Pub Date : 2025-11-29DOI: 10.1016/j.molmet.2025.102294
Dipsikha Biswas , Ever Espino-Gonzalez , Danial Ahwazi , Jordana B. Freemantle , Amy M. Ehrlich , Charline Jomard , Jonas Brorson , Agnete N. Schou , Jean Farup , Julien Gondin , Jesper Just , Marc Foretz , Jonas T. Treebak , Marianne Agerholm , Kei Sakamoto
Objectives
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.
Methods
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. Ex vivo glucose uptake was measured following treatment with AICAR (AMP-mimetic) or MK-8722 (ADaM site activator), and in vivo MK-8722-induced blood glucose lowering was assessed.
Results
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. Ex vivo, 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 in vivo. 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.
Conclusions
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.
{"title":"Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle","authors":"Dipsikha Biswas , Ever Espino-Gonzalez , Danial Ahwazi , Jordana B. Freemantle , Amy M. Ehrlich , Charline Jomard , Jonas Brorson , Agnete N. Schou , Jean Farup , Julien Gondin , Jesper Just , Marc Foretz , Jonas T. Treebak , Marianne Agerholm , 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<sup>−/−</sup>/γ3<sup>−/−</sup>) and single knockout (imγ1<sup>−/−</sup> and imγ3<sup>−/−</sup>) 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<sup>−/−</sup>/γ3<sup>−/−</sup> 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<sup>−/−</sup>, whereas both activators fully retained effects on glucose uptake and glucose lowering in imγ1<sup>−/−</sup> 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":"2025-11-29","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}
Pub Date : 2025-11-28DOI: 10.1016/j.molmet.2025.102291
Manu V. Chakravarthy , Ruben Rodriguez , Anne Hergarden , Michael A. Elliott , Juan P. Frias , Federico A. Argüelles-Tello , Edgar Tenorio , Jonathan E. Rankin , Jingtao Wu , Shyam Krishnan , Daniel A. Erlanson , Raymond V. Fucini , Derek Bone , Jeffrey S. Iwig , Luis Acosta , Ashley Untereiner , Asmita Pant , Avalon Patton , Leyla L. Sanchez-Sanchez , Jian Luo , Stig K. Hansen
Biased agonism of the glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptors (GLP-1R/GIPR) yields greater weight loss and better glycemic control than unbiased agonism in preclinical models. To evaluate whether biased agonism translates into improved efficacy for weight loss and glycemic control in clinical settings, we developed and characterized CT-388, a unimolecular peptide-based dual GLP-1R/GIPR agonist that is cAMP signal-biased at both receptors. In cell-based assays, CT-388 activated GLP-1R and GIPR with both having minimal receptor internalization vs their native ligands. CT-388 improved glycemic control in mice and monkeys, and reduced bodyweight, suppressed appetite, and improved metabolic dysfunction-associated steatohepatitis pathology in mice. In a phase 1, double-blind, randomized, placebo-controlled clinical study (NCT04838405) of CT-388 (subcutaneously administered single doses [0.5–7.5 mg] or 4 once-weekly doses [5–12 mg]) in otherwise healthy participants with overweight or obesity, CT-388 was generally well tolerated with a safety profile consistent with other incretin-based therapies; most treatment-emergent adverse events were mild or moderate. Glycemic parameters were improved during fasting conditions and an oral glucose tolerance test. The mean percent change in bodyweight from baseline to day 29 was −4.7% to −8.0% across CT-388 doses vs −0.5% with placebo. CT-388 pharmacokinetics supported once-weekly dosing. In conclusion, CT-388 demonstrated strong translatability from preclinical to clinical studies with consistent pharmacokinetics and pharmacodynamics across multiple species. In clinical settings, 4 weeks of CT-388 treatment produced clinically meaningful weight loss and improved glycemic control with favorable tolerability. These findings warrant further clinical evaluation of CT-388 for treating obesity and type 2 diabetes.
