RESUMEN
Tissues release microRNAs (miRNAs) in small extracellular vesicles (sEVs) including exosomes, which can regulate gene expression in distal cells, thus acting as modulators of local and systemic metabolism. Here, we show that insulin regulates miRNA secretion into sEVs from 3T3-L1 adipocytes and that this process is differentially regulated from cellular expression. Thus, of the 53 miRNAs upregulated and 66 miRNAs downregulated by insulin in 3T3-L1 sEVs, only 12 were regulated in parallel in cells. Insulin regulated this process in part by phosphorylating hnRNPA1, causing it to bind to AU-rich motifs in miRNAs, mediating their secretion into sEVs. Importantly, 43% of insulin-regulated sEV-miRNAs are implicated in obesity and insulin resistance. These include let-7 and miR-103, which we show regulate insulin signaling in AML12 hepatocytes. Together, these findings demonstrate an important layer to insulin's regulation of adipose biology and provide a mechanism of tissue crosstalk in obesity and other hyperinsulinemic states.
Asunto(s)
Vesículas Extracelulares , Insulina , MicroARNs , Animales , Humanos , Ratones , Células 3T3-L1 , Adipocitos/metabolismo , Adipocitos/efectos de los fármacos , Vesículas Extracelulares/metabolismo , Regulación de la Expresión Génica , Hepatocitos/metabolismo , Ribonucleoproteína Nuclear Heterogénea A1/metabolismo , Ribonucleoproteína Nuclear Heterogénea A1/genética , Insulina/metabolismo , Resistencia a la Insulina , MicroARNs/metabolismo , MicroARNs/genética , Obesidad/metabolismo , Obesidad/genética , Fosforilación , Transducción de SeñalRESUMEN
Muscle regeneration is a complex process relying on precise teamwork between multiple cell types, including muscle stem cells (MuSCs) and fibroadipogenic progenitors (FAPs). FAPs are also the main source of intramuscular adipose tissue (IMAT). Muscles without FAPs exhibit decreased IMAT infiltration but also deficient muscle regeneration, indicating the importance of FAPs in the repair process. Here, we demonstrate the presence of bidirectional crosstalk between FAPs and MuSCs via their secretion of extracellular vesicles (EVs) containing distinct clusters of miRNAs that is crucial for normal muscle regeneration. Thus, after acute muscle injury, there is activation of FAPs leading to a transient rise in IMAT. These FAPs also release EVs enriched with a selected group of miRNAs, a number of which come from an imprinted region on chromosome 12. The most abundant of these is miR-127-3p, which targets the sphingosine-1-phosphate receptor S1pr3 and activates myogenesis. Indeed, intramuscular injection of EVs from immortalized FAPs speeds regeneration of injured muscle. In late stages of muscle repair, in a feedback loop, MuSCs and their derived myoblasts/myotubes secrete EVs enriched in miR-206-3p and miR-27a/b-3p. The miRNAs repress FAP adipogenesis, allowing full muscle regeneration. Together, the reciprocal communication between FAPs and muscle cells via miRNAs in their secreted EVs plays a critical role in limiting IMAT infiltration while stimulating muscle regeneration, hence providing an important mechanism for skeletal muscle repair and homeostasis.
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Vesículas Extracelulares , MicroARNs , Células Satélite del Músculo Esquelético , Fibras Musculares Esqueléticas , Comunicación , MicroARNs/genética , Regeneración/genéticaRESUMEN
Oxidative stress-induced myocardial apoptosis and necrosis are critically involved in ischemic infarction, and several sources of extracellular vesicles appear to be enriched in therapeutic activities. The central objective was to identify and validate the differential exosome miRNA repertoire in human cardiac progenitor cells (CPC). CPC exosomes were first analyzed by LC-MS/MS and compared by RNAseq with exomes of human mesenchymal stromal cells and human fibroblasts to define their differential exosome miRNA repertoire (exo-miRSEL). Proteomics demonstrated a highly significant representation of cardiovascular development functions and angiogenesis in CPC exosomes, and RNAseq analysis yielded about 350 different miRNAs; among the exo-miRSEL population, miR-935 was confirmed as the miRNA most significantly up-regulated; interestingly, miR-935 was also found to be preferentially expressed in mouse primary cardiac Bmi1+high CPC, a population highly enriched in progenitors. Furthermore, it was found that transfection of an miR-935 antagomiR combined with oxidative stress treatment provoked a significant increment both in apoptotic and necrotic populations, whereas transfection of a miR-935 mimic did not modify the response. Conclusion. miR-935 is a highly differentially expressed miRNA in exo-miRSEL, and its expression reduction promotes oxidative stress-associated apoptosis. MiR-935, together with other exosomal miRNA members, could counteract oxidative stress-related apoptosis, at least in CPC surroundings.
