for 14-3-3ζ-regulated adiposity, adipocyte- (<em>Adipoq</em>14-3-3ζKO) and APC-specific (<em>Pdgfra</em>14-3-3ζKO) 14-3-3ζ knockout mice were generated. To further understand how 14-3-3ζ regulates adipogenesis, <u>T</u>andem <u>A</u>ffinity <u>P</u>urification (TAP)-tagged 14-3-3ζ-expressing 3T3-L1 preadipocytes (TAP-3T3-L1) were generated with CRISPR-Cas9, and affinity proteomics was used to examine how the nuclear 14-3-3ζ interactome changes during the initial stages of adipogenesis. ATAC-seq was used to determine how 14-3-3ζ depletion modulates chromatin accessibility during differentiation.</div></div><div><h3>Results</h3><div>We show a pivotal role for 14-3-3ζ in APC differentiation, whereby male and female Pdgfra14-3-3ζKO mice displayed impaired or potentiated weight gain, respectively, as well as fat mass. Proteomics revealed that regulators of chromatin remodeling, like DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1), were significantly enriched in the nuclear 14-3-3ζ interactome and their activities were impacted upon 14-3-3ζ depletion. Enhancing DNMT activity with S-Adenosyl methionine rescued the differentiation of 14-3-3ζ-depleted 3T3-L1 cells. ATAC-seq revealed that 14-3-3ζ depletion impacted the accessibility of up to 1,244 chromatin regions corresponding in part to adipogenic genes, promoters, and enhancers during the initial stages of adipogenesis. Finally, 14-3-3ζ-regulated chromatin accessibility correlated with the expression of key adipogenic genes.</div></div><div><h3>Conclusion</h3><div>Our study establishes 14-3-3ζ as a crucial epigenetic regulator of adipogenesis and highlights the usefulness of deciphering the nuclear 14-3-3ζ interactome to identify novel pro-adipogenic factors and pathways.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"97 ","pages":"Article 102159"},"PeriodicalIF":7.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143928847","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":"Vitamin D receptor signalling regulates the diet-driven metabolic shift during weaning","authors":"Neha Jawla ,&nbsp;Shubhi Khare ,&nbsp;Nidhi Yadav ,&nbsp;Ranjan Kumar Nanda ,&nbsp;G. Aneeshkumar Arimbasseri","doi":"10.1016/j.molmet.2025.102158","DOIUrl":"10.1016/j.molmet.2025.102158","url":null,"abstract":"<div><h3>Objective</h3><div>Weaning in mammals is associated with a shift in the metabolism, driven by the differences in the macronutrient composition of milk and post-weaning diet. Milk has a higher fat content compared with the carbohydrate-enriched solid food. Malnutrition during this stage could affect this transition with long-term adverse effects. The role of micronutrients during this transition is not well understood.</div></div><div><h3>Methods</h3><div>We used mice lacking a functional vitamin D receptor (VDR) to study the role of vitamin D signalling in the metabolic transition during weaning.</div></div><div><h3>Results</h3><div>We demonstrate that after weaning, VDR knockout mice exhibit systemic energy deprivation and higher lipolysis in inguinal white adipose tissue, probably due to increased norepinephrine signalling via protein kinase A (PKA) and extracellular signalling-regulated kinase (ERK) pathways. The energy deprivation in vdr−/− mice is associated with defective liver glycogenolysis, characterized by increased expression of protein phosphatase-1 alpha and decreased glycogen phosphorylase activity. However, restoration of serum calcium and phosphate levels by a rescue diet is sufficient to restore energy metabolism in vdr−/− mice. Interestingly, maintaining a high-fat-containing milk-based diet post-weaning could prevent the onset of energy deprivation, liver glycogen storage defect, and adipose atrophy in these mice.</div></div><div><h3>Conclusion</h3><div>Our data show that vitamin D-signalling is essential for the adaptation of mice to the dietary shift from high-fat-containing milk to post-weaning carbohydrate-enriched diets. It also reveals a novel macronutrient–micronutrient interaction that shapes the metabolic flexibility of the individual based on the dietary composition of nutrients.