{"title":"Effects of CT-388, a once-weekly signaling-biased dual GLP-1/GIP receptor agonist, on weight loss and glycemic control in preclinical models and participants with obesity","authors":"Manu V. Chakravarthy , Ruben Rodriguez , Anne Hergarden , Michael A. Elliott , Juan P. Frias , Federico A. Argüelles-Tello , Edgar Tenorio , Jonathan E. Rankin , Jingtao Wu , Shyam Krishnan , Daniel A. Erlanson , Raymond V. Fucini , Derek Bone , Jeffrey S. Iwig , Luis Acosta , Ashley Untereiner , Asmita Pant , Avalon Patton , Leyla L. Sanchez-Sanchez , Jian Luo , Stig K. Hansen","doi":"10.1016/j.molmet.2025.102291","DOIUrl":"10.1016/j.molmet.2025.102291","url":null,"abstract":"<div><div>Biased agonism of the glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptors (GLP-1R/GIPR) yields greater weight loss and better glycemic control than unbiased agonism in preclinical models. To evaluate whether biased agonism translates into improved efficacy for weight loss and glycemic control in clinical settings, we developed and characterized CT-388, a unimolecular peptide-based dual GLP-1R/GIPR agonist that is cAMP signal-biased at both receptors. In cell-based assays, CT-388 activated GLP-1R and GIPR with both having minimal receptor internalization vs their native ligands. CT-388 improved glycemic control in mice and monkeys, and reduced bodyweight, suppressed appetite, and improved metabolic dysfunction-associated steatohepatitis pathology in mice. In a phase 1, double-blind, randomized, placebo-controlled clinical study (NCT04838405) of CT-388 (subcutaneously administered single doses [0.5–7.5 mg] or 4 once-weekly doses [5–12 mg]) in otherwise healthy participants with overweight or obesity, CT-388 was generally well tolerated with a safety profile consistent with other incretin-based therapies; most treatment-emergent adverse events were mild or moderate. Glycemic parameters were improved during fasting conditions and an oral glucose tolerance test. The mean percent change in bodyweight from baseline to day 29 was −4.7% to −8.0% across CT-388 doses vs −0.5% with placebo. CT-388 pharmacokinetics supported once-weekly dosing. In conclusion, CT-388 demonstrated strong translatability from preclinical to clinical studies with consistent pharmacokinetics and pharmacodynamics across multiple species. In clinical settings, 4 weeks of CT-388 treatment produced clinically meaningful weight loss and improved glycemic control with favorable tolerability. These findings warrant further clinical evaluation of CT-388 for treating obesity and type 2 diabetes.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102291"},"PeriodicalIF":6.6,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145649092","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}
Pub Date : 2025-11-28DOI: 10.1016/j.molmet.2025.102285
Manoj K. Gupta , Dario F. De Jesus , Sevim Kahraman , Ivan A. Valdez , Farnaz Shamsi , Lian Yi , Adam C. Swensen , Yu-Hua Tseng , Wei-Jun Qian , Rohit N. Kulkarni
{"title":"Corrigendum to “Insulin receptor-mediated signaling regulates pluripotency markers and lineage differentiation” [Mol Metab 18 (2018) 153–163]","authors":"Manoj K. Gupta , Dario F. De Jesus , Sevim Kahraman , Ivan A. Valdez , Farnaz Shamsi , Lian Yi , Adam C. Swensen , Yu-Hua Tseng , Wei-Jun Qian , Rohit N. Kulkarni","doi":"10.1016/j.molmet.2025.102285","DOIUrl":"10.1016/j.molmet.2025.102285","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102285"},"PeriodicalIF":6.6,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596873","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}
Pub Date : 2025-11-27DOI: 10.1016/j.molmet.2025.102290
Yang Chen , Lin Liu , Ryan P. Calhoun , Lan Cheng , David Steger , Patrick Seale
Objective
Adipocyte differentiation is critical for the metabolically protective expansion of adipose tissue. Impaired differentiation drives lipodystrophy and pathologic tissue remodeling, major contributors to cardiometabolic diseases. The differentiation process is governed by master transcription factors, including the pioneer factor C/EBPβ, which initiates the adipogenic program. Here, we sought to identify novel C/EBPβ-associated factors that regulate human adipocyte differentiation.