RESUMEN
Senescence in pancreatic beta cells plays a major role in beta cell dysfunction, which leads to impaired glucose homeostasis and diabetes. Therefore, prevention of beta cell senescence could reduce the risk of diabetes. Treatment of nonobese diabetic (NOD) mice, a model of type 1 autoimmune diabetes (T1D), with palmitic acid hydroxy stearic acids (PAHSAs), a novel class of endogenous lipids with antidiabetic and antiinflammatory effects, delays the onset and reduces the incidence of T1D from 82% with vehicle treatment to 35% with PAHSAs. Here, we show that a major mechanism by which PAHSAs protect islets of the NOD mice is by directly preventing and reversing the initial steps of metabolic stress-induced senescence. In vitro PAHSAs increased Mdm2 expression, which decreases the stability of p53, a key inducer of senescence-related genes. In addition, PAHSAs enhanced expression of protective genes, such as those regulating DNA repair and glutathione metabolism and promoting autophagy. We demonstrate the translational relevance by showing that PAHSAs prevent and reverse early stages of senescence in metabolically stressed human islets by the same Mdm2 mechanism. Thus, a major mechanism for the dramatic effect of PAHSAs in reducing the incidence of type 1 diabetes in NOD mice is decreasing cellular senescence; PAHSAs may have a similar benefit in humans.
Asunto(s)
Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Humanos , Ratones , Animales , Ácido Palmítico/farmacología , Ácidos Esteáricos , Ratones Endogámicos NOD , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/prevención & control , Proteína p53 Supresora de Tumor/genética , Senescencia Celular/genética , Estrés Fisiológico , Proteínas Proto-Oncogénicas c-mdm2/genéticaRESUMEN
Exosomes/small extracellular vesicles (sEVs) can serve as multifactorial mediators of cell-to-cell communication through their miRNA and protein cargo. Quantitative proteomic analysis of five cell lines representing metabolically important tissues reveals that each cell type has a unique sEV proteome. While classical sEV markers such as CD9/CD63/CD81 vary markedly in abundance, we identify six sEV markers (ENO1, GPI, HSPA5, YWHAB, CSF1R, and CNTN1) that are similarly abundant in sEVs of all cell types. In addition, each cell type has specific sEV markers. Using fat-specific Dicer-knockout mice with decreased white adipose tissue and increased brown adipose tissue, we show that these cell-type-specific markers can predict the changing origin of the serum sEVs. These results provide a valuable resource for understanding the sEV proteome of the cells and tissues important in metabolic homeostasis, identify unique sEV markers, and demonstrate how these markers can help in predicting the tissue of origin of serum sEVs.
