Molecular Metabolism最新文献

{"title":"An atlas of mitochondrial ATP synthase activity across the lifespan","authors":"Muzna Saqib ,&nbsp;Dylan C. Sarver ,&nbsp;Christy M. Nguyen ,&nbsp;Fangluo Chen ,&nbsp;Marcus M. Seldin ,&nbsp;G. William Wong","doi":"10.1016/j.molmet.2025.102278","DOIUrl":"10.1016/j.molmet.2025.102278","url":null,"abstract":"<div><div>Mitochondrial dysfunction and declining energy production are hallmarks of aging, yet we lack a comprehensive systems-level view of ATP synthase (Complex V) activity across tissues, sex, and age. To overcome this, we leveraged a recently developed method to directly quantify complex V hydrolytic activity at scale in 32 tissues from young (10 weeks) and old (80 weeks) male and female mice. Our high-resolution atlas reveals several notable findings: 1) complex V activity differs markedly across tissues, with the highest levels seen in contractile organs such as the heart and striated muscles (quadriceps, hamstring, diaphragm, tongue); 2) sex influences complex V activity in a tissue-specific manner, with significant differences seen in the heart, liver, fat depots, pancreas, spleen, tongue, and cortex; 3) aging has a much larger impact than sex on complex V activity, with a greater number of age-dependent changes seen across tissues; 4) the directionality and magnitude of change in complex V activity across sex and age is variable and tissue dependent; 5) the expression of complex V related genes in human and mouse tissues across age shows only partial concordance with complex V activity, suggesting functional modulation by posttranscriptional mechanisms. This compendium of ATP synthase activity highlights organ-level variations in the mode and tempo of aging, affording an unprecedented view of the shared and divergent changes in ATP synthase function across sex and organ systems. Our data provide a valuable reference for comparative studies of mitochondrial adaptations across space and time, and in pathophysiological contexts.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102278"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145431956","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":"Long-acting GIPR agonist LY3537021 reduces body weight and fasting blood glucose in patients with T2D: Preclinical development and phase 1 randomized ascending dose studies","authors":"William Roell,&nbsp;Jorge Alsina-Fernandez,&nbsp;Hongchang Qu,&nbsp;Tamer Coskun,&nbsp;Charles Benson,&nbsp;Axel Haupt,&nbsp;Ronan P. Kelly,&nbsp;Libbey O'Farrell,&nbsp;Kyle W. Sloop,&nbsp;James P. Steele,&nbsp;James Ficorilli,&nbsp;Ajit Regmi,&nbsp;Mallikarjuna Rettiganti,&nbsp;Shweta Urva,&nbsp;Kieren J. Mather,&nbsp;Edward Pratt","doi":"10.1016/j.molmet.2025.102298","DOIUrl":"10.1016/j.molmet.2025.102298","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Tirzepatide, a single-molecule dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor (R) agonist, has shown superiority in the reduction of blood glucose and body weight, above selective GLP-1R agonists, but the contribution of GIP to these effects remains incompletely understood.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Objectives&lt;/h3&gt;&lt;div&gt;To characterize the preclinical and in-human effects of a long-acting GIPR agonist monotherapy in healthy participants and patients with type 2 diabetes (T2D).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;A long-acting GIPR agonist (LY3537021) was characterized &lt;em&gt;in vitro&lt;/em&gt; and in Long-Evans diet-induced obese rats and Wistar rats. Next, a phase 1, randomized, placebo-controlled, single ascending dose (SAD)/multiple ascending dose (MAD) study explored the safety, tolerability, pharmacokinetics, and pharmacodynamics of LY3537021 in healthy participants and participants with T2D in Singapore.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;&lt;em&gt;In vitro&lt;/em&gt;, LY3537021 demonstrated potency greater than native GIP and selectivity for the GIPR. &lt;em&gt;In vivo&lt;/em&gt; in rats, chronic treatment with LY3537021 resulted in weight loss and improved glycemic control during a glucose tolerance test. The phase 1 clinical study enrolled 85 healthy participants and patients with T2D (SAD, n = 47 [aged 25–64 years]; MAD, n = 38 [aged 25–69 years]; average baseline BMI was 25.9–27.0 kg/m&lt;sup&gt;2&lt;/sup&gt; across the arms). During the MAD part, dose-dependent decreases in mean body weight were observed in all LY3537021 dose groups, regardless of T2D status, and persisted at 35 days after the last dose. For example, participants with T2D treated with 25 mg of LY3537021 lost a mean of 3.14 kg of body weight compared with 0.36 kg in the placebo group (p &lt; 0.05) at day 57. Transient reductions in fasting glucose were observed in these participants, but the reductions were not sustained and not significantly different from placebo at day 29. The time to maximum observed drug concentrations varied across cohorts (8–96 h), and the half-life was estimated at approximately 12 days for non-T2D and T2D cohorts with the 25-mg dose, supporting once-weekly administration. There was no delay in gastric emptying following a single subcutaneous dose of 0.3–25 mg LY3537021. LY3537021 was well tolerated with infrequent gastrointestinal adverse events.