Molecular Metabolism最新文献

{"title":"Dimorphic regulation of time-restricted feeding effects by hepatocyte Period 1","authors":"Jiameng Sun ,&nbsp;Cassandra B. Higgins ,&nbsp;Joshua A. Adams ,&nbsp;Yiming Zhang ,&nbsp;Shannon C. Kelly ,&nbsp;Hyo-Jin Kim ,&nbsp;Brian J. DeBosch","doi":"10.1016/j.molmet.2025.102270","DOIUrl":"10.1016/j.molmet.2025.102270","url":null,"abstract":"<div><h3>Objectives</h3><div>Obesity is linked to metabolic disorders including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular disease. Lifestyle interventions, such as time-restricted feeding (TRF), have proven to be effective for long-term weight management. The metabolic effects of TRF are closely associated with circadian clock function in the liver. We previously demonstrated that the circadian gene <em>Period 1</em> (<em>Per1</em>) mediates responses to acute fasting in both sexes. We therefore hypothesized that hepatocyte <em>Per1</em> contributes to the long-term adaptations to repeated fasting exposure in the form of TRF, and investigated its role in diet-induced obesity in both sexes.</div></div><div><h3>Methods</h3><div>Male and female mice with or without hepatocyte <em>Per1</em> (<em>Per1</em>^fl/fl and <em>Per1</em>^LKO) were subjected to either <em>ad libitum</em> feeding (ALF) or TRF restricted to the active phase (8 h/day).</div></div><div><h3>Results</h3><div>TRF attenuated Western diet-induced weight gain and peripheral and hepatic lipid accumulation, and improved heat production, metabolic substrate flexibility, and glucose homeostasis in <em>Per1</em>^fl/fl and <em>Per1</em>^LKO males. In contrast, hepatocyte <em>Per1</em> was required for TRF-induced improvements in energy expenditure and peripheral and hepatic lipid accumulation in females. Surprisingly, TRF failed to significantly attenuate diet-induced weight gain or glucose and insulin tolerance in females independent of genotype. Transcriptomic data revealed sex-specific transcriptional responses to TRF and to hepatocyte-specific <em>Per1</em> deletion. Specifically, genes involved in lipid metabolism were differentially regulated when comparing TRF-treated <em>Per1</em>^fl/fl and <em>Per1</em>^LKO female mice.</div></div><div><h3>Conclusions</h3><div>Hepatocyte <em>Per1</em> mediates the energy, lipid, and glucose homeostatic effects of TRF, and this regulation is almost completely sex-dependent.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102270"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313248","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":"Increased mitochondrial fusion via systemic OPA1 overexpression promotes dyslipidemia and atherosclerosis in LDLR deficient mice","authors":"Lorenzo Da Dalt ,&nbsp;Francesca Fantini ,&nbsp;Giulia Giancane ,&nbsp;Annalisa Moregola ,&nbsp;Silvia Roda ,&nbsp;Monika Svecla ,&nbsp;Silvia Pedretti ,&nbsp;Giovanni Battista Vingiani ,&nbsp;Jiangming Sun ,&nbsp;Andreas Edsfeldt ,&nbsp;Isabel Goncalves ,&nbsp;Patrizia Uboldi ,&nbsp;Elena Donetti ,&nbsp;Andrea Baragetti ,&nbsp;Nico Mitro ,&nbsp;Luca Scorrano ,&nbsp;Giuseppe Danilo Norata","doi":"10.1016/j.molmet.2025.102256","DOIUrl":"10.1016/j.molmet.2025.102256","url":null,"abstract":"<div><h3>Objective</h3><div>Mitochondria are involved in cellular metabolism, energy production, calcium homeostasis, and the synthesis of sterols and bile acids (BAs). Emerging evidence suggests that mitochondrial dynamics including biogenesis, fusion, fission, and mitophagy critically influence cardiometabolic diseases, yet their role in atherogenesis remain poorly understood. Mitochondrial fusion ensures metabolic flexibility and stress adaptation, processes highly relevant to lipid handling and vascular cell plasticity. OPA1, a key regulator of inner mitochondrial membrane fusion, has been implicated in metabolic remodeling and cellular stress responses. We therefore investigated whether modulation of OPA1 expression affects lipid homeostasis and plaque formation in LDL receptor-deficient (LDLR KO) mice and in human carotid atherosclerosis.</div></div><div><h3>Methods</h3><div>OPA1^TG/LDLR KO and OPA1^ΔHep/LDLR KO were fed with a Western-type diet (WTD) for 12 weeks. The development of atherosclerosis was compared to that of LDLR KO mice. In humans, the impact of OPA1 was investigated in asymptomatic and symptomatic subjects from the Carotid Plaque Imaging Project (CPIP) biobank.