Molecular Metabolism最新文献

{"title":"Interaction between time-of-day and oxytocin efficacy in mice and humans with and without gestational diabetes","authors":"Thu Van-Quynh Duong ,&nbsp;Alexandra M. Yaw ,&nbsp;Guoli Zhou ,&nbsp;Niharika Sinha ,&nbsp;Aneesh Sai Cherukuri ,&nbsp;Duong Nguyen ,&nbsp;Kylie Cataldo ,&nbsp;Nicollette Ly ,&nbsp;Aritro Sen ,&nbsp;Lorenzo F. Sempere ,&nbsp;Cara Detrie ,&nbsp;Robert Seiler ,&nbsp;I. Nicholas Olomu ,&nbsp;Rene Cortese ,&nbsp;Robert Long ,&nbsp;Hanne M. Hoffmann","doi":"10.1016/j.molmet.2025.102269","DOIUrl":"10.1016/j.molmet.2025.102269","url":null,"abstract":"<div><div>Due to significant risks of peripartum complications, pregnancies complicated by diabetes often require labor induction or augmentation with synthetic oxytocin. However, the efficacy of oxytocin is often compromised in diabetic pregnancies. Given that diabetes deregulates the body's circadian timekeeping system, our objective was to determine how time of day and the circadian clock gene, <em>Bmal1</em>, gate oxytocin efficacy. We compared oxytocin uterotonic efficacy in a smooth muscle-<em>Bmal1</em> conditional knockout mouse (cKO), and a mouse model of food-induced gestational diabetes. We found that in wild-type mice, the oxytocin receptor is expressed in a time-of-day-dependent manner and is under the control of BMAL1. Both <em>Bmal1</em> cKO and food-induced gestational diabetes mice, which presented with a downregulation of <em>Bmal1</em> in the uterus, had decreased uterine contractility in response to oxytocin. To establish the translational value of these findings, we utilized an immortalized term human myometrial cell line. We determined that the time-of-day impacted oxytocin-induced myometrial contractility <em>in vitro</em>. Furthermore, we conducted a retrospective medical record analysis of 2,367 pregnant patients ≥39 weeks gestation undergoing induction of labor. We assessed the timing of labor induction and the impact of gestational diabetes mellitus on labor duration. Induction of labor in the morning compared to midnight was associated with a ∼1.5-hour and ∼7-hour shorter labor duration in controls and patients with gestational diabetes mellitus, respectively. In conclusion, circadian timing plays a key role in induction of labor and oxytocin responsiveness and should be considered when managing labor induction.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102269"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318456","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":"Nutritional regulation of metabolism-dependent and-independent glucosensing in the mammalian taste system","authors":"Lilly Mai ,&nbsp;Aracely Simental Ramos ,&nbsp;A-Hyun Jung ,&nbsp;Devin de Monteiro ,&nbsp;Isabelle Vu ,&nbsp;Tricia Saputera ,&nbsp;Jonathan Fan ,&nbsp;Tatiyana Adkins ,&nbsp;DeHaven Dickerson ,&nbsp;David W. Pittman ,&nbsp;Sandrine Chometton ,&nbsp;Lindsey A. Schier","doi":"10.1016/j.molmet.2025.102280","DOIUrl":"10.1016/j.molmet.2025.102280","url":null,"abstract":"<div><div>Dietary glucose is a preferred source of energy, but it remains unknown how the mammalian brain rapidly detects and discriminates this sugar from other sweeteners, and whether this depends on nutritional environment and metabolic need. Our results show that signals generated by metabolism-dependent and -independent actions of oral glucose can each be recruited to guide nutrient choice. Further, glucose (or its non-metabolizable analog) evokes a discernible pattern of neural activity from calorie-matched fructose in the central gustatory system, and this is conditioned by diet. Although the brain responses and corresponding consummatory behaviors do not require sweet taste receptor input, the results indicate that the sweet receptor is important for integrating nutritional states with metabolic pathways in the taste system and ultimately guiding intake towards glucose-yielding substrates.