Molecular Metabolism最新文献

{"title":"Additive effects of GLY-200 (oral pharmacologic duodenal exclusion therapy) and GLP-1R agonist in obesity management","authors":"Taylor L. Carlson ,&nbsp;Mark Fineman ,&nbsp;Stace Kernodle ,&nbsp;Chelsea R. Hutch ,&nbsp;Christine Bryant ,&nbsp;Kevin Colbert ,&nbsp;Randy J. Seeley ,&nbsp;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}

{"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":"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}

{"title":"NLRP3 inhibition by VTX3232 tempers inflammation resulting in reduced body weight, hyperglycemia, and hepatic steatosis in obese male mice","authors":"Jennyfer Bultinck ,&nbsp;Shendong Yuan ,&nbsp;Ludovico Cantuti-Castelvetri ,&nbsp;Lander Brosens ,&nbsp;Debby Bracke ,&nbsp;James Collins ,&nbsp;Jens Goethals ,&nbsp;Christina Christianson ,&nbsp;John Nuss ,&nbsp;Kathleen Ogilvie","doi":"10.1016/j.molmet.2025.102282","DOIUrl":"10.1016/j.molmet.2025.102282","url":null,"abstract":"<div><div>The NLRP3 inflammasome is a key innate immune sensor that orchestrates inflammatory responses to diverse stress signals, including metabolic danger cues. Dysregulated NLRP3 activation has been implicated in chronic diseases such as type 2 diabetes, atherosclerosis, and neurodegeneration, underscoring the broad pathophysiological role of the NLRP3 pathway. In the context of obesity and its associated conditions, NLRP3 inhibition by VTX3232, an oral, selective, and brain-penetrant NLRP3 inhibitor, potently suppressed the release of proinflammatory cytokines (IL-1β, IL-18, IL-1α, IL-6, and TNF) from macrophages and microglia stimulated with metabolic stressors including palmitic acid and cholesterol crystals. Moreover, NLRP3 inhibition by VTX3232 also blocked NLRP3-driven insulin resistance in primary human hepatocytes and adipocytes while normalizing the acute phase response and FGF-21 secretion in hepatocytes under palmitic acid-induced inflammation. In vivo, NLRP3 inhibition by VTX3232 reduced systemic and tissue-specific inflammation in a mouse model of diet-induced obesity, reflected by decreased circulating inflammatory mediators, reduced hepatic inflammation, fewer crown-like structures in adipose tissue, and diminished hypothalamic gliosis. These anti-inflammatory effects were accompanied by improvements in body weight, food intake, and obesity-associated comorbidities such as hyperglycemia, hepatic steatosis, and markers of cardiovascular and renal disease. Notably, these effects were confined to the context of obesity, as no impact was observed in lean mice. When combined with glucagon-like peptide-1 receptor agonism by semaglutide, NLRP3 inhibition by VTX3232 yielded additive metabolic benefits, highlighting complementary mechanisms of action. Together, these findings reinforce the biological rationale for targeting NLRP3 in inflammatory conditions such as obesity, expand on the role of NLRP3 in metabolic inflammation, and underscore the importance of continued investigation into the NLRP3 pathway as a central node in cardiometabolic disease.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102282"},"PeriodicalIF":6.6,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534087","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":"2025-11-14","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":"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":"2025-11-11","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":"Protective role of soluble CD52 in obesity-associated steatotic liver disease and glucose dysregulation in mice","authors":"Yuichiro Miyazawa ,&nbsp;Tsutomu Wada ,&nbsp;Yuichi Iwasa ,&nbsp;Kento Fuse ,&nbsp;Hisafumi Shioneri ,&nbsp;Yasuhiro Onogi ,&nbsp;Azusa Sameshima ,&nbsp;Tomoyuki Yoshida ,&nbsp;Ichiro Takasaki ,&nbsp;Hisashi Mori ,&nbsp;Keiichi Koizumi ,&nbsp;Hiroshi Tsuneki ,&nbsp;Shigeru Saito ,&nbsp;Toshiyasu Sasaoka","doi":"10.1016/j.molmet.2025.102279","DOIUrl":"10.1016/j.molmet.2025.102279","url":null,"abstract":"<div><h3>Objectives</h3><div>Soluble CD52 (sCD52) derived from activated CD4⁺ T cells regulates T cell immunity under autoimmune conditions; however, its role in obesity-associated chronic inflammation and glucose metabolism remains unclear. Therefore, we herein investigated the significance of CD52 in obesity.