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"97 ","pages":"Article 102158"},"PeriodicalIF":7.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917271","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":"Effects of children's microbiota on adipose and intestinal development in sex-matched mice persist into adulthood following a single fecal microbiota transplantation","authors":"Federica La Rosa ,&nbsp;Maria Angela Guzzardi ,&nbsp;Mercedes Pardo-Tendero ,&nbsp;Monica Barone ,&nbsp;Chiara Ruocco ,&nbsp;Gabriele Conti ,&nbsp;Daniele Panetta ,&nbsp;Daria Riabitch ,&nbsp;Silvia Bernardi ,&nbsp;Assuero Giorgetti ,&nbsp;Daniela Campani ,&nbsp;Daniel Monleon ,&nbsp;Enzo Nisoli ,&nbsp;Patrizia Brigidi ,&nbsp;Patricia Iozzo","doi":"10.1016/j.molmet.2025.102157","DOIUrl":"10.1016/j.molmet.2025.102157","url":null,"abstract":"<div><h3>Background</h3><div>The global prevalence of obesity and type 2 diabetes, particularly among children, is rising, yet the long-term impacts of early-life fecal microbiota transplantation (FMT) on metabolic health remain poorly understood.</div></div><div><h3>Objectives</h3><div>To investigate how early-life FMT from children to young, sex-matched mice influences metabolic outcomes and adipose tissue function in later, adult life.</div></div><div><h3>Methods</h3><div>Germ-free mice were colonized with fecal microbiota from either lean children or children with obesity. The impacts on brown adipose tissue (BAT), white adipose tissue (WAT), glucose metabolism, and gut health were analyzed in male and female mice. Microbial communities and metabolite profiles were characterized using sequencing and metabolomics.</div></div><div><h3>Results</h3><div>Male mice receiving FMT from obese donors exhibited marked BAT whitening and impaired amino acid and glucose metabolism. In contrast, female recipients developed hyperglycemia, accompanied by gut barrier dysfunction and WAT impairment. Distinct microbial and metabolite profiles were associated with these phenotypes: <em>Collinsella</em> and trimethylamine in females; and <em>Paraprevotella</em>, <em>Collinsella</em>, <em>Lachnospiraceae NK4A136</em>, <em>Bacteroides</em>, <em>Coprobacillus</em>, and multiple metabolites in males. These phenotypic effects persisted despite changes in host environment and diet.</div></div><div><h3>Conclusions</h3><div>Early-life FMT induced long-lasting effects on the metabolic landscape, profoundly affecting adipose tissue function and systemic glucose homeostasis in adulthood. Donor dietary habits correlated with the fecal microbial profiles observed in recipient mice. These findings highlight the critical need for identifying and leveraging beneficial exposures during early development to combat obesity and diabetes.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"97 ","pages":"Article 102157"},"PeriodicalIF":7.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143931327","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":"Prolonged fasting promotes systemic inflammation and platelet activation in humans: A medically supervised, water-only fasting and refeeding study","authors":"Serena Commissati ,&nbsp;Maria Lastra Cagigas ,&nbsp;Andrius Masedunskas ,&nbsp;Giovanna Petrucci ,&nbsp;Valeria Tosti ,&nbsp;Isabella De Ciutiis ,&nbsp;Gayathiri Rajakumar ,&nbsp;Kristopher M. Kirmess ,&nbsp;Matthew R. Meyer ,&nbsp;Alan Goldhamer ,&nbsp;Brian K. Kennedy ,&nbsp;Duaa Hatem ,&nbsp;Bianca Rocca ,&nbsp;Giovanni Fiorito ,&nbsp;Luigi Fontana","doi":"10.1016/j.molmet.2025.102152","DOIUrl":"10.1016/j.molmet.2025.102152","url":null,"abstract":"<div><h3>Objective</h3><div>Prolonged fasting (PF), defined as abstaining from energy intake for ≥4 consecutive days, has gained interest as a potential health intervention. However, the biological effects of PF on the plasma proteome are not well understood.</div></div><div><h3>Methods</h3><div>In this study, we investigated the effects of a medically supervised water-only fast (mean duration: 9.8 ± 3.1 days), followed by 5.3 ± 2.4 days of guided refeeding, in 20 middle-aged volunteers (mean age: 52.2 ± 11.8 years; BMI: 28.8 ± 6.4 kg/m²).