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2.
Sci Rep ; 11(1): 16409, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385484

RESUMO

We recently showed that NOTUM, a liver-secreted Wnt inhibitor, can acutely promote browning of white adipose. We now report studies of chronic overexpression of NOTUM in liver indicating that it protects against diet-induced obesity and improves glucose homeostasis in mice. Adeno-associated virus (AAV) vectors were used to overexpress GFP or mouse Notum in the livers of male C57BL/6J mice and the mice were fed an obesifying diet. After 14 weeks of high fat, high sucrose diet feeding, the AAV-Notum mice exhibited decreased obesity and improved glucose tolerance compared to the AAV-GFP mice. Gene expression and immunoblotting analysis of the inguinal fat and brown fat revealed increased expression of beige/brown adipocyte markers in the AAV-Notum group, suggesting enhanced thermogenic capacity by NOTUM. A ß3 adrenergic receptor agonist-stimulated lipolysis test suggested increased lipolysis capacity by NOTUM. The levels of collagen and C-C motif chemokine ligand 2 (CCL2) in the epididymal white adipose tissue of the AAV-Notum mice were significantly reduced, suggesting decreased fibrosis and inflammation, respectively. RNA sequencing analysis of inguinal white adipose of 4-week chow diet-fed mice revealed a highly significant enrichment of extracellular matrix (ECM) functional cluster among the down-regulated genes in the AAV-Notum group, suggesting a potential mechanism contributing to improved glucose homeostasis. Our in vitro studies demonstrated that recombinant human NOTUM protein blocked the inhibitory effects of WNT3A on brown adipocyte differentiation. Furthermore, NOTUM attenuated WNT3A's effects on upregulation of TGF-ß signaling and its downstream targets. Overall, our data suggest that NOTUM modulates adipose tissue function by promoting thermogenic capacity and inhibiting fibrosis through inhibition of Wnt signaling.

3.
Nat Commun ; 12(1): 4917, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389714

RESUMO

APOBEC3A is a cytidine deaminase driving mutagenesis in tumors. While APOBEC3A-induced mutations are common, APOBEC3A expression is rarely detected in cancer cells. This discrepancy suggests a tightly controlled process to regulate episodic APOBEC3A expression in tumors. In this study, we find that both viral infection and genotoxic stress transiently up-regulate APOBEC3A and pro-inflammatory genes using two distinct mechanisms. First, we demonstrate that STAT2 promotes APOBEC3A expression in response to foreign nucleic acid via a RIG-I, MAVS, IRF3, and IFN-mediated signaling pathway. Second, we show that DNA damage and DNA replication stress trigger a NF-κB (p65/IkBα)-dependent response to induce expression of APOBEC3A and other innate immune genes, independently of DNA or RNA sensing pattern recognition receptors and the IFN-signaling response. These results not only reveal the mechanisms by which tumors could episodically up-regulate APOBEC3A but also highlight an alternative route to stimulate the immune response after DNA damage independently of cGAS/STING or RIG-I/MAVS.


Assuntos
Citidina Desaminase/genética , Dano ao DNA , Regulação da Expressão Gênica , Imunidade/genética , Proteínas/genética , Transdução de Sinais/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Citidina Desaminase/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células THP-1 , Fator de Transcrição RelA/metabolismo , Regulação para Cima , Vírus/crescimento & desenvolvimento
4.
JCI Insight ; 6(17)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34314389

RESUMO

Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving more than 1000 nuclear-encoded proteins. Transcriptional networks controlling the nuclear-encoded mitochondrial genes remain to be fully elucidated. Here, we show that histone demethylase LSD1 KO from adult mouse liver (LSD1-LKO) reduces the expression of one-third of all nuclear-encoded mitochondrial genes and decreases mitochondrial biogenesis and function. LSD1-modulated histone methylation epigenetically regulates nuclear-encoded mitochondrial genes. Furthermore, LSD1 regulates gene expression and protein methylation of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), which controls the final step of NAD+ synthesis and limits NAD+ availability in the nucleus. Lsd1 KO reduces NAD+-dependent SIRT1 and SIRT7 deacetylase activity, leading to hyperacetylation and hypofunctioning of GABPß and PGC-1α, the major transcriptional factor/cofactor for nuclear-encoded mitochondrial genes. Despite the reduced mitochondrial function in the liver, LSD1-LKO mice are protected from diet-induced hepatic steatosis and glucose intolerance, partially due to induction of hepatokine FGF21. Thus, LSD1 orchestrates a core regulatory network involving epigenetic modifications and NAD+ synthesis to control mitochondrial function and hepatokine production.

