Molecular Metabolism最新文献

{"title":"TMEM135 deficiency improves hepatic steatosis by suppressing CD36 in a SIRT1-dependent manner","authors":"Arun Chhetri ,&nbsp;Channy Park ,&nbsp;Hyunsoo Kim ,&nbsp;Laxman Manandhar ,&nbsp;Chagtsalmaa Chuluunbaatar ,&nbsp;Jaetaek Hwang ,&nbsp;Xiaofan Wei ,&nbsp;Gyuho Jang ,&nbsp;Batching Chinbold ,&nbsp;Hyug Moo Kwon ,&nbsp;Sang-wook Lee ,&nbsp;Raekil Park","doi":"10.1016/j.molmet.2024.102080","DOIUrl":"10.1016/j.molmet.2024.102080","url":null,"abstract":"<div><h3>Objectives</h3><div>Dysregulation of lipid homeostasis pathway causes many liver diseases, including hepatic steatosis. One of the primary factors contributing to lipid accumulation is fatty acid uptake by the liver. Transmembrane protein 135 (TMEM135), which exists in mitochondria and peroxisomes, participates in intracellular lipid metabolism. This study aims to investigate the role of TMEM135 on regulating cellular lipid import in the liver.</div></div><div><h3>Methods</h3><div>We used <em>in vivo, ex vivo</em>, and <em>in vitro</em> models of steatosis. TMEM135 knockout (TMEM135KO) and wild type (WT) mice were fed a high-fat diet (HFD) to induce hepatic steatosis. Primary mouse hepatocytes and AML12 cells were treated with free fatty acid (FFA). Additionally, TMEM135-deficient stable cells and overexpressed cells were established using AML12 cells.</div></div><div><h3>Results</h3><div>TMEM135 deficiency mitigated lipid accumulation in the liver of HFD-fed TMEM135KO mice. TMEM135-depleted primary hepatocytes and AML12 cells exhibited less lipid accumulation when treated with FFA compared to control cells, as shown as lipid droplets. Consistently, the effect of TMEM135 depletion on lipid accumulation was completely reversed under TMEM135 overexpression conditions. CD36 expression was markedly induced by HFD or FFA, which was reduced by TMEM135 depletion. Among the SIRT family proteins, only SIRT1 expression definitely increased in the liver of HFD-fed TMEM135KO mice along with a significant increase in NAD⁺/NADH ratio. However, inhibition of SIRT1 in TMEM135-depleted cells using siSIRT1 or the SIRT1 inhibitor EX-527 resulted in an increase of CD36 expression and consequent TG levels.</div></div><div><h3>Conclusions</h3><div>TMEM135 depletion attenuates CD36 expression in a SIRT1-dependent manner, thereby reducing cellular lipid uptake and hepatic steatosis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102080"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11728970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia inducible factor-dependent upregulation of Agrp in glomus type I cells of the carotid body","authors":"Luis Leon-Mercado ,&nbsp;Ivan Menendez-Montes ,&nbsp;Jonathan Tao ,&nbsp;Bandy Chen ,&nbsp;David P. Olson ,&nbsp;C. Mackaaij ,&nbsp;C.G.J. Cleypool ,&nbsp;Laurent Gautron","doi":"10.1016/j.molmet.2025.102095","DOIUrl":"10.1016/j.molmet.2025.102095","url":null,"abstract":"<div><div>Agouti-related peptide (AgRP) is a well-established potent orexigenic peptide primarily expressed in hypothalamic neurons. Nevertheless, the expression and functional significance of extrahypothalamic AgRP remain poorly understood. In this study, utilizing histological and molecular biology techniques, we have identified a significant expression of <em>Agrp</em> mRNA and AgRP peptide production in glomus type I cells within the mouse carotid body (CB). Furthermore, we have uncovered evidence supporting the expression of the AgRP receptor melanocortin receptor 3 (Mc3r) in adjacent sympathetic neurons, suggesting a potential local paracrine role for AgRP within the CB. Importantly, AgRP immunoreactivity was also identified in glomus type I cells of the human CB. Given the unexpected abundance of AgRP in glomus type I cells, a chemoreceptor cell specialized in oxygen sensing, we proceeded to investigate whether <em>Agrp</em> expression in the CB is regulated by hypoxemia and associated oxygen-sensing molecular mechanisms. <em>In vitro</em> luciferase assays reveal that hypoxia stimulates the human and mouse Agrp promoters in a Hypoxia Inducible Factor (HIF1/2)-dependent manner. Our <em>in vivo</em> experiments further demonstrate that exposure to environmental hypoxia (10%) robustly induces <em>Agrp</em> expression in type I glomus cells of mice. Furthermore, these findings collectively highlight the hitherto unknown source of AgRP in murine and human type I glomus cells and underscore the direct control of <em>Agrp</em> transcription by HIF signaling.