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Biomarcadores/sangre , Exosomas/metabolismo , Proteoma/metabolismo , Células 3T3 , Adiponectina/sangre , Tejido Adiposo/metabolismo , Animales , RatonesRESUMEN
Exosomes and other small extracellular vesicles (sEVs) provide a unique mode of cell-to-cell communication in which microRNAs (miRNAs) produced and released from one cell are taken up by cells at a distance where they can enact changes in gene expression1-3. However, the mechanism by which miRNAs are sorted into exosomes/sEVs or retained in cells remains largely unknown. Here we demonstrate that miRNAs possess sorting sequences that determine their secretion in sEVs (EXOmotifs) or cellular retention (CELLmotifs) and that different cell types, including white and brown adipocytes, endothelium, liver and muscle, make preferential use of specific sorting sequences, thus defining the sEV miRNA profile of that cell type. Insertion or deletion of these CELLmotifs or EXOmotifs in a miRNA increases or decreases retention in the cell of production or secretion into exosomes/sEVs. Two RNA-binding proteins, Alyref and Fus, are involved in the export of miRNAs carrying one of the strongest EXOmotifs, CGGGAG. Increased miRNA delivery mediated by EXOmotifs leads to enhanced inhibition of target genes in distant cells. Thus, this miRNA code not only provides important insights that link circulating exosomal miRNAs to tissues of origin, but also provides an approach for improved targeting in RNA-mediated therapies.
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Vesículas Extracelulares , MicroARNs , Adipocitos/citología , Comunicación Celular , Endotelio/citología , Exosomas/genética , Exosomas/metabolismo , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Hígado/citología , MicroARNs/genética , MicroARNs/metabolismo , Músculos/citologíaRESUMEN
We identified a microRNA (miRNA) profile characterizing HIV lipodystrophy and explored the downstream mechanistic implications with respect to adipocyte biology and the associated clinical phenotype. miRNA profiles were extracted from small extracellular vesicles (sEVs) of HIV-infected individuals with and without lipodystrophic changes and individuals without HIV, among whom we previously showed significant reductions in adipose Dicer expression related to HIV. miR-20a-3p was increased and miR-324-5p and miR-186 were reduced in sEVs from HIV lipodystrophic individuals. Changes in these miRNAs correlated with adipose Dicer expression and clinical markers of lipodystrophy, including fat redistribution, insulin resistance, and hypertriglyceridemia. Human preadipocytes transfected with mimic miR-20a-3p, anti-miR-324-5p, or anti-miR-186 induced consistent changes in latent transforming growth factor beta binding protein 2 (Ltbp2), Wisp2, and Nebl expression. Knockdown of Ltbp2 downregulated markers of adipocyte differentiation (Fabp4, Pparγ, C/ebpa, Fasn, adiponectin, Glut4, CD36), and Lamin C, and increased expression of genes involved in inflammation (IL1ß, IL6, and Ccl20). Our studies suggest a likely unique sEV miRNA signature related to dysregulation of Dicer in adipose tissue in HIV. Enhanced miR-20a-3p or depletion of miR-186 and miR-324-5p may downregulate Ltbp2 in HIV, leading to dysregulation in adipose differentiation and inflammation, which could contribute to acquired HIV lipodystrophy and associated metabolic and inflammatory perturbations.
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Tejido Adiposo/metabolismo , ARN Helicasas DEAD-box/metabolismo , Síndrome de Lipodistrofia Asociada a VIH/sangre , MicroARNs/sangre , MicroARNs/genética , Ribonucleasa III/metabolismo , Adipocitos/fisiología , Adipogénesis , Adiposidad , Adolescente , Adulto , Animales , Proteínas CCN de Señalización Intercelular/genética , Proteínas Portadoras/genética , Diferenciación Celular/genética , Proteínas del Citoesqueleto/genética , ARN Helicasas DEAD-box/genética , Regulación hacia Abajo , Vesículas Extracelulares/metabolismo , Femenino , Silenciador del Gen , Humanos , Inflamación/genética , Resistencia a la Insulina , Proteínas con Dominio LIM/genética , Proteínas de Unión a TGF-beta Latente/genética , Masculino , Células Madre Mesenquimatosas/fisiología , Ratones , Ratones Noqueados , Persona de Mediana Edad , Proteínas Represoras/genética , Ribonucleasa III/genética , Adulto JovenRESUMEN
The brain is now recognized as an insulin-sensitive tissue; however, the role of changing insulin concentrations in the peripheral circulation in gene expression in the brain is largely unknown. Here, we performed a hyperinsulinemic-euglycemic clamp on 3-month-old male C57BL/6 mice for 3 h. We show that, in comparison with results in saline-infused controls, increases in peripheral insulin within the physiological range regulate expression of a broad network of genes in the brain. Insulin regulates distinct pathways in the hypothalamus (HTM), hippocampus, and nucleus accumbens. Insulin shows its most robust effect in the HTM and regulates multiple genes involved in neurotransmission, including upregulating expression of multiple subunits of GABA-A receptors, Na+ and K+ channels, and SNARE proteins; differentially modulating glutamate receptors; and suppressing multiple neuropeptides. Insulin also strongly modulates metabolic genes in the HTM, suppressing genes in the glycolysis and pentose phosphate pathways, while increasing expression of genes regulating pyruvate dehydrogenase and long-chain fatty acyl-CoA and cholesterol biosynthesis, thereby rerouting of carbon substrates from glucose metabolism to lipid metabolism required for the biogenesis of membranes for neuronal and glial function and synaptic remodeling. Furthermore, based on the transcriptional signatures, these changes in gene expression involve neurons, astrocytes, oligodendrocytes, microglia, and endothelial cells. Thus, peripheral insulin acutely and potently regulates expression of a broad network of genes involved in neurotransmission and brain metabolism. Dysregulation of these pathways could have dramatic effects in normal physiology and diabetes.