5.
Nucleic Acids Res ; 49(W1): W104-W113, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-33978718

RESUMO

The integration of genomics, transcriptomics, proteomics and phenotypic traits across genetically diverse populations is a powerful approach to discover novel biological regulators. The increasing volume of complex data require new and easy-to-use tools accessible to a variety of scientists for the discovery and visualization of functionally relevant associations. To meet this requirement, we developed CoffeeProt, an open-source tool that analyses genetic variants associated to protein networks, other omics datatypes and phenotypic traits. CoffeeProt uses transcriptomics or proteomics data to perform correlation network analyses and annotates results with protein-protein interactions, subcellular localisations and drug associations. It then integrates genetic variants associated with gene expression (eQTLs) or protein abundance (pQTLs) and includes predictions of the potential consequences of variants on gene function. Finally, genetic variants are co-mapped to molecular or phenotypic traits either provided by the user or retrieved directly from publicly available GWAS results. We demonstrate its utility with the analysis of mouse and human population data enabling the rapid identification of genetic variants associated with druggable proteins and clinical traits. We expect that CoffeeProt will serve the systems genetics and basic science research communities, leading to the discovery of novel biologically relevant associations. CoffeeProt is available at www.coffeeprot.com.


Assuntos
Perfilação da Expressão Gênica/métodos , Proteômica/métodos , Software , Animais , Correlação de Dados , Expressão Gênica , Variação Genética , Genômica/métodos , Internet , Metabolismo dos Lipídeos/genética , Camundongos , Fenótipo , Mapeamento de Interação de Proteínas , Proteínas/genética , Proteoma , Locos de Características Quantitativas
6.
Biol Reprod ; 104(6): 1205-1217, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33739372

RESUMO

Polycystic ovary syndrome (PCOS) is one of the most frequent endocrinopathies, affecting 5-10% of women of reproductive age, and is characterized by the presence of ovarian cysts, oligo, or anovulation, and clinical or biochemical hyperandrogenism. Metabolic abnormalities such as hyperinsulinemia, insulin resistance, cardiovascular complications, dyslipidemia, and obesity are frequently present in PCOS women. Several key pathogenic pathways overlap between these metabolic abnormalities, notably chronic inflammation. The observation that this mechanism was shared led to the hypothesis that a chronic inflammatory state could contribute to the pathogenesis of PCOS. Moreover, while physiological inflammation is an essential feature of reproductive events such as ovulation, menstruation, implantation, and labor at term, the establishment of chronic inflammation may be a pivotal feature of the observed reproductive dysfunctions in PCOS women. Taken together, the present work aims to review the available evidence about inflammatory mediators and related mechanisms in women with PCOS, with an emphasis on reproductive function.

7.
Circulation ; 143(18): 1809-1823, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33626882

RESUMO

BACKGROUND: Coronary artery disease (CAD) is a multifactorial condition with both genetic and exogenous causes. The contribution of tissue-specific functional networks to the development of atherosclerosis remains largely unclear. The aim of this study was to identify and characterize central regulators and networks leading to atherosclerosis. METHODS: Based on several hundred genes known to affect atherosclerosis risk in mouse (as demonstrated in knockout models) and human (as shown by genome-wide association studies), liver gene regulatory networks were modeled. The hierarchical order and regulatory directions of genes within the network were based on Bayesian prediction models, as well as experimental studies including chromatin immunoprecipitation DNA-sequencing, chromatin immunoprecipitation mass spectrometry, overexpression, small interfering RNA knockdown in mouse and human liver cells, and knockout mouse experiments. Bioinformatics and correlation analyses were used to clarify associations between central genes and CAD phenotypes in both human and mouse. RESULTS: The transcription factor MAFF (MAF basic leucine zipper transcription factor F) interacted as a key driver of a liver network with 3 human genes at CAD genome-wide association studies loci and 11 atherosclerotic murine genes. Most importantly, expression levels of the low-density lipoprotein receptor (LDLR) gene correlated with MAFF in 600 CAD patients undergoing bypass surgery (STARNET [Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task]) and a hybrid mouse diversity panel involving 105 different inbred mouse strains. Molecular mechanisms of MAFF were tested in noninflammatory conditions and showed positive correlation between MAFF and LDLR in vitro and in vivo. Interestingly, after lipopolysaccharide stimulation (inflammatory conditions), an inverse correlation between MAFF and LDLR in vitro and in vivo was observed. Chromatin immunoprecipitation mass spectrometry revealed that the human CAD genome-wide association studies candidate BACH1 (BTB domain and CNC homolog 1) assists MAFF in the presence of lipopolysaccharide stimulation with respective heterodimers binding at the MAF recognition element of the LDLR promoter to transcriptionally downregulate LDLR expression. CONCLUSIONS: The transcription factor MAFF was identified as a novel central regulator of an atherosclerosis/CAD-relevant liver network. MAFF triggered context-specific expression of LDLR and other genes known to affect CAD risk. Our results suggest that MAFF is a missing link between inflammation, lipid and lipoprotein metabolism, and a possible treatment target.