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102095"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Muscarinic acetylcholine type 1 receptor antagonism activates TRPM3 to augment mitochondrial function and drive axonal repair in adult sensory neurons","authors":"Sanjana Chauhan ,&nbsp;Darrell R. Smith ,&nbsp;Shiva Shariati-Ievari ,&nbsp;Abhay Srivastava ,&nbsp;Sanjiv Dhingra ,&nbsp;Michel Aliani ,&nbsp;Paul Fernyhough","doi":"10.1016/j.molmet.2024.102083","DOIUrl":"10.1016/j.molmet.2024.102083","url":null,"abstract":"<div><h3>Objective</h3><div>Antagonism of the muscarinic acetylcholine type 1 receptor (M₁R) promotes sensory axon repair and is protective in peripheral neuropathy, however, the mechanism remains elusive. We investigated the role of the heat-sensing transient receptor potential melastatin-3 (TRPM3) cation channel in M₁R antagonism-mediated nerve regeneration and explored the potential of TRPM3 activation to facilitate axonal plasticity.</div></div><div><h3>Methods</h3><div>Dorsal root ganglion (DRG) neurons from adult control or diabetic rats were cultured and treated with TRPM3 agonists (CIM0216, pregnenolone sulfate) and M₁R antagonists pirenzepine (PZ) or muscarinic toxin 7 (MT7). Ca²⁺ transients, mitochondrial respiration, AMP-activated protein kinase (AMPK) expression, and mitochondrial inner membrane potential were analyzed. The effect of M₁R activation or blockade on TRPM3 activity mediated by phosphatidylinositol 4,5-bisphosphate (PIP₂) was studied. Metabolic profiling of DRG neurons and human neuroblastoma SH-SY5Y cells was conducted.</div></div><div><h3>Results</h3><div>M₁R antagonism induced by PZ or MT7 increased Ca²⁺ influx in DRG neurons and was inhibited by TRPM3 antagonists or in the absence of extracellular Ca²⁺. TRPM3 agonists elevated Ca²⁺ levels, augmented mitochondrial respiration, AMPK activation and neurite outgrowth. M₁R antagonism stimulated TRPM3 channel activity through inhibition of PIP₂ hydrolysis to activate Ca²⁺/calmodulin-dependent protein kinase kinase β (CaMKKβ)/AMPK, leading to augmented mitochondrial function and neuronal metabolism. DRG neurons with AAV-mediated shRNA knockdown of TRPM3 exhibited suppressed antimuscarinic drug-induced neurite outgrowth. TRPM3 agonists increased glycolysis and TCA cycle metabolites, indicating enhanced metabolism in DRG neurons and SH-SY5Y cells.</div></div><div><h3>Conclusions</h3><div>Activation of the TRPM3/CaMKKβ/AMPK pathway promoted collateral sprouting of sensory axons, positioning TRPM3 as a promising therapeutic target for peripheral neuropathy.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102083"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthetic inhibition of SREBP2 and the mevalonate pathway blocks rhabdomyosarcoma tumor growth in vitro and in vivo and promotes chemosensitization","authors":"Silvia Codenotti ,&nbsp;Michela Asperti ,&nbsp;Maura Poli ,&nbsp;Luisa Lorenzi ,&nbsp;Alberto Pietrantoni ,&nbsp;Matteo Cassandri ,&nbsp;Francesco Marampon ,&nbsp;Alessandro Fanzani","doi":"10.1016/j.molmet.2024.102085","DOIUrl":"10.1016/j.molmet.2024.102085","url":null,"abstract":"<div><h3>Objective</h3><div>The aim of the present study was to investigate the effects of targeting the mevalonate pathway (MVP) in rhabdomyosarcoma (RMS), a soft tissue tumor with a prevalence in young people.