Molecular Metabolism最新文献

{"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}

{"title":"Pre-operative DNA methylation marks as predictors of weight loss outcomes after sleeve gastrectomy","authors":"Guillermo Paz-López ,&nbsp;Teresa M. Linares-Pineda ,&nbsp;Andrés González-Jiménez ,&nbsp;Raquel Sancho-Marín ,&nbsp;Luis Ocaña-Wilhelmi ,&nbsp;Francisco J. Tinahones ,&nbsp;Sonsoles Morcillo ,&nbsp;Carolina Gutiérrez-Repiso","doi":"10.1016/j.molmet.2024.102087","DOIUrl":"10.1016/j.molmet.2024.102087","url":null,"abstract":"<div><h3>Objective</h3><div>Although DNA methylation has been suggested to be a potential predictor of the progression of obesity and obesity-related diseases, little is known about its potential role as predictive marker of successful weight loss after bariatric surgery.</div></div><div><h3>Methods</h3><div>20 patients who underwent sleeve gastrectomy were classified according to the percentage of excess weight loss (%EWL) 1 year after bariatric surgery, using 60% as the cut-off point. Blood DNA methylation was analyzed prior to surgery using the Infinium Methylation EPIC Bead Chip array-based platform.</div></div><div><h3>Results</h3><div>A total number of 76,559 differentially methylated positions (DMPs) (p &lt; 0.05) were found between &lt;60% EWL and &gt;60% EWL groups. Of them, 59,308 DMPs were annotated to genes. KEGG enrichment analysis showed that pathways involved in the signalling of MAPK, Wnt, mTor, FoxO and AMPK, among others, were involved in weight loss trajectory.</div><div>A stepwise logistic regression using the DMPs with an absolute Δβ &gt;0.2 showed that higher methylation levels in the CpG sites cg02405213 (mapping to <em>JAK2</em>) (OR: 1.20098, [0.9586, 1.5044]) and cg01702330 (OR: 2.4426, [0.5761, 10.3567]), were shown to be associated with a higher probability of achieving &gt;60 %EWL after sleeve gastrectomy, whereas higher methylation levels in the CpG site cg04863892 (mapping to <em>HOXA5</em>) were associated with lower probability of achieving &gt;60 %EWL after sleeve gastrectomy (OR: 0.7966, [0.5637, 1.1259]).</div></div><div><h3>Conclusions</h3><div>Our results show a different pre-surgery methylation pattern according to %EWL. We identified three CpG sites (cg04863892, cg02405213, cg01702330) with potential value as predictor markers of weight loss response to bariatric surgery.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102087"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11780120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895388","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":"Metabolic plasticity in pancreatic cancer: The mitochondrial connection","authors":"Noemi Ghiglione ,&nbsp;Damiano Abbo ,&nbsp;Anastasia Bushunova ,&nbsp;Andrea Costamagna,&nbsp;Paolo Ettore Porporato,&nbsp;Miriam Martini","doi":"10.1016/j.molmet.2024.102089","DOIUrl":"10.1016/j.molmet.2024.102089","url":null,"abstract":"<div><h3>Background</h3><div>Cellular metabolism plays a pivotal role in the development and progression of pancreatic ductal adenocarcinoma (PDAC), with dysregulated metabolic pathways contributing to tumorigenesis and therapeutic resistance. Distinct metabolic heterogeneity in pancreatic cancer significantly impacts patient prognosis, as variations in metabolic profiles influence tumor behavior and treatment responses.</div><div>Scope of the Review: This review explores the intricate interplay between mitochondrial dynamics, mitophagy, and cellular metabolism in PDAC. We discuss the significance of mitophagy dysregulation in PDAC pathogenesis, emphasizing its influence on treatment responses and prognosis. Furthermore, we analyze the impact of mitochondrial dynamics alterations, including fission and fusion processes, on PDAC progression and tumorigenesis.</div></div><div><h3>Major Conclusion</h3><div>Targeting mitochondrial metabolism holds promise for advancing PDAC therapeutics. Ongoing clinical trials underscore the therapeutic potential of modulating key regulators of mitochondrial dynamics and mitophagy. Despite inherent challenges, these approaches offer diverse strategies to enhance treatment efficacy and improve patient outcomes.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102089"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907273","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":"Bioenergetic adaptations of small intestinal epithelial cells reduce cell differentiation enhancing intestinal permeability in obese mice","authors":"Thomas Guerbette ,&nbsp;Vincent Ciesielski ,&nbsp;Manon Brien ,&nbsp;Daniel Catheline ,&nbsp;Roselyne Viel ,&nbsp;Mégane Bostoën ,&nbsp;Jean-Baptiste Perrin ,&nbsp;Agnès Burel ,&nbsp;Régis Janvier ,&nbsp;Vincent Rioux ,&nbsp;Annaïg Lan ,&nbsp;Gaëlle Boudry","doi":"10.1016/j.molmet.2025.102098","DOIUrl":"10.1016/j.molmet.2025.102098","url":null,"abstract":"<div><h3><strong>Objective</strong></h3><div>Obesity and overweight are associated with low-grade inflammation induced by adipose tissue expansion and perpetuated by altered intestinal homeostasis, including increased epithelial permeability. Intestinal epithelium functions are supported by intestinal epithelial cells (IEC) mitochondria function. However, diet-induced obesity (DIO) may impair mitochondrial activity of IEC and consequently, intestinal homeostasis. The aim of the project was to determine whether DIO alters the mitochondrial function of IEC, and what are the consequences on intestinal homeostasis.