</div></div><div><h3>Results</h3><div>OPA1^TG/LDLR KO mice showed a significant increase in plasma cholesterol levels mainly in VLDL and LDL fractions. OPA1^TG/LDLR KO display a reduction of unconjugated bile acids and higher percentage of conjugated bile acids leading to an increased lipid adsorption. This phenotype was associated with increased atherosclerosis in the aortic root. OPA1 overexpression also resulted in an altered vascular smooth muscle cell (VSMC) cellular metabolism and differentiation, promoting a shift from a contractile/synthetic phenotype toward a more proliferative and metabolically active state. Concordantly, the deletion of OPA1 in hepatocytes improved systemic lipoprotein metabolism protecting from atherosclerosis. Concordantly in humans, plaque OPA1 mRNA levels are associated with metabolic and smooth muscle cell related pathways.</div></div><div><h3>Conclusions</h3><div>Mitochondrial fusion mediated by OPA1 plays a key role in atherosclerosis by affecting lipoprotein metabolism and vascular smooth muscle cell biology.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102256"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138101","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":"Periodic fasting induced reconstitution of metabolic flexibility improves albuminuria in patients with type 2 diabetes","authors":"Alba Sulaj ,&nbsp;Phong B.H. Nguyen ,&nbsp;Gernot Poschet ,&nbsp;Elisabeth Kliemank ,&nbsp;Thomas Fleming ,&nbsp;Lea Henke ,&nbsp;Wiebke Neibig ,&nbsp;Stefan Kopf ,&nbsp;Rüdiger Hell ,&nbsp;Valter D. Longo ,&nbsp;Stephan Herzig ,&nbsp;Peter P. Nawroth ,&nbsp;Michael P. Menden ,&nbsp;Julia Szendroedi","doi":"10.1016/j.molmet.2025.102257","DOIUrl":"10.1016/j.molmet.2025.102257","url":null,"abstract":"<div><h3>Objective</h3><div>Metabolic inflexibility has been shown to be associated with type 2 diabetes (T2D) and diabetic nephropathy (DN). However, data are lacking, proving that reconstitution of metabolic flexibility by using a 6-month periodic fasting (PF) regimen may improve albuminuria.</div></div><div><h3>Methods</h3><div>In this post hoc analysis of a randomized-controlled trial, we investigated whether the PF regimen enhanced metabolic flexibility in individuals with T2D and DN showing improvement of albuminuria (responders) compared to non-responders. Participants followed every month either a 5-day fasting-mimicking diet or a Mediterranean diet for 6 months. LC-MS/MS-based comprehensive metabolic profiling was performed in plasma samples before, during, and after the intervention. Changes in metabolomic patterns and enriched signalling pathways were analysed between study groups.</div></div><div><h3>Results</h3><div>PF induced a sustained shift toward enhanced fatty acid oxidation, lipid utilization, and amino acids turnover, particularly in responders. Responders exhibited persistent elevations in short-chain acylcarnitines and cholesteryl esters, indicating more efficient lipid oxidation and tighter integration of lipid metabolism with the tricarboxylic acid cycle. Increased glycine and serine levels suggested enhanced cellular maintenance, a protein-sparing effect, and a metabolic shift favouring lipid over carbohydrate. In contrast, non-responders demonstrated only transient and limited metabolic shifts. Unsupervised clustering identified distinct metabolic response patterns, reinforcing the potential of personalized dietary interventions.</div></div><div><h3>Conclusions</h3><div>These findings demonstrate that diet-induced restoration of metabolic flexibility is associated with improved albuminuria in T2D, suggesting broader implications for precise nutritional strategies in diabetes management.