</div></div><div><h3>Methods</h3><div>CD52-knockout mice (KO) and their wild-type littermates were fed a high-fat diet (HFD) for 12 weeks and analyzed.</div></div><div><h3>Results</h3><div>sCD52 preferentially suppressed chronic liver inflammation and protected against impaired glucose tolerance and metabolic dysfunction-associated steatotic liver disease (MASLD) in obesity. No significant differences were observed in weight gain or energy metabolism in KO mice; however, glucose metabolism was impaired. A histological examination revealed more severe chronic inflammation and steatosis in KO mice, accompanied by changes in liver transcriptome profiles, but no significant differences in epididymal white adipose tissue (eWAT). In contrast, CD52 expression was significantly up-regulated in eWAT, with slightly higher levels in the liver and skeletal muscle in HFD-fed obese C57BL/6 mice than in chow-fed controls. sCD52 was released from the cultured eWAT of obese mice, but not lean mice, and circulating sCD52 levels were higher in obese mice. A re-analysis of a public single-nucleus RNA sequencing library revealed that increased CD52 in eWAT was linked to immune cells and adipocytes. T cell-derived purified sCD52 suppressed macrophage activation <em>in vitro</em>. In contrast, sCD52 was not secreted from 3T3-L1 adipocytes, although its protein levels increased with differentiation.</div></div><div><h3>Conclusions</h3><div>T cell-derived sCD52 mitigates the obesity-associated development of MASLD and glucose intolerance in mice.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102279"},"PeriodicalIF":6.6,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145458837","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":"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":"2025-11-01","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":"Cold exposure induces the constitutively active thermogenic receptor, GPR3, via ERRα and ERRγ","authors":"Olivia Sveidahl Johansen ,&nbsp;Rebecca L. McIntyre ,&nbsp;Janane F. Rahbani ,&nbsp;Qiaoqiao Zhang ,&nbsp;Charlotte Scholtes ,&nbsp;Damien Marc Lagarde ,&nbsp;Cyrielle Billon ,&nbsp;Isabelle Côté ,&nbsp;Maria Delgado-Martin ,&nbsp;David Tandio ,&nbsp;Astrid Linde Basse ,&nbsp;Elodie Eury ,&nbsp;Anastasia Kralli ,&nbsp;Thomas P. Burris ,&nbsp;Vincent Giguère ,&nbsp;Lawrence Kazak ,&nbsp;Zachary Gerhart-Hines","doi":"10.1016/j.molmet.2025.102277","DOIUrl":"10.1016/j.molmet.2025.102277","url":null,"abstract":"<div><h3>Objectives</h3><div>Despite transformative advances in obesity pharmacotherapy, safely increasing energy expenditure remains a key unmet need. Exploiting thermogenic adipocytes represents a promising target given their capacity for significant catabolic activity. We previously showed that G protein-coupled receptor 3 (GPR3) can drive energy expenditure in brown and white mouse and human adipocytes. GPR3 is a unique GPCR because it displays high intrinsic activity and leads to constitutive cAMP signaling upon reaching the cell surface. Therefore, the transcriptional induction of GPR3 is analogous to ligand-binding activation of most GPCRs. <em>Gpr3</em> expression is physiologically induced in thermogenic adipocytes by cold exposure, and mimicking this event through overexpression in mice is fully sufficient to increase energy expenditure and counteract metabolic disease. Yet the factors mediating physiological <em>Gpr3</em> expression remain unknown.</div></div><div><h3>Methods</h3><div>Here, we apply ATAC-Seq to identify cold-induced promoter elements of <em>Gpr3</em>. We uncover a role for the estrogen-related receptors, ERRα and ERRγ, in the physiological transcriptional control of <em>Gpr3</em> using adipose-specific double knock-out mice with and without adeno-associated virus (AAV)-mediated rescue.</div></div><div><h3>Results</h3><div>We show that ERRα directly binds the cold-induced promoter element of <em>Gpr3</em> and that ERRα, ERRβ, and ERRγ each activate the <em>Gpr3</em> promoter <em>in vitro</em> when co-transfected with PGC-1α. Adipocyte ERRα and ERRγ are required for the <em>in vivo</em> transcriptional induction of <em>Gpr3</em> during cold exposure. Importantly, deficient <em>Gpr3</em> cold-inducibility in adipose-specific ERRα and ERRγ KO mice is fully rescued by delivery of AAVs re-expressing either ERRα or ERRγ directly into brown adipose tissue.