</div></div><div><h3>Methods</h3><div>C57Bl/6J mice were fed a control diet for 22 weeks or a high fat diet (58 kcal% fat). Bioenergetic adaptations of IEC were evaluated on isolated crypts and villi from mouse jejunum. To determine the link between mitochondrial function and alterations of intestinal homeostasis in response to lipid overload, we used the jejunal epithelial cell line IPEC-J2 <em>in vitro</em> and mouse jejunum organoids.</div></div><div><h3>Results</h3><div>Here, we report that DIO in mice induced lipid metabolism adaptations favoring lipid storage in IEC together with reduced number, altered dynamics and diminished oxidative phosphorylation activity of IEC mitochondria. Using the IPEC-J2 cell line, we showed that IEC lipid metabolism and oxidative stress machinery adaptations preceded mitochondrial bioenergetic ones. Moreover, we unraveled the intricate link between IEC energetic status and proliferation / differentiation balance since enhancing mitochondrial function with the AMPK activator AICAR in jejunal organoids reduced proliferation and initiated IEC differentiation and conversely. We confirmed that the reduced IEC mitochondrial function observed in DIO mice was associated with increased proliferation and reduced differentiation, promoting expression of the permissive <em>Cldn2</em> in the jejunal epithelium of DIO mice.</div></div><div><h3>Conclusions</h3><div>Our study provides new insights into metabolic adaptations of IEC in obesity by revealing that excess lipid intake diminishes mitochondrial number in IEC, reducing IEC differentiation that contribute to increased epithelial permeability.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102098"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008090","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":"Intrahepatic levels of microbiome-derived hippurate associates with improved metabolic dysfunction-associated steatotic liver disease","authors":"Maxime Deslande ,&nbsp;Francesc Puig-Castellvi ,&nbsp;Inés Castro-Dionicio ,&nbsp;Romina Pacheco-Tapia ,&nbsp;Violeta Raverdy ,&nbsp;Robert Caiazzo ,&nbsp;Guillaume Lassailly ,&nbsp;Audrey Leloire ,&nbsp;Petros Andrikopoulos ,&nbsp;Yasmina Kahoul ,&nbsp;Nawel Zaïbi ,&nbsp;Bénédicte Toussaint ,&nbsp;Frédérik Oger ,&nbsp;Nicolas Gambardella ,&nbsp;Philippe Lefebvre ,&nbsp;Mehdi Derhourhi ,&nbsp;Souhila Amanzougarene ,&nbsp;Bart Staels ,&nbsp;François Pattou ,&nbsp;Philippe Froguel ,&nbsp;Marc-Emmanuel Dumas","doi":"10.1016/j.molmet.2024.102090","DOIUrl":"10.1016/j.molmet.2024.102090","url":null,"abstract":"<div><h3>Objective</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterised by lipid accumulation in the liver and is often associated with obesity and type 2 diabetes. The gut microbiome recently emerged as a significant player in liver metabolism and health. Hippurate, a host-microbial co-metabolite has been associated with human gut microbial gene richness and with metabolic health. However, its role on liver metabolism and homeostasis is poorly understood.</div></div><div><h3>Methods</h3><div>We characterised liver biospies from 318 patients with obesity using RNAseq and metabolomics in liver and plasma to derive associations among hepatic hippurate, hepatic gene expression and MASLD and phenotypes. To test a potential beneficial role for hippurate in hepatic insulin resistance, we profile the metabolome of (IHH) using ultra-high-performance liquid chromatography coupled to high-resolution tandem mass spectrometry (UHPLC-MS/MS), and characterised intracellular triglyceride accumulation and glucose internalisation after a 24 h insulin exposure.</div></div><div><h3>Results</h3><div>We first report significant associations among MASLD traits, plasma and hepatic hippurate. Further analysis of the hepatic transcriptome shows that liver and plasma hippurate are inversely associated with MASLD, implicating lipid metabolism and regulation of inflammatory responses pathways. Hippurate treatment inhibits lipid accumulation and rescues insulin resistance induced by 24-hour chronic insulin in IHH. Hippurate also improves hepatocyte metabolic profiles by increasing the abundance of metabolites involved in energy homeostasis that are depleted by chronic insulin treatment while decreasing those involved in inflammation.</div></div><div><h3>Conclusions</h3><div>Altogether, our results further highlight hippurate as a mechanistic marker of metabolic health, by its ability to improve metabolic homeostasis as a postbiotic candidate.