</div></div><div><h3>Methods</h3><div><em>In silico</em> analyses of RNA datasets were performed to correlate MVP with RMS patient survival. The sensitivity of RMS cell lines to MVP inhibitors was assessed <em>in vitro</em> by analysis of cell growth (crystal violet and clonogenic assays), cell migration (wound healing assay), cell survival (neutral red assay), and oxidative stress (ROS assay). The effects of MVP inhibitors were tested <em>in vivo</em> by analyzing RMS xenografts grown in NOD/SCID mice. Quantification of protein targets was performed using immunoblotting or immunohistochemistry analyses.</div></div><div><h3>Results</h3><div><em>In silico</em> analysis showed upregulation of sterol regulatory element-binding protein 2 (SREBP2) and MVP genes, including 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), farnesyl-diphosphate synthase (FDPS), squalene epoxidase (SQLE), which correlated with worse overall patient survival. Targeting of MVP in human RD and RH30 lines by inhibitors of SREBP2 (fatostatin), HMGCR (lovastatin and simvastatin), and FDPS (zoledronic acid) resulted in impaired cell growth, migration, and viability, and increased oxidative cell death in combination with actinomycin D. Conversely, cholesterol (CHO) supplementation enhanced cell growth and migration. Fatostatin and lovastatin produced rapid attenuation of Erk1/2 and Akt1 signaling in RMS lines, and oral administration of lovastatin reduced tumor mass growth of xenografted RD cells in NOD/SCID mice. Finally, we found that forced Akt1 activation in RD cells was sufficient to drive SREBP2, HMGCR and SQLE protein expression, promoting increased susceptibility to MVP inhibitors.</div></div><div><h3>Conclusions</h3><div>These data suggest that the Akt1, SREBP2 and MVP axis is critical for RMS tumor growth, migration, and oxidative stress protection primarily through maintaining adequate CHO levels that enable proper intracellular signaling. Therefore, stimulating CHO depletion via SREBP2 and MVP inhibition may represent a viable option to improve the combination therapy protocol, especially in pAkt1-positive RMS.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102085"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11750561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced dynorphin expression and secretion in pancreatic beta-cells under hyperglycemic conditions","authors":"Miranda Movahed,&nbsp;Ruy A. Louzada,&nbsp;Manuel Blandino-Rosano","doi":"10.1016/j.molmet.2024.102088","DOIUrl":"10.1016/j.molmet.2024.102088","url":null,"abstract":"<div><h3>Objective</h3><div>Dynorphin, an endogenous opioid peptide predominantly expressed in the central nervous system and involved in stress response, pain, and addiction, has intrigued researchers due to its expression in pancreatic β-cells. In this study, we aimed to characterize dynorphin expression in mouse and human islets and explore the mechanisms regulating its expression.</div></div><div><h3>Methods</h3><div>We used primary mouse and human islets with unbiased published datasets to examine how glucose and other nutrients regulate dynorphin expression and secretion in islets.</div></div><div><h3>Results</h3><div>The prodynorphin gene is significantly upregulated in β-cells under hyperglycemic conditions. <em>In vitro</em> studies revealed that increased glucose concentrations correlate with increased dynorphin expression, indicating a critical interplay involving Ca²⁺, CamKII, and CREB pathways in β-cells. Perifusion studies allowed us to measure the dynamic secretion of dynorphin in response to glucose from mouse and human islets for the first time. Furthermore, we confirmed that increased dynorphin content within the β-cells directly correlates with enhanced dynorphin secretion. Finally, our findings demonstrate a synergistic effect of palmitate in conjunction with high glucose, further amplifying dynorphin levels and secretion in pancreatic islets.</div></div><div><h3>Conclusions</h3><div>This study demonstrates that the opioid peptide prodynorphin is expressed in mouse and human β-cells. Prodynorphin levels are regulated in parallel with insulin in response to glucose, palmitate, and amino acids. Our findings elucidate the signaling pathways involved, with CamKII playing a key role in regulating prodynorphin levels in β-cells. Finally, our findings are the first to demonstrate active dynorphin secretion from mouse and human islets in response to glucose.