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102280"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513350","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":"The innate thermogenic capacity of brown adipose tissue develops independently of sympathetic signaling","authors":"Ethan C. Fein ,&nbsp;Sarmistha Mukherjee ,&nbsp;Joseph A. Baur ,&nbsp;Patrick Seale","doi":"10.1016/j.molmet.2025.102299","DOIUrl":"10.1016/j.molmet.2025.102299","url":null,"abstract":"<div><div>Brown adipose tissue (BAT) dissipates energy as heat in response to β-adrenergic signaling induced by the sympathetic nervous system (SNS). While this pathway is essential for the cold-induced remodeling and metabolic activity of BAT, its role in developmental programming is unclear. Here, we show that brown adipocytes acquire thermogenic identity during embryogenesis independently of sympathetic innervation and β-adrenergic signaling. Genetic sympathectomy or disrupted β-adrenergic signaling had minimal effects on thermogenic gene expression or tissue morphology during either embryonic or postnatal BAT development in the absence of cold stress. Functional analyses revealed that the SNS is likely required for circulatory support of BAT activity during β-adrenergic stimulation but not for the development of the thermogenic capacity of BAT itself. These findings demonstrate that developmental and cold-responsive BAT remodeling are mechanistically distinct processes. Defining the molecular programs that drive BAT development may reveal new strategies to enhance BAT formation and function without relying on β-adrenergic stimulation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102299"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743408","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 cell secreted GABA sets appropriate insulin secretion by modulating islet calcium oscillations","authors":"Sandra M. Ferreira ,&nbsp;D. Walker Hagan ,&nbsp;Austin E. Stis ,&nbsp;Adrienne E. Widener ,&nbsp;Alexandra E. Cuaycal ,&nbsp;Chad Rancourt ,&nbsp;Arabella G. Readey ,&nbsp;Dylan S. Smurlick ,&nbsp;Dongtao A. Fu ,&nbsp;Martha Campbell–Thompson ,&nbsp;Marjan Slak Rupnik ,&nbsp;Edward A. Phelps","doi":"10.1016/j.molmet.2025.102268","DOIUrl":"10.1016/j.molmet.2025.102268","url":null,"abstract":"<div><h3>Objectives</h3><div>Gamma-aminobutyric acid (GABA) is produced in pancreatic beta cells and is implicated in modulating islet function, yet its precise physiological role remains uncertain. This study aimed to determine the function of endogenous beta cell-derived GABA on insulin secretion and islet calcium dynamics by developing a conditional beta cell-specific knockout of GABA-synthesizing enzymes (GAD65 and GAD67).</div></div><div><h3>Methods</h3><div>Conditional knockout mice (<em>Gad</em> ^βKO) lacking both GAD65 and GAD67 specifically in pancreatic beta cells were generated. Glucose-stimulated insulin secretion was measured in isolated islets and <em>in vivo</em> and islet Ca²⁺ oscillations were recorded using calcium imaging. The effects of GABA and its receptor agonists/antagonists were tested under various glucose conditions. Additional analyses were performed in high-fat diet-fed mice and human islets from donors with and without type 2 diabetes (T2D).</div></div><div><h3>Results</h3><div><em>Gad</em> ^βKO islets were devoid of GABA and showed excessive insulin secretion in response to glucose without anatomical changes in islet composition. These islets had defective Ca²⁺ oscillations, with prolonged active phases and reduced amplitudes. GABA application suppressed Ca²⁺ oscillations, an effect mediated by GABA_A and GABA_B receptors. High-fat diet-fed and T2D human islets were unresponsive to GABA and exhibited impaired Ca²⁺ oscillations.</div></div><div><h3>Conclusions</h3><div>This is the first study using a beta cell-specific GAD65/GAD67 knockout model. Endogenous beta cell-derived GABA is critical for modulating insulin secretion by maintaining proper Ca²⁺ oscillation dynamics. GABA signaling likely operates as a delayed negative feedback mechanism that reinforces oscillatory homeostasis in islets. The loss of GABA responsiveness, as seen in metabolic stress or T2D, may contribute to islet dysfunction. This work establishes GABA as a key regulator of islet rhythm and glucose responsiveness.