Assuntos
Aterosclerose/metabolismo , Colesterol/metabolismo , Proteínas de Ligação a DNA/metabolismo , Inflamação/metabolismo , Fator de Transcrição MafF/metabolismo , Proteínas Nucleares/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Knockout
8.
Eur Heart J ; 42(9): 919-933, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33532862

RESUMO

AIMS: While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. METHODS AND RESULTS: We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1ß (vs. vehicle), and associated with smooth muscle cell migration in vitro. CONCLUSIONS: A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.


Assuntos
Doença da Artéria Coronariana , Infarto do Miocárdio , Doença da Artéria Coronariana/genética , Células Endoteliais , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Japão , Infarto do Miocárdio/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
9.
Mol Syst Biol ; 17(1): e9684, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33417276

RESUMO

To elucidate the contributions of specific lipid species to metabolic traits, we integrated global hepatic lipid data with other omics measures and genetic data from a cohort of about 100 diverse inbred strains of mice fed a high-fat/high-sucrose diet for 8 weeks. Association mapping, correlation, structure analyses, and network modeling revealed pathways and genes underlying these interactions. In particular, our studies lead to the identification of Ifi203 and Map2k6 as regulators of hepatic phosphatidylcholine homeostasis and triacylglycerol accumulation, respectively. Our analyses highlight mechanisms for how genetic variation in hepatic lipidome can be linked to physiological and molecular phenotypes, such as microbiota composition.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/genética , Glucose/efeitos adversos , Resistência à Insulina/genética , MAP Quinase Quinase 6/genética , Proteínas Nucleares/genética , Animais , Modelos Animais de Doenças , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Variação Genética , Lipidômica , Masculino , Camundongos , Fosfatidilcolinas/metabolismo , Triglicerídeos/metabolismo
10.
Sci Transl Med ; 12(555)2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32759275

RESUMO

Obesity is heightened during aging, and although the estrogen receptor α (ERα) has been implicated in the prevention of obesity, its molecular actions in adipocytes remain inadequately understood. Here, we show that adipose tissue ESR1/Esr1 expression inversely associated with adiposity and positively associated with genes involved in mitochondrial metabolism and markers of metabolic health in 700 Finnish men and 100 strains of inbred mice from the UCLA Hybrid Mouse Diversity Panel. To determine the anti-obesity actions of ERα in fat, we selectively deleted Esr1 from white and brown adipocytes in mice. In white adipose tissue, Esr1 controlled oxidative metabolism by restraining the targeted elimination of mitochondria via the E3 ubiquitin ligase parkin. mtDNA content was elevated, and adipose tissue mass was reduced in adipose-selective parkin knockout mice. In brown fat centrally involved in body temperature maintenance, Esr1 was requisite for both mitochondrial remodeling by dynamin-related protein 1 (Drp1) and uncoupled respiration thermogenesis by uncoupled protein 1 (Ucp1). In both white and brown fat of female mice and adipocytes in culture, mitochondrial dysfunction in the context of Esr1 deletion was paralleled by a reduction in the expression of the mtDNA polymerase γ subunit Polg1 We identified Polg1 as an ERα target gene by showing that ERα binds the Polg1 promoter to control its expression in 3T3L1 adipocytes. These findings support strategies leveraging ERα action on mitochondrial function in adipocytes to combat obesity and metabolic dysfunction.