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102088"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SF1-specific deletion of the energy sensor AMPKγ2 induces obesity","authors":"Óscar Freire-Agulleiro ,&nbsp;Ánxela Estévez-Salguero ,&nbsp;Vitor Ferreira ,&nbsp;Cassie Lynn Holleman ,&nbsp;Julia García-Currás ,&nbsp;Ismael González-García ,&nbsp;Rubén Nogueiras ,&nbsp;Manuel Tena-Sempere ,&nbsp;Cristina García-Cáceres ,&nbsp;Carlos Diéguez ,&nbsp;Miguel López","doi":"10.1016/j.molmet.2024.102091","DOIUrl":"10.1016/j.molmet.2024.102091","url":null,"abstract":"<div><h3>Objective</h3><div>AMP-activated protein kinase (AMPK) is a heterotrimer complex consisting of a catalytic α subunit (α1, α2) with a serine/threonine kinase domain, and two regulatory subunits, β (β1, β2) and γ (γ1, γ2, γ3), encoded by different genes. In the hypothalamus, AMPK plays a crucial role in regulating energy balance, including feeding, energy expenditure, peripheral glucose and lipid metabolism. However, most research on hypothalamic AMPK has concentrated on the catalytic subunits AMPKα1 and AMPKα2, with little focus on the regulatory subunits.</div></div><div><h3>Methods</h3><div>To fill this gap of knowledge, we investigated the effects of selectively deleting the regulatory isoform AMPKγ2, which is a primary “energy sensor”, in steroidogenic factor 1 (SF1) neurons of the ventromedial hypothalamic nucleus (VMH). Complete metabolic phenotyping and molecular analyses in brown adipose tissue (BAT), white adipose tissue (WAT) and liver were carried out.</div></div><div><h3>Results</h3><div>Our findings reveal that, in contrast to the obesity-protective effect of the genetic deletion of AMPKα subunits, the loss of AMPKγ2 in SF1 neurons leads to a sex-independent and feeding-independent obesity-prone phenotype due to decreased thermogenesis in brown adipose tissue (BAT) and reduced browning of WAT, resulting in lower energy expenditure. Additionally, SF1-Cre AMPKγ2 mice exhibit hepatic lipid accumulation, but surprisingly maintain normal glucose homeostasis.</div></div><div><h3>Conclusions</h3><div>Overall, these results highlight the distinct roles of AMPK subunits within the hypothalamus.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102091"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782900/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LGR4 is essential for maintaining β-cell homeostasis through suppression of RANK","authors":"Joanna Filipowska ,&nbsp;Zelda Cisneros ,&nbsp;Sneha S. Varghese ,&nbsp;Nancy Leon-Rivera ,&nbsp;Peng Wang ,&nbsp;Randy Kang ,&nbsp;Geming Lu ,&nbsp;Yate-Ching Yuan ,&nbsp;Hung-Ping Shih ,&nbsp;Supriyo Bhattacharya ,&nbsp;Sangeeta Dhawan ,&nbsp;Adolfo Garcia-Ocaña ,&nbsp;Nagesha Guthalu Kondegowda ,&nbsp;Rupangi C. Vasavada","doi":"10.1016/j.molmet.2025.102097","DOIUrl":"10.1016/j.molmet.2025.102097","url":null,"abstract":"<div><h3>Objective</h3><div>Loss of functional β-cell mass is a major cause of diabetes. Thus, identifying regulators of β-cell health is crucial for treating this disease. The Leucine-rich repeat-containing G-protein-coupled receptor (GPCR) 4 (LGR4) is expressed in β-cells and is the fourth most abundant GPCR in human islets. Although LGR4 has regenerative, anti-inflammatory, and anti-apoptotic effects in other tissues, its functional significance in β-cells remains unknown. We have previously identified Receptor Activator of Nuclear Factor Kappa B (NFκB) (RANK) as a negative regulator of β-cell health. In this study, we assessed the regulation of <em>Lgr4</em> in islets, and the role of LGR4 and LGR4/RANK stoichiometry in β-cell health under basal and stress-induced conditions, <em>in vitro</em> and <em>in vivo</em>.