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;&lt;em&gt;In vivo&lt;/em&gt; studies demonstrated that LY3537021 reduced body weight and improved glycemia during a glucose challenge in rats. The phase 1 study demonstrated that the long-acting GIPR agonist LY3537021 was well tolerated, induced weight loss, and improved glucose control in humans. These observations better define the therapeutic benefit of long-acting GIPR agonists and support a distinct contribution of GIP agonism to the benefits observed with multi-agonist peptides that act via the GIPR. Future studies are needed in more di","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102298"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757074","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":"Long-term high-protein diet intake accelerates adipocyte senescence through macrophage CD38-mediated NAD+ depletion","authors":"Xiaohan Yang ,&nbsp;Lun Hua ,&nbsp;Dengfeng Gao ,&nbsp;Yanni Wu ,&nbsp;Yi Yang ,&nbsp;Xianyang Jin ,&nbsp;Xuemei Jiang ,&nbsp;Chao Jin ,&nbsp;Bin Feng ,&nbsp;Lianqiang Che ,&nbsp;Shengyu Xu ,&nbsp;Yan Lin ,&nbsp;Long Jin ,&nbsp;Yong Zhuo ,&nbsp;Mingzhou Li ,&nbsp;De Wu","doi":"10.1016/j.molmet.2025.102306","DOIUrl":"10.1016/j.molmet.2025.102306","url":null,"abstract":"<div><div>High-protein (HP) diets are widely adopted in Western societies for body-weight management; yet, they exacerbate senescence-associated metabolic deterioration, posing an unresolved pathophysiological conundrum. Here, we demonstrate that long-term HP intake mediates adipocyte-specific NAD⁺ depletion and mitochondrial dysfunction in white adipose tissue (WAT). Single-nucleus transcriptomic analyses revealed adipocyte-restricted senescence signatures in HP-fed mice. Mechanistically, HP intake triggers macrophage-specific upregulation of CD38 (a key NAD⁺ hydrolase), which depletes adipocyte NAD⁺ pools and thereby accelerates cellular senescence. Restoration of NAD⁺ levels, either via supplementation with NAD⁺ precursor or pharmacological inhibition of CD38 activity, alleviated the senescence-associated metabolic sequelae induced by HP diets. Our findings establish macrophage-adipocyte NAD⁺ crosstalk as a central axis linking dietary protein excess to WAT aging, providing actionable targets for the prevention and treatment of age-related metabolic disorders.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102306"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145763253","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":"Cross-species studies implicate the melanocortin 3 receptor more strongly in the control of pubertal development than energy balance","authors":"Katie Duckett ,&nbsp;Alyce McClellan ,&nbsp;Laura J. Corbin ,&nbsp;Irene Cimino ,&nbsp;Ahmed Elhakeem ,&nbsp;Ana Goncalves Soares ,&nbsp;Alice Williamson ,&nbsp;Eloise Cross ,&nbsp;Zammy Fairhurst-Hunter ,&nbsp;Slavé Petrovski ,&nbsp;Debra Rimmington ,&nbsp;Jesús Alegre-Díaz ,&nbsp;Jaime Berumen ,&nbsp;Pablo Kuri-Morales ,&nbsp;Roberto Tapia-Conyer ,&nbsp;BELIEVE study,,&nbsp;Jacek Mokrosinski ,&nbsp;I. Sadaf Farooqi ,&nbsp;Asif Rasheed ,&nbsp;Danish Saleheen ,&nbsp;Stephen O’Rahilly","doi":"10.1016/j.molmet.2025.102301","DOIUrl":"10.1016/j.molmet.2025.102301","url":null,"abstract":"<div><div>Hypothalamic neurons expressing either POMC or AGRP sense nutritional state directly and indirectly and transmit these neuropeptide signals to other brain centres through the melanocortin 3 and 4 receptors. MC4R is primarily concerned with the control of appetite and energy expenditure while MC3R is more closely related to the control of linear growth and the timing of puberty. The role of MC3R in the long-term control of energy balance and body composition is less clear, particularly in humans. We have undertaken studies in humans, domestic dogs and mice with the goal of clarifying the relative impact of MC3R deficiency on energy balance, growth and sexual development. By studying three large consanguineously enriched cohorts, totalling approximately 300K people, we identified nine individuals who are homozygous for functionally null <em>MC3R</em> variants. The body mass index (BMI) of the homozygous <em>MC3R</em> variant carriers was not significantly different from that of age, sex and demographically matched controls, with six of the nine homozygotes having a BMI &lt;30 kg/m².