Physiological genomics最新文献

{"title":"The genetic regulation of the gastric transcriptome is associated with metabolic and obesity-related traits and diseases.","authors":"Laura L Koebbe, Timo Hess, Ann-Sophie Giel, Jessica Bigge, Jan Gehlen, Vitalia Schueller, Michael Geppert, Franz Ludwig Dumoulin, Joerg Heller, Michael Schepke, Dominik Plaßmann, Michael Vieth, Marino Venerito, Johannes Schumacher, Carlo Maj","doi":"10.1152/physiolgenomics.00120.2023","DOIUrl":"10.1152/physiolgenomics.00120.2023","url":null,"abstract":"<p><p>Tissue-specific gene expression and gene regulation lead to a better understanding of tissue-specific physiology and pathophysiology. We analyzed the transcriptome and genetic regulatory profiles of two distinct gastric sites, corpus and antrum, to identify tissue-specific gene expression and its regulation. Gastric corpus and antrum mucosa biopsies were collected during routine gastroscopies from up to 431 healthy individuals. We obtained genotype and transcriptome data and performed transcriptome profiling and expression quantitative trait locus (eQTL) studies. We further used data from genome-wide association studies (GWAS) of various diseases and traits to partition their heritability and to perform transcriptome-wide association studies (TWAS). The transcriptome data from corpus and antral mucosa highlights the heterogeneity of gene expression in the stomach. We identified enriched pathways revealing distinct and common physiological processes in gastric corpus and antrum. Furthermore, we found an enrichment of the single nucleotide polymorphism (SNP)-based heritability of metabolic, obesity-related, and cardiovascular traits and diseases by considering corpus- and antrum-specifically expressed genes. Particularly, we could prioritize gastric-specific candidate genes for multiple metabolic traits, like <i>NQO1</i> which is involved in glucose metabolism, <i>MUC1</i> which contributes to purine and protein metabolism or <i>RAB27B</i> being a regulator of weight and body composition. Our findings show that gastric corpus and antrum vary in their transcriptome and genetic regulatory profiles indicating physiological differences which are mostly related to digestion and epithelial protection. Moreover, our findings demonstrate that the genetic regulation of the gastric transcriptome is linked to biological mechanisms associated with metabolic, obesity-related, and cardiovascular traits and diseases. <b>NEW & NOTEWORTHY</b> We analyzed the transcriptomes and genetic regulatory profiles of gastric corpus and for the first time also of antrum mucosa in 431 healthy individuals. Through tissue-specific gene expression and eQTL analyses, we uncovered unique and common physiological processes across both primary gastric sites. Notably, our findings reveal that stomach-specific eQTLs are enriched in loci associated with metabolic traits and diseases, highlighting the pivotal role of gene expression regulation in gastric physiology and potential pathophysiology.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139973058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Divergent selection for feed efficiency in pigs altered the duodenum transcriptomic response to feed intake and its DNA methylation profiles.","authors":"Guillaume Devailly, Katia Fève, Safia Saci, Julien Sarry, Sophie Valière, Jérôme Lluch, Olivier Bouchez, Laure Ravon, Yvon Billon, Hélène Gilbert, Juliette Riquet, Martin Beaumont, Julie Demars","doi":"10.1152/physiolgenomics.00123.2023","DOIUrl":"10.1152/physiolgenomics.00123.2023","url":null,"abstract":"<p><p>Feed efficiency is a trait of interest in pigs as it contributes to lowering the ecological and economical costs of pig production. A divergent genetic selection experiment from a Large White pig population was performed for 10 generations, leading to pig lines with relatively low- (LRFI) and high- (HRFI) residual feed intake (RFI). Feeding behavior and metabolic differences have been previously reported between the two lines. We hypothesized that part of these differences could be related to differential sensing and absorption of nutrients in the proximal intestine. We investigated the duodenum transcriptome and DNA methylation profiles comparing overnight fasting with ad libitum feeding in LRFI and HRFI pigs (<i>n</i> = 24). We identified 1,106 differentially expressed genes between the two lines, notably affecting pathways of the transmembrane transport activity and related to mitosis or chromosome separation. The LRFI line showed a greater transcriptomic response to feed intake than the HRFI line. Feed intake affected genes from both anabolic and catabolic pathways in the pig duodenum, such as rRNA production and autophagy. Several nutrient transporter and tight junction genes were differentially expressed between lines and/or by short-term feed intake. We also identified 409 differentially methylated regions in the duodenum mucosa between the two lines, while this epigenetic mark was less affected by feeding. Our findings highlighted that the genetic selection for feed efficiency in pigs changed the transcriptome profiles of the duodenum, and notably its response to feed intake, suggesting key roles for this proximal gut segment in mechanisms underlying feed efficiency.