Methods
We used chromatin immunoprecipitation followed by selective isolation of chromatin-associated proteins (ChIP-SICAP) to identify proteins that interact with C/EBPβ on chromatin during human adipocyte differentiation. Candidate factors were assessed for their effects on differentiation, through conducting a CRISPR/Cas9-based knockout screen in human adipocyte precursor cells (hAPCs). The transcription factor CUX1 emerged as a top candidate. We performed gain- and loss-of-function studies in primary human and mouse adipocyte differentiation models, coupled with RNA-seq and ChIP-seq, to define CUX1-regulated genes and pathways. In vivo relevance was tested using adipocyte precursor–selective Cux1 knockout and lineage reporter mice.
Results
Loss of CUX1 impaired, whereas its overexpression enhanced, adipocyte differentiation in hAPCs. RNA-seq and ChIP-seq analyses revealed that CUX1 promotes the expression of key adipogenic genes, including PPARG in hAPCs. By contrast, CUX1 exerted the opposite effect in mouse adipocyte differentiation. Cux1 deletion enhanced, while CUX1 overexpression suppressed, differentiation in mouse APCs (mAPCs). CUX1 exhibited distinct chromatin-binding patterns and motif enrichment profiles in mouse versus human cells. In vivo, Cux1 deletion in APCs of mice increased de novo adipocyte formation during early stages of obesity development.
Conclusions
The transcription factor CUX1 regulates adipocyte differentiation in opposite directions in humans and mice, emphasizing the need for species-specific models in metabolic disease research,
{"title":"The transcription factor CUX1 exerts opposing roles in human and mouse adipocyte differentiation","authors":"Yang Chen , Lin Liu , Ryan P. Calhoun , Lan Cheng , David Steger , Patrick Seale","doi":"10.1016/j.molmet.2025.102290","DOIUrl":"10.1016/j.molmet.2025.102290","url":null,"abstract":"<div><h3>Objective</h3><div>Adipocyte differentiation is critical for the metabolically protective expansion of adipose tissue. Impaired differentiation drives lipodystrophy and pathologic tissue remodeling, major contributors to cardiometabolic diseases. The differentiation process is governed by master transcription factors, including the pioneer factor C/EBPβ, which initiates the adipogenic program. Here, we sought to identify novel C/EBPβ-associated factors that regulate human adipocyte differentiation.</div></div><div><h3>Methods</h3><div>We used chromatin immunoprecipitation followed by selective isolation of chromatin-associated proteins (ChIP-SICAP) to identify proteins that interact with C/EBPβ on chromatin during human adipocyte differentiation. Candidate factors were assessed for their effects on differentiation, through conducting a CRISPR/Cas9-based knockout screen in human adipocyte precursor cells (hAPCs). The transcription factor CUX1 emerged as a top candidate. We performed gain- and loss-of-function studies in primary human and mouse adipocyte differentiation models, coupled with RNA-seq and ChIP-seq, to define CUX1-regulated genes and pathways. <em>In vivo</em> relevance was tested using adipocyte precursor–selective <em>Cux1</em> knockout and lineage reporter mice.</div></div><div><h3>Results</h3><div>Loss of CUX1 impaired, whereas its overexpression enhanced, adipocyte differentiation in hAPCs. RNA-seq and ChIP-seq analyses revealed that CUX1 promotes the expression of key adipogenic genes, including <em>PPARG</em> in hAPCs. By contrast, CUX1 exerted the opposite effect in mouse adipocyte differentiation. <em>Cux1</em> deletion enhanced, while CUX1 overexpression suppressed, differentiation in mouse APCs (mAPCs). CUX1 exhibited distinct chromatin-binding patterns and motif enrichment profiles in mouse versus human cells. <em>In vivo</em>, <em>Cux1</em> deletion in APCs of mice increased <em>de novo</em> adipocyte formation during early stages of obesity development.</div></div><div><h3>Conclusions</h3><div>The transcription factor CUX1 regulates adipocyte differentiation in opposite directions in humans and mice, emphasizing the need for species-specific models in metabolic disease research,</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102290"},"PeriodicalIF":6.6,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636144","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}
Pub Date : 2025-11-26DOI: 10.1016/j.molmet.2025.102284
Gabriel Brawerman , Jasmine Pipella , Peter J. Thompson
{"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 , Jasmine Pipella , 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":"2025-11-26","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}
Pub Date : 2025-11-24DOI: 10.1016/j.molmet.2025.102289
Koy Min Chue , Sunny Hei Wong , Tao Zuo , Yusuf Ali
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.