</div></div><div><h3>Results</h3><div>Fasting resulted in a 7.7% mean weight loss and significant increases in serum beta-hydroxybutyrate (BHB), confirming adherence. Untargeted high-dimensional plasma proteomics (SOMAScan, 1,317 proteins) revealed multiple adaptations to PF, including preservation of skeletal muscle and bone, enhanced lysosomal biogenesis, increased lipid metabolism via PPARα signaling, and reduced amyloid fiber formation. Notably, PF significantly reduced circulating amyloid beta proteins Aβ40 and Aβ42, key components of brain amyloid plaques. In addition, PF induced an acute inflammatory response, characterized by elevated plasma C-reactive protein (CRP), hepcidin, midkine, and interleukin 8 (IL-8), among others. A retrospective cohort analysis of 1,422 individuals undergoing modified fasting confirmed increased CRP levels (from 2.8 ± 0.1 to 4.3 ± 0.2 mg/L). The acute phase response, associated with transforming growth factor (TGF)-β signaling, was accompanied by increased platelet degranulation and upregulation of the complement and coagulation cascade, validated by ELISAs in blood and urine.</div></div><div><h3>Conclusions</h3><div>While the acute inflammatory response during PF may serve as a transient adaptive mechanism, it raises concerns regarding potential cardiometabolic effects that could persist after refeeding. Further investigation is warranted to elucidate the long-term molecular and clinical implications of PF across diverse populations.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102152"},"PeriodicalIF":7.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143891315","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":"CPT1C deficiency in SF1 neurons impairs early metabolic adaptation to dietary fats, leading to obesity","authors":"A. Fosch ,&nbsp;D.S. Pizarro ,&nbsp;S. Zagmutt ,&nbsp;A.C. Reguera ,&nbsp;G. Batallé ,&nbsp;M. Rodríguez-García ,&nbsp;J. García-Chica ,&nbsp;O. Freire-Agulleiro ,&nbsp;C. Miralpeix ,&nbsp;P. Zizzari ,&nbsp;D. Serra ,&nbsp;L. Herrero ,&nbsp;M. López ,&nbsp;D. Cota ,&nbsp;R. Rodríguez-Rodríguez ,&nbsp;N. Casals","doi":"10.1016/j.molmet.2025.102155","DOIUrl":"10.1016/j.molmet.2025.102155","url":null,"abstract":"<div><h3>Objectives</h3><div>SF1 neurons of the ventromedial hypothalamus (VMH) play a pivotal role in regulating body weight and adiposity, particularly in response to a high-fat diet (HFD), as well as in the recovery from insulin-induced hypoglycemia. While the brain-specific CPT1C isoform is well known for its role in controlling food intake and energy homeostasis, its function within specific hypothalamic neuronal populations remains largely unexplored. Here, we explore the role of CPT1C in SF1 neurons.</div></div><div><h3>Methods</h3><div>Mice deficient in CPT1C within SF1 neurons were generated, and their response to a HFD was investigated.</div></div><div><h3>Results</h3><div>SF1-<em>Cpt1c</em>-KO mice fail to adjust their caloric intake during initial HFD exposure, which is associated with impaired activation of the melanocortin system. Furthermore, these mice exhibit disrupted metabolic gene expression in the liver, muscle, and adipose tissue, leading to increased adiposity independently of food intake. In contrast, their response to glucose or insulin challenges remains intact. After long-term HFD exposure, SF1-Cpt1c-KO mice are more prone to developing obesity and glucose intolerance than control littermates, with males exhibiting a more severe phenotype. Interestingly, CPT1C deficiency in SF1 neurons also results in elevated hypothalamic endocannabinoid (eCB) levels under both chow and HFD conditions. We propose that this sustained eCB elevation reduces VMH activation by fatty acids and impairs the SF1-POMC drive upon fat intake.</div></div><div><h3>Conclusion</h3><div>Our findings establish CPT1C in SF1 neurons as essential for VMH-driven dietary fat sensing, satiety, and lipid metabolic adaptation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102155"},"PeriodicalIF":7.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143887406","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}