<b>NEW & NOTEWORTHY</b> The duodenum is a key organ for the hunger/satiety loop and nutrient sensing. We investigated how the duodenum transcriptome and DNA methylation profiles are affected by feed intakes in pigs. We observed thousands of changes in gene expression levels between overnight-fasted and fed pigs in high-feed efficiency pig lines, but almost none in the related low-feed efficiency pig line.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140144022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uromodulin in sepsis and severe pneumonia: a two-sample Mendelian randomization study.","authors":"Mikael Eriksson, Miklós Lipcsey, Yann Ilboudo, Satoshi Yoshiji, Brent Richards, Michael Hultström","doi":"10.1152/physiolgenomics.00145.2023","DOIUrl":"10.1152/physiolgenomics.00145.2023","url":null,"abstract":"<p><p>The outcome for patients with sepsis-associated acute kidney injury in the intensive care unit (ICU) remains poor. Low serum uromodulin (sUMOD) protein levels have been proposed as a causal mediator of this effect. We investigated the effect of different levels of sUMOD on the risk of sepsis and severe pneumonia and outcomes in these conditions. A two-sample Mendelian randomization (MR) study was performed. Single-nucleotide polymorphisms (SNPs) associated with increased levels of sUMOD were identified and used as instrumental variables for association with outcomes. Data from different cohorts were combined based on disease severity and meta-analyzed. Five SNPs associated with increased sUMOD levels were identified and tested in six datasets from two biobanks. There was no protective effect of increased levels of sUMOD on the risk of sepsis [two cohorts, odds ratio (OR) 0.99 (95% confidence interval 0.95-1.03), <i>P</i> = 0.698, and OR 0.95 (0.91-1.00), <i>P</i> = 0.060, respectively], risk of sepsis requiring ICU admission [OR 1.04 (0.93-1.16), <i>P</i> = 0.467], ICU mortality in sepsis [OR 1.00 (0.74-1.37), <i>P</i> = 0.987], risk of pneumonia requiring ICU admission [OR 1.05 (0.98-1.14), <i>P</i> = 0.181], or ICU mortality in pneumonia [OR 1.17 (0.98-1.39), <i>P</i> = 0.079]. Meta-analysis of hospital-admitted and ICU-admitted patients separately yielded similar results [OR 0.98 (0.95-1.01), <i>P</i> = 0.23, and OR 1.05 (0.99-1.12), <i>P</i> = 0.86, respectively]. Among patients with sepsis and severe pneumonia, there was no protective effect of different levels of sUMOD. Results were consistent regardless of geographic origins and not modified by disease severity. <b>NEW & NOTEWORTHY</b> The presence of acute kidney injury in severe infections increases the likelihood of poor outcome severalfold. A decrease in serum uromodulin (sUMOD), synthetized in the kidney, has been proposed as a mediator of this effect. Using the Mendelian randomization technique, we tested the hypothesis that increased sUMOD is protective in severe infections. Analyses, however, showed no evidence of a protective effect of higher levels of sUMOD in sepsis or severe pneumonia.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139900274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gonadal sex and chromosome complement influence the gut microbiome in a mouse model of allergic airway inflammation","authors":"Carolyn Damilola Ekpruke, Rachel Alford, Erik Parker, Patricia Silveyra","doi":"10.1152/physiolgenomics.00003.2024","DOIUrl":"https://doi.org/10.1152/physiolgenomics.00003.2024","url":null,"abstract":"Evidence abounds that gut microbiome components are associated with sex disparities in the immune system. However, it remains unclear whether the observed sex disparity in asthma incidence is associated with sex-dependent differences in immune-modulating gut microbiota, and/or its influence on allergic airway inflammatory processes. Using a mouse model of house dust mite (HDM)-induced allergic inflammation and the four core genotypes (FCG) model, we have previously reported sex differences in lung inflammatory phenotypes. Here, we investigated associations of gut microbiomes to these phenotypes by challenging FCG mice (XXM, XXF, XYM, XYF, n=7/group) withHDM (25 μg) or PBS intranasally for 5 weeks and collecting fecal samples. We extracted fecal DNA and analyzed the 16S microbiome via Targeted Metagenomic Sequencing. We compared alpha and beta diversity across genotypes and assessed the <i>Firmicutes/Bacteroidetes</i> ratio (F/B). When comparing baseline and after exposure for the FCG, we found that the gut F/B was only increased in the XXM genotype. We also found that alpha diversity was significantly increased in all FCG mice upon HDM challenge, with the highest increase in the XXF, and the lowest in the XXM