Asunto(s)
Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/metabolismo , Hipotálamo/metabolismo , Insulina/farmacología , Lipogénesis/fisiología , Núcleo Accumbens/metabolismo , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Técnica de Clampeo de la Glucosa , Hipocampo/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Lipogénesis/efectos de los fármacos , Masculino , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Núcleo Accumbens/efectos de los fármacosAsunto(s)
Humanos , Femenino , Anciano , Taponamiento Cardíaco/diagnóstico por imagen , Taponamiento Cardíaco/etiología , Quistes/complicaciones , Quistes/diagnóstico por imagen , Hepatopatías , Pacientes Internos , Examen Físico , Radiografía Torácica , Tomografía Computarizada por Rayos X , EcocardiografíaAsunto(s)
Taponamiento Cardíaco/etiología , Quistes/complicaciones , Hepatopatías/complicaciones , Anciano , Taponamiento Cardíaco/diagnóstico por imagen , Quistes/diagnóstico por imagen , Ecocardiografía , Femenino , Humanos , Hepatopatías/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
miRNAs can be found in serum and other body fluids and serve as biomarkers for disease. More importantly, secreted miRNAs, especially those in extracellular vesicles (EVs) such as exosomes, may mediate paracrine and endocrine communication between different tissues and thus modulate gene expression and the function of distal cells. When impaired, these processes can lead to tissue dysfunction, aging, and disease. Adipose tissue is an especially important contributor to the pool of circulating exosomal miRNAs. As a result, alterations in adipose tissue mass or function, which occur in many metabolic conditions, can lead to changes in circulating miRNAs, which then function systemically. Here we review the findings that led to these conclusions and discuss how this sets the stage for new lines of investigation in which extracellular miRNAs are recognized as important mediators of intercellular communication and potential candidates for therapy of disease.
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Enfermedades Metabólicas/tratamiento farmacológico , Enfermedades Metabólicas/metabolismo , MicroARNs/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Tejido Adiposo/metabolismo , Animales , Biomarcadores/análisis , Biomarcadores/metabolismo , Comunicación Celular , Línea Celular , Exosomas/metabolismo , Humanos , Ratones , MicroARNs/análisis , RatasRESUMEN
Regulation of gene expression is an important aspect of insulin action but in vivo is intertwined with changing levels of glucose and counter-regulatory hormones. Here we demonstrate that under euglycemic clamp conditions, physiological levels of insulin regulate interrelated networks of more than 1,000 transcripts in muscle and liver. These include expected pathways related to glucose and lipid utilization, mitochondrial function, and autophagy, as well as unexpected pathways, such as chromatin remodeling, mRNA splicing, and Notch signaling. These acutely regulated pathways extend beyond those dysregulated in mice with chronic insulin deficiency or insulin resistance and involve a broad network of transcription factors. More than 150 non-coding RNAs were regulated by insulin, many of which also responded to fasting and refeeding. Pathway analysis and RNAi knockdown revealed a role for lncRNA Gm15441 in regulating fatty acid oxidation in hepatocytes. Altogether, these changes in coding and non-coding RNAs provide an integrated transcriptional network underlying the complexity of insulin action.