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102268"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313216","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":"Isotype-selective roles of hepatic acetyl-CoA carboxylases in a mouse model of fatty liver disease","authors":"Martina Beretta ,&nbsp;Calum S. Vancuylenburg ,&nbsp;Riya Shrestha ,&nbsp;Ellen M. Olzomer ,&nbsp;Brenna Osborne ,&nbsp;Mingyan Zhou ,&nbsp;Suri Zhang ,&nbsp;Adam Hargreaves ,&nbsp;Frances L. Byrne ,&nbsp;Kyle L. Hoehn","doi":"10.1016/j.molmet.2025.102264","DOIUrl":"10.1016/j.molmet.2025.102264","url":null,"abstract":"<div><h3>Objectives</h3><div>Acetyl-CoA carboxylase enzymes ACC1 and ACC2 promote liver fat storage. Accordingly, ACC inhibition represents a strategy to reverse fatty liver disease and related disorders. Human and rodent studies show that targeting both ACC isotypes can reverse some fatty liver phenotypes, but also result in unwanted metabolic phenotypes including hypertriglyceridemia. The objective of this study was to determine whether liver-selective genetic inhibition of ACC1 or ACC2 individually can reverse fatty liver disease phenotypes without adverse metabolic phenotypes in a mouse model of fatty liver disease.</div></div><div><h3>Methods</h3><div>Four genotypes of male C57BL/6J mice floxed for ACC1, ACC2, both ACC alleles, or no ACC alleles were fed an Amylin diet for 28 weeks to induce fatty liver disease. After 20 weeks of Amylin feeding, ACC genes were deleted in the liver by adeno-associated virus 8 (AAV8)-mediated Cre recombinase expression. Mice were metabolically phenotyped and liver disease was assessed by histopathology.</div></div><div><h3>Results</h3><div>Dual inhibition of ACC enzymes was necessary to achieve significant reversal of fatty liver disease and fibrosis; however, it also caused hypertriglyceridemia, weight gain, and glucose intolerance. ACC1 inhibition alone resulted in partial reversal of fatty liver disease phenotypes but drove all undesired metabolic phenotypes. In contrast, ACC2 inhibition alone had minimal effect on fatty liver, fibrosis, or metabolic phenotypes.</div></div><div><h3>Conclusions</h3><div>Our results indicate that complete inhibition of liver ACC activity is required to resolve fatty liver disease and fibrosis, with ACC1 inhibition being the dominant driver of unwanted metabolic dysregulation. Accordingly, selective inhibition of ACC2 with partial inhibition of ACC1 may represent a refined future approach to reverse fatty liver disease phenotypes while minimizing metabolic dysregulation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102264"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233086","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":"Furin may contribute to proglucagon processing and glucagon-like Peptide-1 production in human alpha cells","authors":"Janyne Koepke,&nbsp;Wentong Long,&nbsp;Amy Barr,&nbsp;Peter E. Light","doi":"10.1016/j.molmet.2025.102259","DOIUrl":"10.1016/j.molmet.2025.102259","url":null,"abstract":"<div><h3>Objectives</h3><div>While glucagon-like peptide-1 (GLP-1) production has been previously documented in human alpha cells, the steps regulating its production and secretion are poorly characterized. We investigated the enzymes implicated in proglucagon processing, characterizing their expression and localization in primary human alpha cells and αTC1/9 cells.</div></div><div><h3>Methods</h3><div>Human alpha cells and αTC1/9 cells were maintained in control conditions or exposed to proinflammatory and Akt-activating stimuli to enhance GLP-1 levels. Proglucagon and convertase enzyme gene expression, protein content, and subcellular localization were evaluated by qPCR, Western Blot, and immunofluorescent microscopy, respectively.