genotypes. Similarly, beta diversity of the microbial community was also affected by challenge in a gonad- and chromosome-dependent manner. In summary, our results indicated that HDM treatment, gonads, and sex chromosomes significantly influence the gut microbial community composition. We concluded that allergic lung inflammation may be affected by the gut microbiome in a sex-dependent manner involving both hormonal and genetic influences.","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140630515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiac Biomarker Responses Following High-Intensity Interval and Continuous Exercise: The Influence of ACE-I/D Gene Polymorphism and Training Status in Men","authors":"Akram Falahati, Hamid Arazi","doi":"10.1152/physiolgenomics.00129.2023","DOIUrl":"https://doi.org/10.1152/physiolgenomics.00129.2023","url":null,"abstract":"Physiological Genomics, Ahead of Print. <br/>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temporal shifts to the gut microbiome associated with cognitive dysfunction following high-fat diet consumption in a juvenile model of traumatic brain injury.","authors":"Allie M Smith, Lavanya Challagundla, Ian G McGee, Zyra J Warfield, Christiano Dos Santos E Santos, Michael R Garrett, Bernadette E Grayson","doi":"10.1152/physiolgenomics.00113.2023","DOIUrl":"10.1152/physiolgenomics.00113.2023","url":null,"abstract":"<p><p>The gut-brain axis interconnects the central nervous system (CNS) and the commensal bacteria of the gastrointestinal tract. The composition of the diet consumed by the host influences the richness of the microbial populations. Traumatic brain injury (TBI) produces profound neurocognitive damage, but it is unknown how diet influences the microbiome following TBI. The present work investigates the impact of a chow diet versus a 60% fat diet (HFD) on fecal microbiome populations in juvenile rats following TBI. Twenty-day-old male rats were placed on one of two diets for 9 days before sustaining either a Sham or TBI via the Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA). Fecal samples were collected at both 1- and 9-days postinjury. Animals were cognitively assessed in the novel object recognition tests at 8 days postinjury. Fecal microbiota DNA was isolated and sequenced. Twenty days of HFD feeding did not alter body weight, but fat mass was elevated in HFD compared with Chow rats. TBI animals had a greater percentage of entries to the novel object quadrant than Sham counterparts, <i>P</i> < 0.05. The Firmicutes/Bacteroidetes ratio was significantly higher in TBI than in the Sham, <i>P</i> < 0.05. Microbiota of the Firmicutes lineage exhibited perturbations by both injury and diet that were sustained at both time points. Linear regression analyses were performed to associate bacteria with metabolic and neurocognitive endpoints. For example, counts of <i>Lachnospiraceae</i> were negatively associated with percent entries into the novel object quadrant. Taken together, these data suggest that both diet and injury produce robust shifts in microbiota, which may have long-term implications for chronic health.<b>NEW & NOTEWORTHY</b> Traumatic brain injury (TBI) produces memory and learning difficulties. Diet profoundly influences the populations of gut microbiota. Following traumatic brain injury in a pediatric model consuming either a healthy or high-fat diet (HFD), significant shifts in bacterial populations occur, of which, some are associated with diet, whereas others are associated with neurocognitive performance. More work is needed to determine whether these microbes can therapeutically improve learning following trauma to the brain.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11283908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139032462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the connection between gut microbiome and metabolic health in individuals with chronic spinal cord injury.","authors":"Jia Li, Stephen Barnes, Elliot Lefkowitz, Ceren Yarar-Fisher","doi":"10.1152/physiolgenomics.00107.2023","DOIUrl":"10.1152/physiolgenomics.00107.2023","url":null,"abstract":"<p><p>Accumulating evidence has revealed that alterations in the gut microbiome following spinal cord injury (SCI) exhibit similarities to those observed in metabolic syndrome. Considering the causal role of gut dysbiosis in metabolic syndrome development, SCI-induced gut dysbiosis may be a previously unidentified contributor to the increased risk of cardiometabolic diseases, which has garnered attention. With a cross-sectional design, we evaluated the correlation between gut microbiome composition and functional potential with indicators of metabolic health among 46 individuals with chronic SCI. Gut microbiome communities were profiled using next-generation sequencing techniques. Indices of metabolic health, including fasting lipid profile, glucose tolerance, insulin resistance, and inflammatory markers, were assessed through fasting blood tests and an