Assuntos
Adipócitos Marrons , Receptor alfa de Estrogênio , Adipócitos Marrons/metabolismo , Adipócitos Brancos/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Camundongos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Termogênese , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
11.
Cell ; 182(3): 545-562.e23, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32621799

RESUMO

Scar tissue size following myocardial infarction is an independent predictor of cardiovascular outcomes, yet little is known about factors regulating scar size. We demonstrate that collagen V, a minor constituent of heart scars, regulates the size of heart scars after ischemic injury. Depletion of collagen V led to a paradoxical increase in post-infarction scar size with worsening of heart function. A systems genetics approach across 100 in-bred strains of mice demonstrated that collagen V is a critical driver of postinjury heart function. We show that collagen V deficiency alters the mechanical properties of scar tissue, and altered reciprocal feedback between matrix and cells induces expression of mechanosensitive integrins that drive fibroblast activation and increase scar size. Cilengitide, an inhibitor of specific integrins, rescues the phenotype of increased post-injury scarring in collagen-V-deficient mice. These observations demonstrate that collagen V regulates scar size in an integrin-dependent manner.


Assuntos
Cicatriz/metabolismo , Colágeno Tipo V/deficiência , Colágeno Tipo V/metabolismo , Traumatismos Cardíacos/metabolismo , Contração Miocárdica/genética , Miofibroblastos/metabolismo , Animais , Cicatriz/genética , Cicatriz/fisiopatologia , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Colágeno Tipo V/genética , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Feminino , Fibrose/genética , Fibrose/metabolismo , Regulação da Expressão Gênica/genética , Integrinas/antagonistas & inibidores , Integrinas/genética , Integrinas/metabolismo , Isoproterenol/farmacologia , Masculino , Mecanotransdução Celular/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia de Força Atômica/instrumentação , Microscopia Eletrônica de Transmissão , Contração Miocárdica/efeitos dos fármacos , Miofibroblastos/citologia , Miofibroblastos/patologia , Miofibroblastos/ultraestrutura , Análise de Componente Principal , Proteômica , RNA-Seq , Análise de Célula Única
12.
Nat Commun ; 11(1): 1465, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32193374

RESUMO

Genetic variation in the FAM13A (Family with Sequence Similarity 13 Member A) locus has been associated with several glycemic and metabolic traits in genome-wide association studies (GWAS). Here, we demonstrate that in humans, FAM13A alleles are associated with increased FAM13A expression in subcutaneous adipose tissue (SAT) and an insulin resistance-related phenotype (e.g. higher waist-to-hip ratio and fasting insulin levels, but lower body fat). In human adipocyte models, knockdown of FAM13A in preadipocytes accelerates adipocyte differentiation. In mice, Fam13a knockout (KO) have a lower visceral to subcutaneous fat (VAT/SAT) ratio after high-fat diet challenge, in comparison to their wild-type counterparts. Subcutaneous adipocytes in KO mice show a size distribution shift toward an increased number of smaller adipocytes, along with an improved adipogenic potential. Our results indicate that GWAS-associated variants within the FAM13A locus alter adipose FAM13A expression, which in turn, regulates adipocyte differentiation and contribute to changes in body fat distribution.


Assuntos
Adipócitos/metabolismo , Distribuição da Gordura Corporal , Proteínas Ativadoras de GTPase/genética , Adipogenia/genética , Animais , Diferenciação Celular/genética , Proteínas Ativadoras de GTPase/metabolismo , Técnicas de Silenciamento de Genes , Loci Gênicos , Estudo de Associação Genômica Ampla , Células HEK293 , Humanos , Resistência à Insulina/genética , Gordura Intra-Abdominal/metabolismo , Masculino , Metabolômica , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Gordura Subcutânea/metabolismo
13.
Mol Metab ; 30: 30-47, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31767179