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102257"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176773","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":"Salivary extracellular vesicle-derived microRNAs are related to variances in parameters of obesity, taste and eating behaviour","authors":"Kristin Röhrborn ,&nbsp;Anne Hoffmann ,&nbsp;Andrea Lorenz ,&nbsp;Peter Kovacs ,&nbsp;Tobias Hagemann ,&nbsp;Paul Czechowski ,&nbsp;Maria Sehm ,&nbsp;Annette Horstmann ,&nbsp;Michael Stumvoll ,&nbsp;Matthias Blüher ,&nbsp;Imke Schamarek ,&nbsp;Kerstin Rohde-Zimmermann","doi":"10.1016/j.molmet.2025.102265","DOIUrl":"10.1016/j.molmet.2025.102265","url":null,"abstract":"<div><h3>Background</h3><div>Extracellular vesicles (EVs), conveyors of microRNAs, have recently been linked to obesity. As taste is a potent driver of eating behaviour and food intake, it's connection to EVs is of increasing interest. This study aimed at deciphering the salivary EV-microRNA profile in relation to taste perception and metabolic pathways of obesity.</div></div><div><h3>Methods</h3><div>Small RNA sequencing was performed on isolated salivary EVs of 90 participants from the Obese-Taste-Bud study. Pathway enrichment and association analyses were conducted to link identified microRNAs to taste recognition, eating behaviour, food intake and various anthropometric-, metabolic- and oral health parameter.</div></div><div><h3>Results</h3><div>The 626 identified microRNAs clustered into pathways related to energy regulation, obesity and diabetes, cell signaling and taste perception. The top three enriched microRNAs are miR-1246, miR-1290 and miR-148a-3p which showed significant associations with fasting blood glucose and cholesterol level, anthropometrics and blood pressure (p &lt; 0.05). Additionally, these microRNAs associate with trait eating behaviour (p &lt; 0.05). Several other microRNAs were linked to differences in taste recognition scores and are further related to parameters of glucose metabolism and periodontal health, salivary insulin level or food intake (p &lt; 0.05).</div></div><div><h3>Conclusions</h3><div>This study, one of the largest on salivary EVs, supports an interrelation of EV's microRNA load with metabolism, eating behaviour and taste recognition offering potential targets for obesity intervention.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102265"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233021","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":"Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia","authors":"Fernando M. Ponce-Garcia ,&nbsp;Yasmin R. Jenkins ,&nbsp;Victoria D. Assmann ,&nbsp;Silpita Paul ,&nbsp;Nitesh D. Sharma ,&nbsp;Catherine Moore ,&nbsp;Eric H. Ma ,&nbsp;Paraskevi Diamanti ,&nbsp;Marc Hennequart ,&nbsp;Julianna Blagih ,&nbsp;Le Le ,&nbsp;Benjamin J. Jenkins ,&nbsp;Sophie Rouvray ,&nbsp;James G. Cronin ,&nbsp;Russell G. Jones ,&nbsp;Marc Mansour ,&nbsp;Allison Blair ,&nbsp;Christina Halsey ,&nbsp;Ksenia Matlawska-Wasowska ,&nbsp;Daniel Herranz ,&nbsp;Nicholas Jones","doi":"10.1016/j.molmet.2025.102275","DOIUrl":"10.1016/j.molmet.2025.102275","url":null,"abstract":"<div><div>T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy commonly driven by <em>NOTCH1</em> activating mutations. A concomitant feature associated with <em>NOTCH1</em> mutations is heightened oxidative metabolism enabling the exponential proliferation of T-ALL blasts. As such, targeting mitochondrial metabolism in T-ALL is an attractive therapeutic avenue. Related to this, canagliflozin (cana), is an FDA-approved sodium glucose co-transporter 2 inhibitor with known off-target effects on complex I and glutamate dehydrogenase, but its potential anti-leukaemic effects remain unexplored. Here, we show that cana possesses potent anti-leukaemic effects underpinned by proliferative defects, cell cycle disruption and apoptosis. These anti-leukaemic effects driven by cana, are attributed to a perturbed tricarboxylic acid (TCA) cycle and mitochondrial metabolism, and elevated mitochondrial ROS. Proteomic analysis revealed that cana treatment resulted in a compensatory increase in the expression of ATF4 targets, including upregulation of serine biosynthesis pathway and one-carbon metabolism enzymes. As such, restriction of serine and glycine synergized with cana treatment, further enhancing its anti-leukaemic effects. Collectively, our study reveals a cana-driven metabolic vulnerability that can be further exploited via dietary manipulation to treat T-ALL.