</div><div>We detected a canine <em>MC3R</em> missense variant (p.M320I) which is common in labrador retrievers and showed that this significantly impairs receptor signalling. Dogs homozygous for p.M320I were lighter and showed delayed pubertal development but were not significantly more obese than wild-type or heterozygous dogs. We also established that the lack of <em>Mc3r</em> delayed pubertal development in both male and female mice.</div><div>Finally, we studied growth and pubertal trajectories of individuals carrying rare loss-of-function <em>MC3R</em> variants and found that male carriers had delayed peak weight velocity and genital development but had no evidence for excess body fat compared to non-carriers.</div><div>Our results support MC3R having a conserved role across mammals in controlling growth and pubertal timing. While MC3R deficiency may influence linear growth and body composition, complete loss of MC3R does not result in a penetrant human obesity syndrome.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102301"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743434","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":"Corrigendum to “DNA damage to β cells in culture recapitulates features of senescent β cells that accumulate in type 1 diabetes” [Mol Metabol 62 (2022) 101524]","authors":"Gabriel Brawerman ,&nbsp;Jasmine Pipella ,&nbsp;Peter J. Thompson","doi":"10.1016/j.molmet.2025.102284","DOIUrl":"10.1016/j.molmet.2025.102284","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102284"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588384","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":"Regulation of HDL dysfunctionality by phosphatidylethanolamine links poly-unsaturated fatty acids with atherosclerotic cardiovascular diseases","authors":"Malik Taradeh ,&nbsp;Lise M. Hardy ,&nbsp;Veronica D. Dahik ,&nbsp;Marie Lhomme ,&nbsp;Hua Wang ,&nbsp;Canelle Reydellet ,&nbsp;Clément Materne ,&nbsp;Pukar KC ,&nbsp;Eric Bun ,&nbsp;Maud Clemessy ,&nbsp;Jean-Paul Pais-De-Barros ,&nbsp;Sophie Galier ,&nbsp;Eric Frisdal ,&nbsp;Hervé Durand ,&nbsp;Maharajah Ponnaiah ,&nbsp;Petra El Khoury ,&nbsp;Elise F. Villard ,&nbsp;Philippe Lesnik ,&nbsp;Antonio Gallo ,&nbsp;Laurent Kappeler ,&nbsp;Wilfried Le Goff","doi":"10.1016/j.molmet.2025.102281","DOIUrl":"10.1016/j.molmet.2025.102281","url":null,"abstract":"<div><h3>Aims</h3><div>Low plasma high-density lipoprotein (HDL)-cholesterol levels are associated with increased risk of atherosclerotic cardiovascular disease (ASCVD), potentially reflecting impaired antiatherogenic HDL functions. These latter are strongly influenced by the HDL phospholipidome, which is frequently altered in ASCVD patients. Several studies reported that plasma levels of phosphatidylethanolamine (PE) species, particularly PE (36:5), were positively associated with ASCVD, but the underlying mechanisms remain unclear. Plasma PE (36:5) exists as eicosapentaenoic (EPA)-PE and arachidonic acid (ARA)-PE, with the latter predominating in ASCVD. This study investigated whether the association of PE (36:5) with ASCVD might result from an impairment of the antiatherogenic functions of HDL.</div></div><div><h3>Methods and results</h3><div>Total PE and PE (36:5) content of large HDL isolated from 86 women with metabolic syndrome was positively associated with carotid intima-media thickness in multivariate regression analysis adjusted for traditional risk factors. In Tg<em>CETP x Ldlr</em>^−/− mice fed a high-cholesterol diet, the atherosclerotic plaque size was greater when reconstituted HDL (rHDL) containing ARA-PE was injected retro-orbitally, compared with injection of control rHDL containing only phosphatidylcholine (PC). <em>In vitro</em>, PE rHDL showed reduced cholesterol efflux capacity and impaired anti-inflammatory activity in THP-1 macrophages, together with diminished anti-oxidative activity against LDL oxidation compared to control rHDL. Strikingly, ARA-PE rHDL profoundly weakened of the HDL functions, while EPA-PE counteracted the ARA-PE-induced dysfunction and potentiated the functionality of rHDL.