RESUMO

OBJECTIVE: Lipocalin-2 (LCN2) is a secreted protein involved in innate immunity and has also been associated with several cardiometabolic traits in both mouse and human studies. However, the causal relationship of LCN2 to these traits is unclear, and most studies have examined only males. METHODS: Using adeno-associated viral vectors we expressed LCN2 in either adipose or liver in a tissue specific manner on the background of a whole-body Lcn2 knockout or wildtype mice. Metabolic phenotypes including body weight, body composition, plasma and liver lipids, glucose homeostasis, insulin resistance, mitochondrial phenotyping, and metabolic cage studies were monitored. RESULTS: We studied the genetics of LCN2 expression and associated clinical traits in both males and females in a panel of 100 inbred strains of mice (HMDP). The natural variation in Lcn2 expression across the HMDP exhibits high heritability, and genetic mapping suggests that it is regulated in part by Lipin1 gene variation. The correlation analyses revealed striking tissue dependent sex differences in obesity, insulin resistance, hepatic steatosis, and dyslipidemia. To understand the causal relationships, we examined the effects of expression of LCN2 selectively in liver or adipose. On a Lcn2-null background, LCN2 expression in white adipose promoted metabolic disturbances in females but not males. It acted in an autocrine/paracrine manner, resulting in mitochondrial dysfunction and an upregulation of inflammatory and fibrotic genes. On the other hand, on a null background, expression of LCN2 in liver had no discernible impact on the traits examined despite increasing the levels of circulating LCN2 more than adipose LCN2 expression. The mechanisms underlying the sex-specific action of LCN2 are unclear, but our results indicate that adipose LCN2 negatively regulates its receptor, LRP2 (or megalin), and its repressor, ERα, in a female-specific manner and that the effects of LCN2 on metabolic traits are mediated in part by LRP2. CONCLUSIONS: Following up on our population-based studies, we demonstrate that LCN2 acts in a highly sex- and tissue-specific manner in mice. Our results have important implications for human studies, emphasizing the importance of sex and the tissue source of LCN2.


Assuntos
Tecido Adiposo/metabolismo , Lipocalina-2/metabolismo , Adiposidade , Animais , Composição Corporal , Peso Corporal , Feminino , Glucose/análise , Homeostase , Resistência à Insulina , Lipídeos/análise , Lipocalina-2/genética , Lipocalina-2/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Obesidade/metabolismo , Fatores Sexuais
14.
Mol Metab ; 24: 44-63, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30948248

RESUMO

OBJECTIVE: Activation of the Wnt-signaling pathway is known to inhibit differentiation in adipocytes. However, there is a gap in our understanding of the transcriptional network regulated by components of the Wnt-signaling pathway during adipogenesis and in adipocytes during postnatal life. The key intracellular effectors of the Wnt-signaling pathway occur through TCF transcription factors such as TCF7L2 (transcription factor-7-like 2). Several genetic variants in proximity to TCF7L2 have been linked to type 2 diabetes through genome-wide association studies in various human populations. Our work aims to functionally characterize the adipocyte specific gene program regulated by TCF7L2 and understand how this program regulates metabolism. METHODS: We generated Tcf7l2F/F mice and assessed TCF7L2 function in isolated adipocytes and adipose specific knockout mice. ChIP-sequencing and RNA-sequencing was performed on the isolated adipocytes with control and TCF7L2 knockout cells. Adipose specific TCF7L2 knockout mice were challenged with high fat diet and assessed for body weight, glucose tolerance, and lipolysis. RESULTS: Here we report that TCF7L2 regulates adipocyte size, endocrine function, and glucose metabolism. Tcf7l2 is highly expressed in white adipose tissue, and its expression is suppressed in genetic and diet-induced models of obesity. Genome-wide distribution of TCF7L2 binding and gene expression analysis in adipocytes suggests that TCF7L2 directly regulates genes implicated in cellular metabolism and cell cycle control. When challenged with a high-fat diet, conditional deletion of TCF7L2 in adipocytes led to impaired glucose tolerance, impaired insulin sensitivity, promoted weight gain, and increased adipose tissue mass. This was accompanied by reduced expression of triglyceride hydrolase, reduced fasting-induced free fatty acid release, and adipocyte hypertrophy in subcutaneous adipose tissue. CONCLUSIONS: Together our studies support that TCF7L2 is a central transcriptional regulator of the adipocyte metabolic program by directly regulating the expression of genes involved in lipid and glucose metabolism.