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102275"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145346226","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":"TERT expression attenuates metabolic disorders in obese mice by promoting adipose stem and progenitor cell expansion and differentiation","authors":"Laura Braud ,&nbsp;Manuel Bernabe ,&nbsp;Julien Vernerey ,&nbsp;Antonio M.A. Miranda ,&nbsp;Andrea Dominguez ,&nbsp;Dmitri Churikov ,&nbsp;Manon Richaud ,&nbsp;Frédéric Jourquin ,&nbsp;Liam Mc Allan ,&nbsp;Christophe Lachaud ,&nbsp;Jesus Gil ,&nbsp;Will Scott ,&nbsp;Vincent Géli","doi":"10.1016/j.molmet.2025.102262","DOIUrl":"10.1016/j.molmet.2025.102262","url":null,"abstract":"<div><h3>Background and aims</h3><div>Adipose tissue (AT) senescence, induced by obesity or aging, leads to a reduced capacity for tissue remodeling and a chronic pro-inflammatory state, which leads to the onset of metabolic pathologies. Cellular senescence is triggered by various stresses, in particular excessive shortening of telomeres, which activates the p21 pathway and leads to the arrest of the cell cycle. We used the mouse model p21^+/Tert expressing TERT from the Cdkn1a locus to investigate whether counteracting telomere shortening by telomerase (TERT) specifically in pre-senescent cells could improve obesity-induced metabolic disorders.</div></div><div><h3>Results</h3><div>Our study demonstrates that conditional expression of TERT reduces insulin-resistance and glucose intolerance associated with obesity. In AT, this is accompanied by a decrease in the number of senescent p21-positive cells, very short telomeres, and oxidative DNA damage. Single nucleus RNA-seq data reveal TERT expression attenuates senescence induced by HFD in particular in adipose stem and progenitor cells (ASPC). We demonstrate that ASPC expansion and differentiation are promoted in p21^+/Tert obese mice, thereby improving AT plasticity. Furthermore, we show that TERT expression enhances mitochondrial function and alleviates oxidative stress in ASPC. This process contributes to the AT hyperplasia with increased number of adipocytes which has been shown to have a protective effect against obesity-associated metabolic disorders.</div></div><div><h3>Conclusions</h3><div>These results underscore TERT's role in mitigating obesity-related metabolic dysfunction. Conditional TERT expression may therefore represent as a promising therapeutic strategy for obesity-associated metabolic disorders.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102262"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233108","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":"Weight loss reverses obesity-associated impairments in acute gastrointestinal stretch-induced suppression of food intake and glucose homeostasis","authors":"Maigen Bethea ,&nbsp;Tyler Cook ,&nbsp;Marwa Mommandi ,&nbsp;Andrew McClennan ,&nbsp;Allison Martin ,&nbsp;Jasmine J. Hendrix ,&nbsp;Chelsea R. Hutch ,&nbsp;Alfor Lewis ,&nbsp;Randy J. Seeley ,&nbsp;Henning Fenselau ,&nbsp;Silvania da Silva Teixeria ,&nbsp;Darleen A. Sandoval","doi":"10.1016/j.molmet.2025.102260","DOIUrl":"10.1016/j.molmet.2025.102260","url":null,"abstract":"<div><h3>Objective</h3><div>Chemical and mechanical signals from the gastrointestinal tract are critical for regulating satiety and glucose metabolism. While both nutrient sensing in the intestine and gastric distension has been well studied, the role of intestinal stretch in these metabolic processes remain unclear. This study evaluates the role of intestinal stretch in regulating food intake and glucose homeostasis in the context of normal body weight, obesity, and weight loss occurring via both dietary intervention and vertical sleeve gastrectomy (VSG).</div></div><div><h3>Methods</h3><div>We used the nonnutritive substance mannitol to selectively induce intestinal stretch in conscious mice. We assessed food intake, glucose tolerance, and neuronal activation in mice with normal body weight, obesity, or after dietary or surgically-induced weight loss. We employed chemogenetic approaches to inhibit GLP-1R and OxtR-expressing vagal afferents, and genetic and pharmacological strategies to ablate GLP-1 signaling to explore mechanisms for mannitol-induced suppression of feeding.