</div></div><div><h3>Results</h3><div>Our data suggests that the canonical GLP-1-producing enzyme, Prohormone Convertase 1/3 (PC1/3), is poorly expressed and localized in alpha cells, while its homologue furin is optimally positioned for GLP-1 production. We also note that GLP-1 and glucagon processing occur in different subcellular compartments, creating two distinct pools of secretory granules which respond to similar secretory stimuli.</div></div><div><h3>Conclusion</h3><div>Our study suggests that furin, rather than PC1/3, is positioned to process proglucagon into GLP-1, and despite coming from the same precursor molecule, GLP-1 and glucagon are separately packaged in primary human alpha cells.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102259"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192112","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":"Activin receptor type IIA/IIB blockade increases muscle mass and strength, but compromises glycemic control in mice","authors":"Michala Carlsson ,&nbsp;Emma Frank ,&nbsp;Joan M. Màrmol ,&nbsp;Mona Sadek Ali ,&nbsp;Steffen H. Raun ,&nbsp;Edmund Battey ,&nbsp;Nicoline Resen Andersen ,&nbsp;Andrea Irazoki ,&nbsp;Camilla Lund ,&nbsp;Carlos Henríquez-Olguin ,&nbsp;Martina Kubec Højfeldt ,&nbsp;Pauline Blomquist ,&nbsp;Frederik Duch Bromer ,&nbsp;Gabriele Mocciaro ,&nbsp;Andreas Lodberg ,&nbsp;Christian Brix Folsted Andersen ,&nbsp;Marco Eijken ,&nbsp;Andreas Mæchel Fritzen ,&nbsp;Jonas Roland Knudsen ,&nbsp;Erik A. Richter ,&nbsp;Lykke Sylow","doi":"10.1016/j.molmet.2025.102261","DOIUrl":"10.1016/j.molmet.2025.102261","url":null,"abstract":"<div><h3>Purpose</h3><div>Blocking the Activin receptor type IIA and IIB (ActRIIA/IIB) has clinical potential to increase muscle mass and improve glycemic control in obesity, cancer, and aging. However, the impact of blocking ActRIIA/IIB on strength, metabolic regulation, and insulin action remains unclear.</div></div><div><h3>Methods</h3><div>Here, we investigated the effect of short- (10 mg kg⁻¹ bw, once, 40h) or long-term (10 mg kg⁻¹ bw, twice weekly, 21 days) antibody treatment targeting ActRIIA/IIB (αActRIIA/IIB) in lean and diet-induced obese mice and engineered human muscle tissue.</div></div><div><h3>Results</h3><div>Short-term <span><math><mrow><mi>α</mi></mrow></math></span> ActRIIA/IIB administration in lean mice increased insulin-stimulated glucose uptake in skeletal muscle by 76–105%. Despite this, <span><math><mi>α</mi></math></span>ActRIIA/IIB-treated mice exhibited 33% elevated blood glucose and glucose intolerance. Long-term αActRIIA/IIB treatment increased muscle mass (+20%) and reduced fat mass (−8%) in obese mice but failed to enhance insulin-stimulated glucose uptake in muscle or adipose tissue. Instead, it induced glucose intolerance, cardiac hypertrophy with glycogen accumulation, and elevated hepatic triacylglycerol and glucose output in response to pyruvate. Concomitantly, long-term <span><math><mrow><mi>α</mi></mrow></math></span>ActRIIA/IIB treatment increased strength (+30%) in mouse soleus muscle and prevented activin A-induced loss of tissue strength in engineered human muscle tissue. Surprisingly, long-term <span><math><mrow><mi>α</mi></mrow></math></span> ActRIIA/IIB treatment lowered volitional running (−250%).</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate that, in accordance with human studies, ActRIIA/IIB blockade holds promise for increasing muscle mass, strength, and muscle insulin sensitivity. However, contrary to the improved glycemic control in humans, ActRIIA/IIB blockade in mice causes severe glucose intolerance and lowers voluntary physical activity. Our study underscores the complex metabolic and functional consequences of ActRIIA/IIB blockade, and highlight species differences on glycemic control, which warrant further investigation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102261"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192177","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":"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":"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}