</div></div><div><h3>Conclusions</h3><div>This study reveals a causal link between PE species, particularly ARA-PE, and HDL dysfunction, contributing to atherosclerosis. EPA-PE can restore HDL function, supporting the therapeutic potential of EPA reducing ASCVD risk.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102281"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145540912","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":"Myokine IL-6 activity enhances post-exercise fatty acid accumulation in skeletal muscle but does not affect glycogen resynthesis","authors":"Timothy M. Kistner ,&nbsp;Beckey Trinh ,&nbsp;Karl Mfeketo ,&nbsp;Gerrit van Hall ,&nbsp;Bente K. Pedersen ,&nbsp;Daniel E. Lieberman ,&nbsp;Helga Ellingsgaard","doi":"10.1016/j.molmet.2025.102283","DOIUrl":"10.1016/j.molmet.2025.102283","url":null,"abstract":"<div><h3>Background/Purpose</h3><div>During exercise, myokine interleukin 6 (IL-6) plays a variety of metabolic roles including acting as a muscular energy sensor and liberating somatic energy stores. While the effects of IL-6 are relatively well-defined <em>during</em> exercise, its role in muscular metabolism during exercise recovery in humans has not been addressed.</div></div><div><h3>Methods</h3><div>To test whether myokine IL-6 allocates fat and glucose towards muscle, we conducted a randomized double-blind trial with 30 men (Age: 25.2 ± 3 yrs. BMI: 23.0 ± 1.5 kg/m2) where participants exercised at a moderate intensity for 2 h and received either tocilizumab to block IL-6 activity, or placebo. Continuous infusions of isotopically labeled palmitate, glucose, and glycerol paired with blood, breath, and muscle samples were used to measure muscle-specific metabolism.</div></div><div><h3>Results</h3><div>IL-6 blockade did not affect exercise performance, substrate utilization, or glucose, fatty acid and glycerol kinetics during exercise. During recovery, IL-6 blockade decreased the appearance of oral glucose and lowered the insulin response to a glucose drink. Despite this difference in glucose and insulin, the rate of post-exercise glycogen resynthesis before and after the ingestion of glucose was not altered between groups. Although IL-6 blockade did not affect lipolysis during exercise, it attenuated the accumulation of esterified oleate in muscle during recovery before the glucose drink was given. Furthermore, IL-6 blockade attenuated IL-1RA production in recovery but did not alter IL-10 secretion.</div></div><div><h3>Conclusion</h3><div>Together, these results imply that during recovery from moderate-intensity exercise, myokine IL-6 primarily regulates fatty acid metabolism within muscle and leaves glucose metabolism largely unaffected.</div></div><div><h3>Clinical Trial Registration Number</h3><div><span><span>Clinicaltrials.gov</span><svg><path></path></svg></span> (NCT05349149).</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102283"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534028","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":"Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle","authors":"Dipsikha Biswas ,&nbsp;Ever Espino-Gonzalez ,&nbsp;Danial Ahwazi ,&nbsp;Jordana B. Freemantle ,&nbsp;Amy M. Ehrlich ,&nbsp;Charline Jomard ,&nbsp;Jonas Brorson ,&nbsp;Agnete N. Schou ,&nbsp;Jean Farup ,&nbsp;Julien Gondin ,&nbsp;Jesper Just ,&nbsp;Marc Foretz ,&nbsp;Jonas T. Treebak ,&nbsp;Marianne Agerholm ,&nbsp;Kei Sakamoto","doi":"10.1016/j.molmet.2025.102294","DOIUrl":"10.1016/j.molmet.2025.102294","url":null,"abstract":"<div><h3>Objectives</h3><div>Small-molecule activators targeting the allosteric drug and metabolite (ADaM) site of AMPK enhance insulin-independent glucose uptake in skeletal muscle and lower glucose in preclinical models of hyperglycemia. The regulatory AMPKγ subunit plays a central role in energy sensing. While the skeletal muscle-selective γ3 isoform is essential for AMP/ZMP-induced glucose uptake, it is dispensable for ADaM site-binding activators. We hypothesized that the predominant γ1 isoform is required for ADaM site activator-stimulated glucose uptake in skeletal muscle.</div></div><div><h3>Methods</h3><div>Single-nucleus RNA sequencing (snRNA-seq) was performed on mouse and human skeletal muscle mapping AMPK subunit isoform distribution across resident cell types. To determine γ isoform-specific requirements for activator-stimulated glucose uptake, skeletal muscle-specific inducible AMPKγ1/γ3 double knockout (imγ1^−/−/γ3^−/−) and single knockout (imγ1^−/− and imγ3^−/−) mice were generated<em>. Ex vivo</em> glucose uptake was measured following treatment with AICAR (AMP-mimetic) or MK-8722 (ADaM site activator), and <em>in vivo</em> MK-8722-induced blood glucose lowering was assessed.