</div></div><div><h3>Results</h3><div>Mannitol-induced intestinal stretch acutely suppressed food intake and improved oral glucose tolerance independent of GLP-1 signaling and vagal intestinal mechanosensation. Diet induced obesity impairs mannitol-induced intestinal stretch reductions in food intake and attenuates neuronal activation in the nucleus of the solitary tract (NTS) upon induction of intestinal stretch. Both dietary and surgical weight loss restored intestinal stretch-induced feeding suppression and enhanced NTS neuronal activation. Importantly, VSG heightened NTS neuronal activation in response to oral but not IP glucose.</div></div><div><h3>Conclusions</h3><div>Together, these data demonstrate that intestinal stretch contributes to the regulation of feeding and glucose metabolism independently of intestinal nutrient-sensing or classical gut hormones.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102260"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182172","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":"Dax1 in AgRP neurons regulates thermogenesis via GR-HDAC3-mediated CRFR1 suppression","authors":"Zhuodu Wei ,&nbsp;Jooseon Cha ,&nbsp;Seunghee Lee","doi":"10.1016/j.molmet.2025.102258","DOIUrl":"10.1016/j.molmet.2025.102258","url":null,"abstract":"<div><h3>Objectives</h3><div>The arcuate nucleus of the hypothalamus plays a pivotal role in metabolic homeostasis by integrating the functions of AgRP and POMC neurons. Dax1, a nuclear receptor-like transcription factor, is highly enriched in AgRP neurons; however, its role in energy balance regulation remains largely unexplored. Here, we demonstrate the function of Dax1 in hypothalamic AgRP neurons and its contribution to systemic energy homeostasis and thermogenesis in mice.</div></div><div><h3>Methods</h3><div>We generated AgRP neuron-specific Dax1 conditional knockout mice and assessed their physiological and metabolic responses under high-fat diet feeding and cold exposure. Energy expenditure, brown adipose tissue (BAT) thermogenesis, neuronal activation, and neuropeptide expression were evaluated. Molecular mechanisms were investigated by gene expression analysis, chromatin immunoprecipitation, and biochemical assays.</div></div><div><h3>Results</h3><div>We show that conditional deletion of Dax1 in AgRP neurons enhances energy expenditure, stimulates BAT thermogenesis, and confers resistance to diet-induced obesity in female mice. Notably, these mice exhibit blunted AgRP neuron activation upon cold challenge. Mechanistically, corticotropin-releasing factor receptor type 1 (CRFR1), a key regulator of AgRP neuronal excitability, was upregulated in Dax1-deficient AgRP neurons. We further identified that Dax1 recruits the HDAC3 corepressor complex to the glucocorticoid receptor at the glucocorticoid response element within the <em>Crfr1</em> promoter, thereby repressing <em>Crfr1</em> transcription in response to glucocorticoid signaling.</div></div><div><h3>Conclusions</h3><div>Our findings establish Dax1 as a critical transcriptional repressor of <em>Crfr1</em> in AgRP neurons, linking hypothalamic steroid signaling to the regulation of adaptive thermogenesis and systemic energy balance.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102258"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192137","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":"Evaluation of the effects of metformin on gut functions and microbiota and their contribution to improving glucose tolerance in diabetic mice","authors":"Murielle Godet ,&nbsp;Emmanuelle Meugnier ,&nbsp;Oriane Vitalis ,&nbsp;Nadia Bendridi ,&nbsp;Aurélie Vieille-Marchiset ,&nbsp;Nathalie Vega ,&nbsp;Bérengère Benoit ,&nbsp;Claudie Pinteur ,&nbsp;Dominique Rainteau ,&nbsp;David Cheillan ,&nbsp;Marie-Caroline Michalski ,&nbsp;Karim Chikh ,&nbsp;Hubert Vidal","doi":"10.1016/j.molmet.2025.102263","DOIUrl":"10.1016/j.molmet.2025.102263","url":null,"abstract":"<div><h3>Objectives</h3><div>Although the mechanism of action of the antidiabetic drug metformin is still a matter of discussions, increasing evidence points to a pivotal role of the gut. Aiming to clarify whether metformin-induced changes in the intestinal tract directly contribute to metabolic improvement, we evaluated the effects of escalating doses (from 50 to 200 mg/kg/day) of metformin orally administered for 4 weeks in mice made glucose intolerant by ten weeks of high fat high sucrose diet.