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Hepatocitos/metabolismo , Resistencia a la Insulina , Insulina/farmacología , Hígado/metabolismo , ARN Largo no Codificante/metabolismo , Factores de Transcripción/metabolismo , Animales , Línea Celular , Técnica de Clampeo de la Glucosa , Masculino , RatonesRESUMEN
The replication stress inflicted on retinal endothelial cells (ECs) in the context of hypoxia-induced pathological neovascularization during proliferative retinopathy is linked with activation of the deoxyribonucleic acid (DNA) repair response. Here, we studied the effect of deficiency of the DNA damage response adaptor 53BP1, which is an antagonist of homologous recombination (HR), in the context of proliferative retinopathy. In the model of retinopathy of prematurity (ROP), 53BP1-deficient mice displayed increased hypoxia-driven pathological neovascularization and tuft formation, accompanied by increased EC proliferation and reduced EC apoptosis, as compared with 53BP1-sufficient mice. In contrast, physiological retina angiogenesis was not affected by 53BP1 deficiency. Knockdown of 53BP1 in ECs in vitro also resulted in enhanced proliferation and reduced apoptosis of the cells under hypoxic conditions. Additionally, upon 53BP1 knockdown, ECs displayed increased HR rate in hypoxia. Consistently, treatment with an HR inhibitor reversed the hyper-proliferative angiogenic phenotype associated with 53BP1 deficiency in ROP. Thus, by unleashing HR, 53BP1 deletion increases pathological EC proliferation and neovascularization in the context of ROP. Our data shed light to a previously unknown interaction between the DNA repair response and pathological neovascularization in the retina.
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Proliferación Celular , Células Endoteliales/metabolismo , Recombinación Homóloga , Neovascularización Retiniana/metabolismo , Vasos Retinianos/metabolismo , Retinopatía de la Prematuridad/metabolismo , Proteína 1 de Unión al Supresor Tumoral P53/deficiencia , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo , Animales , Apoptosis , Hipoxia de la Célula , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Predisposición Genética a la Enfermedad , Recombinación Homóloga/efectos de los fármacos , Humanos , Ratones Noqueados , Morfolinas/farmacología , Fenotipo , Pirroles/farmacología , Neovascularización Retiniana/genética , Neovascularización Retiniana/patología , Neovascularización Retiniana/prevención & control , Vasos Retinianos/efectos de los fármacos , Vasos Retinianos/patología , Retinopatía de la Prematuridad/genética , Retinopatía de la Prematuridad/patología , Retinopatía de la Prematuridad/prevención & control , Transducción de Señal , Proteína 1 de Unión al Supresor Tumoral P53/genéticaRESUMEN
BACKGROUND: Local relapse and peritoneal carcinomatosis (PC) for pT4 colon cancer is estimated in 15,6% and 36,7% for 12 months and 36 months from surgical resection respectively, achieving a 5 years overall survival of 6%. There are promising results using prophylactic HIPEC in this group of patients, and it is estimated that up to 26% of all T4 colon cancer could benefit from this treatment with a minimal morbidity. Adjuvant HIPEC is effective to avoid the possibility of peritoneal seeding after surgical resection. Taking into account these results and the cumulative experience in HIPEC use, we will lead a randomized controlled trial to determine the effectiveness and safety of adjuvant treatment with HIPEC vs. standard treatment in patients with colon cancer at high risk of peritoneal recurrence (pT4). METHODS/DESIGN: The aim of this study is to determine the effectiveness and safety of adjuvant HIPEC in preventing the development of PC in patients with colon cancer with a high risk of peritoneal recurrence (cT4). This study will be carried out in 15 Spanish HIPEC centres. Eligible for inclusion are patients who underwent curative resection for cT4NxM0 stage colon cancer. After resection of the primary tumour, 200 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously after the primary resection. Mitomycin C will be used as chemotherapeutic agent, for 60 min at 42-43 °C. Primary endpoint is loco-regional control (LC) in months and the rate of loco-regional control (%LC) at 12 months and 36 months after resection. DISCUSSION: We assumed that adjuvant HIPEC will reduce the expected absolute risk of peritoneal recurrence from 36% to 18% at 36 months for T4 colon-rectal carcinoma. TRIAL REGISTRATION: NCT02614534 ( clinicaltrial.gov ) Nov-2015.