Assuntos
Adipócitos/metabolismo , Glucose/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Ganho de Peso/genética , Adipócitos/patologia , Animais , Células Cultivadas , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo
15.
Nature ; 567(7747): 187-193, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30814737

RESUMO

Dysregulation of lipid homeostasis is a precipitating event in the pathogenesis and progression of hepatosteatosis and metabolic syndrome. These conditions are highly prevalent in developed societies and currently have limited options for diagnostic and therapeutic intervention. Here, using a proteomic and lipidomic-wide systems genetic approach, we interrogated lipid regulatory networks in 107 genetically distinct mouse strains to reveal key insights into the control and network structure of mammalian lipid metabolism. These include the identification of plasma lipid signatures that predict pathological lipid abundance in the liver of mice and humans, defining subcellular localization and functionality of lipid-related proteins, and revealing functional protein and genetic variants that are predicted to modulate lipid abundance. Trans-omic analyses using these datasets facilitated the identification and validation of PSMD9 as a previously unknown lipid regulatory protein. Collectively, our study serves as a rich resource for probing mammalian lipid metabolism and provides opportunities for the discovery of therapeutic agents and biomarkers in the setting of hepatic lipotoxicity.


Assuntos
Metabolismo dos Lipídeos/genética , Lipídeos/análise , Lipídeos/genética , Proteômica , Animais , Células HEK293 , Humanos , Metabolismo dos Lipídeos/fisiologia , Lipídeos/sangue , Lipídeos/classificação , Fígado/química , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Obesidade/genética , Obesidade/metabolismo , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo
16.
Cell Metab ; 29(4): 932-949.e4, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30639359

RESUMO

We studied sex differences in over 50 cardio-metabolic traits in a panel of 100 diverse inbred strains of mice. The results clearly showed that the effects of sex on both clinical phenotypes and gene expression depend on the genetic background. In support of this, genetic loci associated with the traits frequently showed sex specificity. For example, Lyplal1, a gene implicated in human obesity, was shown to underlie a sex-specific locus for diet-induced obesity. Global gene expression analyses of tissues across the panel implicated adipose tissue "beiging" and mitochondrial functions in the sex differences. Isolated mitochondria showed gene-by-sex interactions in oxidative functions, such that some strains (C57BL/6J) showed similar function between sexes, whereas others (DBA/2J and A/J) showed increased function in females. Reduced adipose mitochondrial function in males as compared to females was associated with increased susceptibility to obesity and insulin resistance. Gonadectomy studies indicated that gonadal hormones acting in a tissue-specific manner were responsible in part for the sex differences.


Assuntos
Doenças Cardiovasculares/metabolismo , Mitocôndrias/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Doenças Cardiovasculares/patologia , Feminino , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Obesidade/metabolismo , Obesidade/patologia , Fenótipo , Análise de Componente Principal , Caracteres Sexuais
17.
J Lipid Res ; 60(3): 450-455, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30617149

RESUMO

Secreted proteins serve as crucial mediators of many physiology processes, and beginning with the discovery of insulin, studies have revealed numerous context-specific regulatory networks across various cell types. Here, we review "omics" approaches to deconvolute the complex milieu of proteins that are released from the cell. We emphasize a novel "systems genetics" approach our laboratory has developed to investigate mechanisms of tissue-tissue communication using population-based datasets. Finally, we highlight potential future directions for these studies, discuss several caveats, and propose new ways to investigate modes of endocrine communication.


Assuntos
Proteínas/metabolismo , Biologia de Sistemas/métodos , Animais , Células/metabolismo , Humanos
18.
Nat Metab ; 1(11): 1038-1050, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-32259026

RESUMO

The common forms of metabolic diseases are highly complex, involving hundreds of genes, environmental and lifestyle factors, age-related changes, sex differences and gut-microbiome interactions. Systems genetics is a population-based approach to address this complexity. In contrast to commonly used 'reductionist' approaches, such as gain or loss of function, that examine one element at a time, systems genetics uses high-throughput 'omics' technologies to quantitatively assess the many molecular differences among individuals in a population and then to relate these to physiologic functions or disease states. Unlike genome-wide association studies, systems genetics seeks to go beyond the identification of disease-causing genes to understand higher-order interactions at the molecular level. The purpose of this review is to introduce the systems genetics applications in the areas of metabolic and cardiovascular disease. Here, we explain how large clinical and omics-level data and databases from both human and animal populations are available to help researchers place genes in the context of pathways and networks and formulate hypotheses that can then be experimentally examined. We provide lists of such databases and examples of the integration of reductionist and systems genetics data. Among the important applications emerging is the development of improved nutritional and pharmacological strategies to address the rise of metabolic diseases.