</div></div><div><h3>Methods</h3><div>Several intestinal parameters were studied, including caecal microbiota composition and bile acids profile, ileal FXR signaling, abundance of GLP1-producing cells and goblet cells and blood metabolome.</div></div><div><h3>Results</h3><div>Metformin restored glucose tolerance, fasting insulinemia and HOMA-IR index in a dose-dependent manner. Only a subset of gut-related effects, including mucus production and GLP-1 expression, exhibited a parallel dose–response relationship, suggesting a possible contribution to the observed metabolic improvements. In contrast, other changes, including ileal Fxr-Fgf15 inhibition and hepatic ceramide reduction did not scale with dose, suggesting they are not the main drivers of metformin dose-dependent effects on glycemic control. We also pointed out marked differential sensitivity of gut bacteria to metformin supporting complex interactions of the drug with the microbial ecosystem.</div></div><div><h3>Conclusion</h3><div>Finally, metformin enhanced the proliferation of intestinal epithelium, resulting in increased length of ileal villi. Altogether, this study offers new insights into the metformin mechanism of action and revealed potential novel microbial biomarkers and targets for enhancing its therapeutic efficacy.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102263"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206910","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":"Eloralintide (LY3841136), a novel amylin receptor agonist for the treatment of obesity: From discovery to clinical proof of concept","authors":"Daniel A. Briere,&nbsp;Hongchang Qu,&nbsp;Katherine Lansu,&nbsp;Minxia Michelle He,&nbsp;Julie S. Moyers,&nbsp;Tamer Coskun,&nbsp;Annie Long,&nbsp;Dawn Allen,&nbsp;Libbey O'Farrell,&nbsp;Breanna Bowen,&nbsp;Edward Pratt,&nbsp;Beth Tidemann-Miller,&nbsp;Lai San Tham,&nbsp;Hilda Ibriga,&nbsp;Jorge Alsina-Fernandez,&nbsp;Kieren J. Mather,&nbsp;Axel Haupt,&nbsp;Shobha N. Bhattachar","doi":"10.1016/j.molmet.2025.102271","DOIUrl":"10.1016/j.molmet.2025.102271","url":null,"abstract":"<div><h3>Objectives</h3><div>Eloralintide (LY3841136), a novel amylin analog, was evaluated in translational studies to characterize its therapeutic potential for treating obesity.</div></div><div><h3>Methods</h3><div>In vitro assays were performed in cell lines selectively expressing rat or human amylin 1 receptor (AMY1R), amylin 3 receptor (AMY3R), or calcitonin receptor (CTR). In vivo studies were conducted in rats and monkeys. A phase 1, randomized, placebo-controlled, participant/investigator-blinded trial evaluated the safety and tolerability of single-ascending eloralintide doses (0.04–12 mg) in healthy participants (NCT05295940).</div></div><div><h3>Results</h3><div>In vitro, eloralintide preferentially activated human AMY1R (12-fold &gt; CTR, 11-fold &gt; AMY3R), while in rats, both AMY1R and AMY3R were activated more potently than CTR. Eloralintide induced significantly less conditioned taste avoidance in lean rats than cagrilintide, a non-selective amylin receptor agonist (p &lt; 0.05). Eloralintide dose dependently reduced food intake and lowered body weight, primarily through fat mass loss, in diet-induced obese rats. Eloralintide demonstrated favorable pharmacokinetics in both rats and monkeys. In the phase 1 trial, 48 healthy participants had a mean body mass index of 27.5 kg/m². Nine participants in the eloralintide cohorts reported 16 adverse events, with most being mild (n = 15/16). Two participants reported 4 gastrointestinal events, including one moderate vomiting event. The pharmacokinetic profile of eloralintide supports once-weekly dosing. In eloralintide cohorts receiving single doses of 4 or 12 mg, week-4 mean percent change from baseline in body weight was −2.5% (p &lt; 0.01) and −4.4% (p &lt; 0.001), respectively, vs placebo (+0.6%).</div></div><div><h3>Conclusions</h3><div>Once-weekly dosing with eloralintide, an AMY1R-selective agonist, may offer a promising new therapeutic with favorable gastrointestinal tolerability for the treatment of obesity.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102271"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318511","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}