{"title":"The role of the gut non-bacterial microbiome (virome, mycobiome, archaeome) and its impact on obesity","authors":"Koy Min Chue , Sunny Hei Wong , Tao Zuo , 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":"2025-11-24","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}
Pub Date : 2025-11-24DOI: 10.1016/j.molmet.2025.102288
Orion S. Willoughby , Anna S. Nichenko , Matthew H. Brisendine , Niloufar Amiri , Shelby N. Henry , Daniel S. Braxton , John R. Brown , Braeden J. Kraft , Kalyn S. Jenkins , Adele K. Addington , Alexey V. Zaitsev , Steven T. Burrows , Ryan P. McMillan , Haiyan Zhang , Spencer A. Tye , Charles P. Najt , Siobhan E. Craige , Timothy W. Rhoads , Junco S. Warren , Joshua C. Drake
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.
{"title":"Ulk1(S555) inhibition alters nutrient stress response by prioritizing amino acid metabolism","authors":"Orion S. Willoughby , Anna S. Nichenko , Matthew H. Brisendine , Niloufar Amiri , Shelby N. Henry , Daniel S. Braxton , John R. Brown , Braeden J. Kraft , Kalyn S. Jenkins , Adele K. Addington , Alexey V. Zaitsev , Steven T. Burrows , Ryan P. McMillan , Haiyan Zhang , Spencer A. Tye , Charles P. Najt , Siobhan E. Craige , Timothy W. Rhoads , Junco S. Warren , 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":"2025-11-24","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}
Pub Date : 2025-11-19DOI: 10.1016/j.molmet.2025.102287
Taylor L. Carlson , Mark Fineman , Stace Kernodle , Chelsea R. Hutch , Christine Bryant , Kevin Colbert , Randy J. Seeley , Ashish Nimgaonkar
Type 2 diabetes and obesity impact billions of people and the global prevalence is only growing. Current treatment options, which include pharmacotherapy, e.g., GLP-1 receptor agonists (GLP-1RA) and bariatric surgical approaches have limitations. GLY-200 is an investigational clinical-stage oral non-absorbed polymeric drug designed to target proximal intestinal mucin and enhance its barrier function, emulating duodenal exclusion physiology for the treatment of diabetes and obesity. The efficacy of GLY-200 as a monotherapy and in combination with semaglutide, a leading GLP-1 receptor agonist (GLP-1RA) for obesity weight management was evaluated in diet-induced obesity (DIO) mice. Significant improvements in metabolic parameters were seen in mice treated with GLY-200 monotherapy. Moreover, an additive effect was observed when GLY-200 was combined with semaglutide, resulting in enhanced weight loss and metabolic improvements beyond those achieved with either treatment alone. GLY-200 showed promise as a weight maintenance drug, significantly blunting the weight rebound seen after GLP-1RA discontinuation. Phase 2a data from patients with type 2 diabetes (T2D) showed reductions in fasting and postprandial blood glucose, improved fasting lipid profiles, and progressive weight loss with GLY-200 treatment. These findings suggest that GLY-200, in combination with GLP-1RAs, holds promise as a novel therapeutic strategy for obesity, potentially offering a valuable approach for GLP-1RA dose reduction or weight maintenance following GLP-1RA discontinuation.