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102090"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921096","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":"Deficiency of the mitochondrial transporter SLC25A47 minimally impacts hepatic lipid metabolism in fasted and diet-induced obese mice","authors":"Brecht Attema ,&nbsp;Montserrat A. de la Rosa Rodriguez ,&nbsp;Evert M. van Schothorst ,&nbsp;Sander Grefte ,&nbsp;Guido JEJ. Hooiveld ,&nbsp;Sander Kersten","doi":"10.1016/j.molmet.2024.102092","DOIUrl":"10.1016/j.molmet.2024.102092","url":null,"abstract":"<div><h3>Objective</h3><div>The peroxisome proliferator-activated receptor-alpha (PPARα) plays a central role in lipid metabolism in the liver by stimulating the expression of hundreds of genes. Accordingly, regulation by PPARα could be a screening tool to identify novel genes involved in hepatic lipid metabolism. Previously, the mitochondrial transporter SLC25A47 was suggested to play a role in energy metabolism and liver-specific uncoupling, but further research is lacking.</div></div><div><h3>Methods</h3><div>We explored the potential role of SLC25A47 through in vitro studies and using mice overexpressing and lacking SLC25A47.</div></div><div><h3>Results</h3><div><em>SLC25A47</em> was identified as a PPARα-regulated and fasting-induced gene in human and mouse hepatocytes. Adenoviral-mediated overexpression of SLC25A47 minimally impacted metabolic parameters during fasting and high-fat feeding. During high-fat feeding, SLC25A47 ablation also did not influence any metabolic parameters, apart from a minor improvement in glucose tolerance. In fasted mice, SLC25A47 ablation was associated with modest, reproducible, and likely indirect reductions in plasma triglycerides and glycerol. SLC25A47 ablation did not influence energy expenditure. Depending on the nutritional status, metabolomic analysis showed modest alterations in plasma, liver, and hepatic mitochondrial levels of various metabolites related to amino acid metabolism, TCA cycle, and fatty acid metabolism. No major and consistent alterations in levels of specific metabolites were found that establish the substrate for and function of SLC25A47.</div></div><div><h3>Conclusion</h3><div>Collectively, our results hint at a role of SLC25A47 in amino acid and fatty acid metabolism, yet suggest that SLC25A47 is dispensable for hepatic lipid homeostasis during fasting and high-fat feeding.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102092"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920573","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":"Cannabinoid type-1 receptors in CaMKII neurons drive impulsivity in pathological eating behavior","authors":"Elena Martin-Garcia ,&nbsp;Laura Domingo-Rodriguez ,&nbsp;Beat Lutz ,&nbsp;Rafael Maldonado ,&nbsp;Inigo Ruiz de Azua","doi":"10.1016/j.molmet.2025.102096","DOIUrl":"10.1016/j.molmet.2025.102096","url":null,"abstract":"<div><h3>Objectives</h3><div>Overconsumption of palatable food and energy accumulation are evolutionary mechanisms of survival when food is scarce. These innate mechanisms becom detrimental in obesogenic environment promoting obesity and related comorbidities, including mood disorders. This study aims at elucidating the role of the endocannabinoid system in energy accumulation and hedonic feeding.</div></div><div><h3>Methods</h3><div>We applied a genetic strategy to reconstitute cannabinoid type-1 receptor (CB1) expression at functional levels specifically in CaMKII+ neurons (CaMKII-CB1-RS) and adipocytes (Ati-CB1-RS), respectively, in a CB1 deficient background.</div></div><div><h3>Results</h3><div>Rescued CB1 expression in CaMKII+ neurons, but not in adipocytes, promotes feeding behavior, leading to fasting-induced hyperphagia, increased motivation, and impulsivity to palatable food seeking. In a diet-induced obesity model, CB1 re-expression in CaMKII+ neurons, but not in adipocytes, compared to complete CB1 deficiency, was sufficient to largely restore weight gain, food intake without any effect on glucose intolerance associated with high-fat diet consumption. In a model of glucocorticoid-mediated metabolic syndrome, CaMKII-CB1-RS mice showed all metabolic alterations linked to the human metabolic syndrome except of glucose intolerance. In a binge-eating model mimicking human pathological feeding, CaMKII-CB1-RS mice showed increased seeking and compulsive behavior to palatable food, suggesting crucial roles in foraging and an enhanced susceptibility to addictive-like eating behaviors. Importantly, other contingent behaviors, including increased cognitive flexibility and reduced anxiety-like behaviors, but not depressive-like behaviors, were also observed.</div></div><div><h3>Conclusions</h3><div>CB1 in CaMKII+ neurons is instrumental in feeding behavior and energy storage under physiological conditions. The exposure to risk factors (hypercaloric diet, glucocorticoid dysregulation) leads to obesity, metabolic syndrome, binge-eating and food addiction.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102096"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11787564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951447","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}