Assuntos
Genética Humana , Metabolismo/genética , Metabolômica , Biologia de Sistemas , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Humanos , Estilo de Vida
19.
Mol Metab ; 21: 51-67, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30591411

RESUMO

OBJECTIVE: Mitochondria are organelles primarily responsible for energy production, and recent evidence indicates that alterations in size, shape, location, and quantity occur in response to fluctuations in energy supply and demand. We tested the impact of acute and chronic exercise on mitochondrial dynamics signaling and determined the impact of the mitochondrial fission regulator Dynamin related protein (Drp)1 on exercise performance and muscle adaptations to training. METHODS: Wildtype and muscle-specific Drp1 heterozygote (mDrp1+/-) mice, as well as dysglycemic (DG) and healthy normoglycemic men (control) performed acute and chronic exercise. The Hybrid Mouse Diversity Panel, including 100 murine strains of recombinant inbred mice, was used to identify muscle Dnm1L (encodes Drp1)-gene relationships. RESULTS: Endurance exercise impacted all aspects of the mitochondrial life cycle, i.e. fission-fusion, biogenesis, and mitophagy. Dnm1L gene expression and Drp1Ser616 phosphorylation were markedly increased by acute exercise and declined to baseline during post-exercise recovery. Dnm1L expression was strongly associated with transcripts known to regulate mitochondrial metabolism and adaptations to exercise. Exercise increased the expression of DNM1L in skeletal muscle of healthy control and DG subjects, despite a 15% ↓(P = 0.01) in muscle DNM1L expression in DG at baseline. To interrogate the role of Dnm1L further, we exercise trained male mDrp1+/- mice and found that Drp1 deficiency reduced muscle endurance and running performance, and altered muscle adaptations in response to exercise training. CONCLUSION: Our findings highlight the importance of mitochondrial dynamics, specifically Drp1 signaling, in the regulation of exercise performance and adaptations to endurance exercise training.


Assuntos
Dinaminas/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/fisiologia , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/fisiologia , Condicionamento Físico Animal/fisiologia , Desempenho Físico Funcional , Adaptação Fisiológica , Adulto , Idoso , Animais , Glicemia/metabolismo , Dinaminas/genética , Feminino , Deleção de Genes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fosforilação , Resistência Física
20.
G3 (Bethesda) ; 8(11): 3499-3506, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30201759

RESUMO

We describe a simple bioinformatics method for biomarker discovery that is based on the analysis of global transcript levels in a population of inbred mouse strains showing variation for disease-related traits. This method has advantages such as controlled environment and accessibility to heart and plasma tissue in the preclinical selection stage. We illustrate the approach by identifying candidate heart failure (HF) biomarkers by overlaying mouse transcriptome and clinical traits from 91 Hybrid Mouse Diversity Panel (HMDP) inbred strains and human HF transcriptome from the Myocardial Applied Genomics Network (MAGNet) consortium. We found that some of the top differentially expressed genes correlated with known human HF biomarkers, such as galectin-3 and tissue inhibitor of metalloproteinase 1. Using ELISA assays, we investigated one novel candidate, Glycoprotein NMB, in a mouse model of chronic ß-adrenergic stimulation by isoproterenol (ISO) induced HF. We observed significantly lower GPNMB plasma levels in the ISO model compared to the control group (p-value = 0.007). In addition, we assessed GPNMB plasma levels among 389 HF cases and controls from the METabolic Syndrome In Men (METSIM) study. Lower levels of GPNMB were also observed in patients with HF from the METSIM study compared to non-HF controls (p-value < 0.0001). In summary, we have identified several candidate biomarkers for HF using the cardiac transcriptome data in a population of mice that may be directly relevant and applicable to human populations.


Assuntos
Proteínas do Olho/metabolismo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Glicoproteínas de Membrana/sangue , Glicoproteínas de Membrana/metabolismo , Idoso , Animais , Biomarcadores/metabolismo , Biologia Computacional , Modelos Animais de Doenças , Feminino , Galectina 3/genética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Inibidor Tecidual de Metaloproteinase-1/genética , Transcriptoma
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