oral glucose tolerance test. We used multivariate statistical techniques (i.e., regularized canonical correlation analysis) to identify correlations between gut bacterial communities, functional pathways, and metabolic health indicators. Our findings spotlight bacterial species and functional pathways associated with complex carbohydrate degradation and maintenance of gut barrier integrity as potential contributors to improved metabolic health. Conversely, those correlated with detrimental microbial metabolites and gut inflammatory pathways demonstrated associations with poorer metabolic health outcomes. This cross-sectional investigation represents a pivotal initial step toward comprehending the intricate interplay between the gut microbiome and metabolic health in SCI. Furthermore, our results identified potential targets for future research endeavors to elucidate the role of the gut microbiome in metabolic syndrome in this population.<b>NEW & NOTEWORTHY</b> Spinal cord injury (SCI) is accompanied by gut dysbiosis and the impact of this on the development of metabolic syndrome in this population remains to be investigated. Our study used next-generation sequencing and multivariate statistical analyses to explore the correlations between gut microbiome composition, function, and metabolic health indices in individuals with chronic SCI. Our results point to potential gut microbial species and functional pathways that may be implicated in the development of metabolic syndrome.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11283909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139723663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune and metabolic challenges induce changes in pain sensation and related pathways in the hypothalamus.","authors":"Sandra L Rodriguez-Zas, Romana A Nowak, Adrienne M Antonson, Laurie Rund, Sreelaya Bhamidi, Andrea N Gomez, Bruce R Southey, Rodney W Johnson","doi":"10.1152/physiolgenomics.00134.2023","DOIUrl":"10.1152/physiolgenomics.00134.2023","url":null,"abstract":"<p><p>The hypothalamic molecular processes participate in the regulation of the neuro-immune-endocrine system, including hormone, metabolite, chemokine circulation, and corresponding physiological and behavioral responses. RNA-sequencing profiles were analyzed to understand the effect of juvenile immune and metabolic distress 100 days after virally elicited maternal immune activation during gestation in pigs. Over 1,300 genes exhibited significant additive or interacting effects of gestational immune activation, juvenile distress, and sex. One-third of these genes presented multiple effects, emphasizing the complex interplay of these factors. Key functional categories enriched among affected genes included sensory perception of pain, steroidogenesis, prolactin, neuropeptide, and inflammatory signaling. These categories underscore the intricate relationship between gestational immune activation during gestation, distress, and the response of hypothalamic pathways to insults. These effects were sex-dependent for many genes, such as <i>Prdm12</i>, <i>Oprd1</i>, <i>Isg20</i>, <i>Prl</i>, <i>Oxt</i>, and <i>Vip</i>. The prevalence of differentially expressed genes annotated to proinflammatory and cell cycle processes suggests potential implications for synaptic plasticity and neuronal survival. The gene profiles affected by immune activation, distress, and sex pointed to the action of transcription factors SHOX2, STAT1, and REST. These findings underscore the importance of considering sex and postnatal challenges when studying causes of neurodevelopmental disorders and highlight the complexity of the \"two-hit\" hypothesis in understanding their etiology. Our study furthers the understanding of the intricate molecular responses in the hypothalamus to gestational immune activation and subsequent distress, shedding light on the sex-specific effects and the potential long-lasting consequences on pain perception, neuroendocrine regulation, and inflammatory processes.<b>NEW & NOTEWORTHY</b> The interaction of infection during gestation and insults later in life influences the molecular mechanisms in the hypothalamus that participate in pain sensation. The response of the hypothalamic transcriptome varies between sexes and can also affect synapses and immune signals. The findings from this study assist in the identification of agonists or antagonists that can guide pretranslational studies to ameliorate the effects of gestational insults interacting with postnatal challenges on physiological or behavioral disorders.