</div></div><div><h3>Methods</h3><div>We evaluated <em>Lgr4</em> expression in mouse and human islets in response to acute (proinflammatory cytokines), or chronic (high fat fed mice, db/db mice, and aging) stress. To determine the role of LGR4 we employed <em>in vitro Lgr4</em> loss and gain of function in primary rodent and human β-cells and examined its mechanism of action in the rodent INS1 cell line. Using <em>Lgr4</em>^fl/fl and <em>Lgr4</em>^fl/fl/<em>Rank</em>^fl/fl × <em>Ins1</em>-Cre mice we generated _{β-cell-specific} conditional knockout (cko) mice to test the role of LGR4 and its interaction with RANK <em>in vivo</em> under basal and stress-induced conditions.</div></div><div><h3>Results</h3><div><em>Lgr4</em> expression in rodent and human islets was reduced by multiple stressors. <em>In vitro</em>, <em>Lgr4</em> knockdown decreased proliferation and survival in rodent β-cells, while overexpression protected against cytokine-induced cell death in rodent and human β-cells. Mechanistically, LGR4 protects β-cells by suppressing RANK- Tumor necrosis factor receptor associated factor 6 (TRAF6) interaction and subsequent activation of NFκB. <em>Lgr4</em>cko mice exhibit normal glucose homeostasis but increased β-cell death in both sexes and decreased β-cell proliferation and maturation only in females. Male <em>Lgr4</em>cko mice under stress displayed reduced β-cell proliferation and a further increase in β-cell death. The impaired β-cell phenotype in <em>Lgr4</em>cko mice was rescued in <em>Lgr4</em>/<em>Rank</em> double ko (dko) mice. Upon aging, both male and female <em>Lgr4</em>cko mice displayed impaired β-cell homeostasis, however, only female mice became glucose intolerant with decreased plasma insulin.</div></div><div><h3>Conclusions</h3><div>These data demonstrate a novel role for LGR4 as a positive regulator of β-cell health under basal and stress-induced conditions, through suppressing the negative effects of RANK.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102097"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased cardiac myosin super-relaxation as an energy saving mechanism in hibernating grizzly bears","authors":"Robbert J. Van der Pijl ,&nbsp;Weikang Ma ,&nbsp;Christopher T.A. Lewis ,&nbsp;Line Haar ,&nbsp;Amalie Buhl ,&nbsp;Gerrie P. Farman ,&nbsp;Marcus Rhodehamel ,&nbsp;Vivek P. Jani ,&nbsp;O Lynne Nelson ,&nbsp;Chengxin Zhang ,&nbsp;Henk Granzier ,&nbsp;Julien Ochala","doi":"10.1016/j.molmet.2024.102084","DOIUrl":"10.1016/j.molmet.2024.102084","url":null,"abstract":"<div><h3>Aim</h3><div>The aim of the present study was to define whether cardiac myosin contributes to energy conservation in the heart of hibernating mammals.</div></div><div><h3>Methods</h3><div>Thin cardiac strips were isolated from the left ventricles of active and hibernating grizzly bears; and subjected to loaded Mant-ATP chase assays, X-ray diffraction and proteomics.</div></div><div><h3>Main findings</h3><div>Hibernating grizzly bears displayed an unusually high proportion of ATP-conserving super-relaxed cardiac myosin molecules that are likely due to altered levels of phosphorylation and rod region stability.</div></div><div><h3>Conclusions</h3><div>Cardiac myosin depresses the heart's energetic demand during hibernation by modulating its function.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102084"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic GIPR agonism results in pancreatic islet GIPR functional desensitisation","authors":"Iona Davies ,&nbsp;Alice E. Adriaenssens ,&nbsp;William R. Scott ,&nbsp;David Carling ,&nbsp;Kevin G. Murphy ,&nbsp;James S. Minnion ,&nbsp;Stephen R. Bloom ,&nbsp;Ben Jones ,&nbsp;Tricia M-M. Tan","doi":"10.1016/j.molmet.2025.102094","DOIUrl":"10.1016/j.molmet.2025.102094","url":null,"abstract":"<div><h3>Objectives</h3><div>There is renewed interest in targeting the glucose-dependent insulinotropic polypeptide receptor (GIPR) for treatment of obesity and type 2 diabetes. G-protein coupled receptor desensitisation is suggested to reduce the long-term efficacy of glucagon-like-peptide 1 receptor (GLP-1R) agonists and may similarly affect the efficacy of GIPR agonists. We explored the extent of pancreatic GIPR functional desensitisation with sustained agonist exposure.