</div></div><div><h3>Results</h3><div>snRNA-seq revealed distinct AMPK isoform distribution: γ1 was ubiquitously expressed, whereas γ3 was enriched in glycolytic myofibers in both mouse and human skeletal muscle. <em>Ex vivo</em>, glucose uptake stimulated by either AICAR or MK-8722 was severely blunted in imγ1^−/−/γ3^−/− muscle, and MK-8722-induced blood glucose lowering was significantly blunted <em>in vivo</em>. AICAR but not MK-8722-stimulated muscle glucose uptake was abolished in imγ3^−/−, whereas both activators fully retained effects on glucose uptake and glucose lowering in imγ1^−/− mice.</div></div><div><h3>Conclusions</h3><div>While γ1 predominates in stabilizing the AMPKα2β2γ1 complex, it is dispensable for AMPK activator-stimulated glucose uptake in skeletal muscle, whether mediated via the nucleotide-binding or ADaM site.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102294"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654769","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":"Ulk1(S555) inhibition alters nutrient stress response by prioritizing amino acid metabolism","authors":"Orion S. Willoughby ,&nbsp;Anna S. Nichenko ,&nbsp;Matthew H. Brisendine ,&nbsp;Niloufar Amiri ,&nbsp;Shelby N. Henry ,&nbsp;Daniel S. Braxton ,&nbsp;John R. Brown ,&nbsp;Braeden J. Kraft ,&nbsp;Kalyn S. Jenkins ,&nbsp;Adele K. Addington ,&nbsp;Alexey V. Zaitsev ,&nbsp;Steven T. Burrows ,&nbsp;Ryan P. McMillan ,&nbsp;Haiyan Zhang ,&nbsp;Spencer A. Tye ,&nbsp;Charles P. Najt ,&nbsp;Siobhan E. Craige ,&nbsp;Timothy W. Rhoads ,&nbsp;Junco S. Warren ,&nbsp;Joshua C. Drake","doi":"10.1016/j.molmet.2025.102288","DOIUrl":"10.1016/j.molmet.2025.102288","url":null,"abstract":"<div><div>Metabolic flexibility, the capacity to adapt fuel utilization in response to nutrient availability, is essential for maintaining energy homeostasis and preventing metabolic disease. Here, we investigate the role of Ulk1 phosphorylation at serine 555 (S555), a site regulated by AMPK, in coordinating metabolic switching following short-term caloric restriction and fasting. Using Ulk1(S555A) global knock-in mice, we show loss of S555 phosphorylation impairs glucose oxidation in skeletal muscle and liver during short-term CR, despite improved glucose tolerance. Metabolomic, transcriptomic, and mitochondrial respiration analyses suggest a compensatory reliance on autophagy-derived amino acids in Ulk1(S555A) mice. These findings suggest Ulk1(S555) phosphorylation as a critical regulatory event linking nutrient stress to substrate switching. This work highlights an underappreciated role of Ulk1 in maintaining metabolic flexibility, with implications for metabolic dysfunction.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102288"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636164","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 role of the gut non-bacterial microbiome (virome, mycobiome, archaeome) and its impact on obesity","authors":"Koy Min Chue ,&nbsp;Sunny Hei Wong ,&nbsp;Tao Zuo ,&nbsp;Yusuf Ali","doi":"10.1016/j.molmet.2025.102289","DOIUrl":"10.1016/j.molmet.2025.102289","url":null,"abstract":"<div><div>The epidemic of obesity and metabolic syndrome is a major public health concern internationally. There is increasing knowledge and research in areas of appetite regulation and drivers of obesity but there is still a gap on how the interactomes are altered in a metabolically dysregulated human body. The human microbiome has been implicated in the pathogenesis of obesity. While the association of gut bacteriome dysbiosis is well described in obesity and metabolic syndrome, there is a lack of an integrative understanding about the roles of the non-bacterial microbiome (virome, mycobiome, and archaeome) in the pathogenesis and protection of obesity and metabolic syndrome. Accumulating studies have revealed that the non-bacterial microbes in the gut, including viruses/phages, fungi, and archaea, are profoundly altered in obesity, and impact host adiposity and physiology in nuanced manners. In this review, we aim to provide a comprehensive view on the role and the mechanisms of the gut virome, mycobiome, and archaeome in obesity. These insights will shed light on the translational value as well as the future research directions for harnessing the gut non-bacterial microbial entities in the therapeutics and prevention of metabolic diseases.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102289"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636123","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}