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11283907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139378183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic dysregulation of transcriptomic networks in brainstem autonomic nuclei during hypertension development in the female spontaneously hypertensive rat.","authors":"Alison Moss, Lakshmi Kuttippurathu, Ankita Srivastava, James S Schwaber, Rajanikanth Vadigepalli","doi":"10.1152/physiolgenomics.00073.2023","DOIUrl":"10.1152/physiolgenomics.00073.2023","url":null,"abstract":"<p><p>Neurogenic hypertension stems from an imbalance in autonomic function that shifts the central cardiovascular control circuits toward a state of dysfunction. Using the female spontaneously hypertensive rat and the normotensive Wistar-Kyoto rat model, we compared the transcriptomic changes in three autonomic nuclei in the brainstem, nucleus of the solitary tract (NTS), caudal ventrolateral medulla, and rostral ventrolateral medulla (RVLM) in a time series at 8, 10, 12, 16, and 24 wk of age, spanning the prehypertensive stage through extended chronic hypertension. RNA-sequencing data were analyzed using an unbiased, dynamic pattern-based approach that uncovered dominant and several subtle differential gene regulatory signatures. Our results showed a persistent dysregulation across all three autonomic nuclei regardless of the stage of hypertension development as well as a cascade of transient dysregulation beginning in the RVLM at the prehypertensive stage that shifts toward the NTS at the hypertension onset. Genes that were persistently dysregulated were heavily enriched for immunological processes such as antigen processing and presentation, the adaptive immune response, and the complement system. Genes with transient dysregulation were also largely region-specific and were annotated for processes that influence neuronal excitability such as synaptic vesicle release, neurotransmitter transport, and an array of neuropeptides and ion channels. Our results demonstrate that neurogenic hypertension is characterized by brainstem region-specific transcriptomic changes that are highly dynamic with significant gene regulatory changes occurring at the hypertension onset as a key time window for dysregulation of homeostatic processes across the autonomic control circuits.<b>NEW & NOTEWORTHY</b> Hypertension is a major disease and is the primary risk factor for cardiovascular complications and stroke. The gene expression changes in the central nervous system circuits driving hypertension are understudied. Here, we show that coordinated and region-specific gene expression changes occur in the brainstem autonomic circuits over time during the development of a high blood pressure phenotype in a rat model of human essential hypertension.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11283910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139032435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Krüppel-like factor 4 in transcriptional control of the three unique isoforms of Agouti-related peptide in mice.","authors":"McKenzie L Ritter, Valerie A Wagner, Kirthikaa Balapattabi, Megan A Opichka, Ko-Ting Lu, Kelsey K Wackman, John J Reho, Henry L Keen, Anne E Kwitek, Lisa L Morselli, Aron M Geurts, Curt D Sigmund, Justin L Grobe","doi":"10.1152/physiolgenomics.00042.2023","DOIUrl":"10.1152/physiolgenomics.00042.2023","url":null,"abstract":"<p><p>Agouti-related peptide (AgRP/<i>Agrp</i>) within the hypothalamic arcuate nucleus (ARC) contributes to the control of energy balance, and dysregulated <i>Agrp</i> may contribute to metabolic adaptation during prolonged obesity. In mice, three isoforms of <i>Agrp</i> are encoded via distinct first exons. <i>Agrp-A</i> (ENSMUST00000005849.11) contributed 95% of total <i>Agrp</i> in mouse ARC, whereas <i>Agrp-B</i> (ENSMUST00000194654.2) dominated in placenta (73%). Conditional deletion of <i>Klf4</i> from <i>Agrp</i>-expressing cells (<i>Klf4^Agrp</i>^-KO mice) reduced <i>Agrp</i> mRNA and increased energy expenditure but had no effects on food intake or the relative abundance of <i>Agrp</i> isoforms in the ARC. Chronic high-fat diet feeding masked these effects of <i>Klf4</i> deletion, highlighting the context-dependent contribution of KLF4 to <i>Agrp</i> control. In the GT1-7 mouse hypothalamic cell culture model, which expresses all three isoforms of <i>Agrp</i> (including <i>Agrp-C</i>, ENSMUST00000194091.6), inhibition of extracellular signal-regulated kinase (ERK) simultaneously increased KLF4 binding to the <i>Agrp</i> promoter and stimulated <i>Agrp</i> expression. In addition, siRNA-mediated knockdown of <i>Klf4</i> reduced expression of <i>Agrp</i>. We conclude that the expression of individual isoforms of <i>Agrp</i> in the mouse is dependent upon cell type and that KLF4 directly promotes the transcription of <i>Agrp</i> via a mechanism that is superseded during obesity.<b>NEW & NOTEWORTHY</b> In mice, three distinct isoforms of Agouti-related peptide are encoded via distinct first exons. In the arcuate nucleus of the hypothalamus, Krüppel-like factor 4 stimulates transcription of the dominant isoform in lean mice, but this mechanism is altered during diet-induced obesity.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10866620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139032461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}