</div></div><div><h3>Methods</h3><div>A long-acting GIPR agonist, GIP108, was used to probe the effect of sustained agonist exposure on cAMP responses in dispersed pancreatic islets using live cell imaging, with rechallenge cAMP responses after prior agonist treatment used to quantify functional desensitisation. Receptor internalisation and β-arrestin-2 activation were investigated <em>in vitro</em> using imaging-based assays. Pancreatic mouse GIPR desensitisation was assessed <em>in vivo</em> via intraperitoneal glucose tolerance testing.</div></div><div><h3>Results</h3><div>GIP108 treatment led to weight loss and improved glucose homeostasis in mice. Prolonged exposure to GIPR agonists produced homologous functional GIPR desensitisation in isolated islets. GIP108 pre-treatment <em>in vivo</em> also reduced the subsequent anti-hyperglycaemic response to GIP re-challenge. GIPR showed minimal agonist-induced internalisation or β-arrestin-2 activation.</div></div><div><h3>Conclusions</h3><div>Although GIP108 chronic treatment improved glucose tolerance, it also resulted in partial desensitisation of the pancreatic islet GIPR. This suggests that ligands with reduced desensitisation tendency might lead to improved <em>in vivo</em> efficacy. Understanding whether pancreatic GIPR desensitisation affects the long-term benefits of GIPR agonists in humans is vital to design effective metabolic pharmacotherapies.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102094"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Roles for Prlhr/GPR10 and Npffr2/GPR74 in feeding responses to PrRP","authors":"Yi Wang ,&nbsp;Weiwei Qiu ,&nbsp;Stace Kernodle ,&nbsp;Carly Parker ,&nbsp;Marc-Antonio Padilla ,&nbsp;Jiaao Su ,&nbsp;Abigail J. Tomlinson ,&nbsp;Stephanie Oldham ,&nbsp;Joss Field ,&nbsp;Elise Bernard ,&nbsp;David Hornigold ,&nbsp;Christopher J. Rhodes ,&nbsp;David P. Olson ,&nbsp;Randy J. Seeley ,&nbsp;Martin G. Myers Jr","doi":"10.1016/j.molmet.2024.102093","DOIUrl":"10.1016/j.molmet.2024.102093","url":null,"abstract":"<div><h3>Objective</h3><div>Several groups of neurons in the NTS suppress food intake, including <em>Prlh</em>-expressing neurons (NTS^Prlh cells). Not only does the artificial activation of NTS^Prlh cells decrease feeding, but also the expression of <em>Prlh</em> (which encodes the neuropeptide PrRP) and neurotransmission by NTS^Prlh neurons contributes to the restraint of food intake and body weight, especially in animals fed a high fat diet (HFD). We set out to determine roles for putative PrRP receptors in the response to NTS PrRP and exogenous PrRP-related peptides.</div></div><div><h3>Methods</h3><div>We used animals lacking PrRP receptors GPR10 and/or GPR74 (encoded by <em>Prlhr</em> and <em>Npffr2</em>, respectively) to determine roles for each in the restraint of food intake and body weight by the increased expression of <em>Prlh</em> in NTS^Prlh neurons (NTS^PrlhOX mice) and in response to the anorectic PrRP analog, p52.</div></div><div><h3>Results</h3><div>Although <em>Prlhr</em> played a crucial role in the restraint of food intake and body weight in HFD-fed control animals, the combined absence of <em>Prlhr</em> and <em>Npffr2</em> was required to abrogate the restraint of food intake in NTS^PrlhOX mice. p52 suppressed feeding independently of both receptors, however.</div></div><div><h3>Conclusions</h3><div>Hence, each receptor can participate in the NTS^Prlh-mediated suppression of food intake and body weight gain, while PrRP analog treatment can mediate its effects via distinct systems. While <em>Prlhr</em> plays a crucial role in the physiologic restraint of weight gain, the action of either receptor is capable of ameliorating obesity in response to enhanced NTS^Prlh signaling.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102093"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}