{"title":"Additive effects of GLY-200 (oral pharmacologic duodenal exclusion therapy) and GLP-1R agonist in obesity management","authors":"Taylor L. Carlson , Mark Fineman , Stace Kernodle , Chelsea R. Hutch , Christine Bryant , Kevin Colbert , Randy J. Seeley , Ashish Nimgaonkar","doi":"10.1016/j.molmet.2025.102287","DOIUrl":"10.1016/j.molmet.2025.102287","url":null,"abstract":"<div><div>Type 2 diabetes and obesity impact billions of people and the global prevalence is only growing. Current treatment options, which include pharmacotherapy, e.g., GLP-1 receptor agonists (GLP-1RA) and bariatric surgical approaches have limitations. GLY-200 is an investigational clinical-stage oral non-absorbed polymeric drug designed to target proximal intestinal mucin and enhance its barrier function, emulating duodenal exclusion physiology for the treatment of diabetes and obesity. The efficacy of GLY-200 as a monotherapy and in combination with semaglutide, a leading GLP-1 receptor agonist (GLP-1RA) for obesity weight management was evaluated in diet-induced obesity (DIO) mice. Significant improvements in metabolic parameters were seen in mice treated with GLY-200 monotherapy. Moreover, an additive effect was observed when GLY-200 was combined with semaglutide, resulting in enhanced weight loss and metabolic improvements beyond those achieved with either treatment alone. GLY-200 showed promise as a weight maintenance drug, significantly blunting the weight rebound seen after GLP-1RA discontinuation. Phase 2a data from patients with type 2 diabetes (T2D) showed reductions in fasting and postprandial blood glucose, improved fasting lipid profiles, and progressive weight loss with GLY-200 treatment. These findings suggest that GLY-200, in combination with GLP-1RAs, holds promise as a novel therapeutic strategy for obesity, potentially offering a valuable approach for GLP-1RA dose reduction or weight maintenance following GLP-1RA discontinuation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102287"},"PeriodicalIF":6.6,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573932","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}
Pub Date : 2025-11-15DOI: 10.1016/j.molmet.2025.102281
Malik Taradeh , Lise M. Hardy , Veronica D. Dahik , Marie Lhomme , Hua Wang , Canelle Reydellet , Clément Materne , Pukar KC , Eric Bun , Maud Clemessy , Jean-Paul Pais-De-Barros , Sophie Galier , Eric Frisdal , Hervé Durand , Maharajah Ponnaiah , Petra El Khoury , Elise F. Villard , Philippe Lesnik , Antonio Gallo , Laurent Kappeler , Wilfried Le Goff
Aims
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.
Methods and results
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 TgCETP x Ldlr−/− 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). In vitro, 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.
Conclusions
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.
目的：低血浆高密度脂蛋白(HDL)-胆固醇水平与动脉粥样硬化性心血管疾病（ASCVD）风险增加相关，可能反映抗动脉粥样硬化HDL功能受损。后者受高密度脂蛋白磷脂组的强烈影响，在ASCVD患者中经常发生改变。一些研究报道，血浆中磷脂酰乙醇胺（PE）种类的水平，特别是PE（36:5）与ASCVD呈正相关，但其潜在机制尚不清楚。血浆PE（36:5）以二十碳五烯酸(EPA)-PE和花生四烯酸(ARA)-PE存在，后者在ASCVD中占主导地位。这项研究调查了PE（36:5）与ASCVD的关联是否可能是由于HDL抗动脉粥样硬化功能的损害。方法与结果：86例代谢综合征女性总PE和大HDL（36:5）含量与颈动脉内膜-中膜厚度呈正相关。在喂食高胆固醇饮食的TgCETP x Ldlr-/-小鼠中，与只注射含磷脂酰胆碱（PC）的对照rHDL相比，眶后注射含有ARA-PE的重构HDL （rHDL）时，动脉粥样硬化斑块的大小更大。在体外，与对照rHDL相比，PE rHDL显示胆固醇外排能力降低，THP-1巨噬细胞的抗炎活性受损，同时抗LDL氧化活性降低。值得注意的是，ARA-PE rHDL严重削弱了HDL功能，而EPA-PE抵消了ARA-PE诱导的功能障碍，增强了rHDL的功能。结论：本研究揭示了PE（特别是ARA-PE）与HDL功能障碍之间的因果关系，有助于动脉粥样硬化。EPA- pe可以恢复HDL功能，支持EPA降低ASCVD风险的治疗潜力。
{"title":"Regulation of HDL dysfunctionality by phosphatidylethanolamine links poly-unsaturated fatty acids with atherosclerotic cardiovascular diseases","authors":"Malik Taradeh , Lise M. Hardy , Veronica D. Dahik , Marie Lhomme , Hua Wang , Canelle Reydellet , Clément Materne , Pukar KC , Eric Bun , Maud Clemessy , Jean-Paul Pais-De-Barros , Sophie Galier , Eric Frisdal , Hervé Durand , Maharajah Ponnaiah , Petra El Khoury , Elise F. Villard , Philippe Lesnik , Antonio Gallo , Laurent Kappeler , 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><sup>−/−</sup> 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":"2025-11-15","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}
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