</div></div><div><h3>Conclusions</h3><div>ERRα and ERRγ are critical regulators of cold-induced transcription of <em>Gpr3</em> and represent a targetable strategy for pharmacologically unlocking GPR3-induced energy expenditure.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102277"},"PeriodicalIF":6.6,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145422226","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":"Reframing metformin as a gut-targeted glucose-lowering therapy: Mechanistic insights and translational relevance","authors":"Tongzhi Wu ,&nbsp;Michael Horowitz ,&nbsp;Karen L. Jones ,&nbsp;Christopher K. Rayner","doi":"10.1016/j.molmet.2025.102276","DOIUrl":"10.1016/j.molmet.2025.102276","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102276"},"PeriodicalIF":6.6,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145458891","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":"Transient juvenile hypoglycemia in GH insensitive Laron syndrome pigs is associated with insulin hypersensitivity","authors":"Arne Hinrichs ,&nbsp;Kalliopi Pafili ,&nbsp;Gencer Sancar ,&nbsp;Laeticia Laane ,&nbsp;Silja Zettler ,&nbsp;Malek Torgeman ,&nbsp;Barbara Kessler ,&nbsp;Judith Leonie Nono ,&nbsp;Sonja Kunz ,&nbsp;Birgit Rathkolb ,&nbsp;Cristina Barosa ,&nbsp;Cornelia Prehn ,&nbsp;Alexander Cecil ,&nbsp;Simone Renner ,&nbsp;Elisabeth Kemter ,&nbsp;Sabine Kahl ,&nbsp;Julia Szendroedi ,&nbsp;Martin Bidlingmaier ,&nbsp;John Griffith Jones ,&nbsp;Martin Hrabĕ de Angelis ,&nbsp;Eckhard Wolf","doi":"10.1016/j.molmet.2025.102273","DOIUrl":"10.1016/j.molmet.2025.102273","url":null,"abstract":"<div><h3>Background and aims</h3><div>Fasting hypoglycemia has clinical implications for children with growth hormone (GH)-insensitivity syndrome. This study investigates the pathophysiology of juvenile hypoglycemia in a large animal model for GH receptor (GHR) deficiency (the <em>GHR</em>-KO pig) and elucidates mechanisms underlying the transition to normoglycemia in adulthood.</div></div><div><h3>Methods</h3><div>Insulin sensitivity was assessed in juvenile and adult <em>GHR</em>-KO pigs and wild-type (WT) controls via hyperinsulinemic-euglycemic clamp (HEC) tests. Glucose turnover was measured using D-[6,6-²H₂] glucose and ²H₂O. Clinical chemical and targeted metabolomics parameters in blood serum were correlated with qPCR and western blot analyses of liver and adipose tissue.</div></div><div><h3>Results</h3><div><em>GHR</em>-KO pigs showed increased insulin sensitivity (p = 0.0019), especially at young age (M-value +34% vs. WT), insignificantly reduced insulin levels, and reduced endogenous glucose production (p = 0.0007), leading to fasting hypoglycemia with depleted liver glycogen, elevated β-hydroxybutyrate, but no increase in NEFA levels. Low hormone-sensitive lipase phosphorylation in adipose tissue suggested impaired lipolysis in young <em>GHR</em>-KO pigs. Metabolomics indicated enhanced fatty acid beta-oxidation and use of glucogenic amino acids, likely serving as compensatory pathways to maintain energy homeostasis. In adulthood, insulin sensitivity remained elevated but less pronounced (M-value +20%), while insulin levels were significantly reduced, enabling normoglycemia and improved NEFA availability. Increased fat mass, but not sex hormones, appeared key to this metabolic transition, as early castration had no effect.</div></div><div><h3>Conclusions</h3><div>Juvenile hypoglycemia in GH insensitivity results from excessive insulin sensitivity, reduced glucose production, and impaired lipolysis. Normoglycemia in adulthood emerges through increased adiposity and moderated insulin sensitivity, independently of sex hormones. These findings elucidate the age-dependent metabolic adaptations in GH insensitivity.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102273"},"PeriodicalIF":6.6,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145346213","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}