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Neoplasias Colorrectales/cirugía , Neoplasias Colorrectales/terapia , Hipertermia Inducida/métodos , Mitomicina/uso terapéutico , Adulto , Anciano , Antibióticos Antineoplásicos/uso terapéutico , Terapia Combinada , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
In obesity, inflammation of white adipose tissue (AT) is associated with diminished generation of beige adipocytes ('beige adipogenesis'), a thermogenic and energy-dissipating function mediated by beige adipocytes that express the uncoupling protein UCP1. Here we delineated an inflammation-driven inhibitory mechanism of beige adipogenesis in obesity that required direct adhesive interactions between macrophages and adipocytes mediated by the integrin α4 and its counter-receptor VCAM-1, respectively; expression of the latter was upregulated in obesity. This adhesive interaction reciprocally and concomitantly modulated inflammatory activation of macrophages and downregulation of UCP1 expression dependent on the kinase Erk in adipocytes. Genetic or pharmacological inactivation of the integrin α4 in mice resulted in elevated expression of UCP1 and beige adipogenesis of subcutaneous AT in obesity. Our findings, established in both mouse systems and human systems, reveal a self-sustained cycle of inflammation-driven impairment of beige adipogenesis in obesity.
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Adipocitos Beige , Adipogénesis/inmunología , Tejido Adiposo Blanco/inmunología , Diferenciación Celular/inmunología , Inflamación/inmunología , Macrófagos/inmunología , Obesidad/inmunología , Células 3T3-L1 , Adipocitos/inmunología , Adipocitos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Adhesión Celular/inmunología , Dieta Alta en Grasa , Regulación hacia Abajo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Retroalimentación , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Immunoblotting , Integrina alfa4/genética , Macrófagos/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Monocitos/inmunología , Obesidad/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Grasa Subcutánea , Linfocitos T/inmunología , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/metabolismo , Adulto JovenRESUMEN
Adipose tissue is a major site of energy storage and has a role in the regulation of metabolism through the release of adipokines. Here we show that mice with an adipose-tissue-specific knockout of the microRNA (miRNA)-processing enzyme Dicer (ADicerKO), as well as humans with lipodystrophy, exhibit a substantial decrease in levels of circulating exosomal miRNAs. Transplantation of both white and brown adipose tissue-brown especially-into ADicerKO mice restores the level of numerous circulating miRNAs that are associated with an improvement in glucose tolerance and a reduction in hepatic Fgf21 mRNA and circulating FGF21. This gene regulation can be mimicked by the administration of normal, but not ADicerKO, serum exosomes. Expression of a human-specific miRNA in the brown adipose tissue of one mouse in vivo can also regulate its 3' UTR reporter in the liver of another mouse through serum exosomal transfer. Thus, adipose tissue constitutes an important source of circulating exosomal miRNAs, which can regulate gene expression in distant tissues and thereby serve as a previously undescribed form of adipokine.
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Tejido Adiposo/metabolismo , Regulación de la Expresión Génica , MicroARNs/sangre , MicroARNs/metabolismo , Comunicación Paracrina , Regiones no Traducidas 3'/genética , Adipoquinas/metabolismo , Tejido Adiposo/trasplante , Tejido Adiposo Pardo/citología , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/trasplante , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/trasplante , Animales , Exosomas/genética , Factores de Crecimiento de Fibroblastos/sangre , Factores de Crecimiento de Fibroblastos/genética , Genes Reporteros/genética , Prueba de Tolerancia a la Glucosa , Hígado/metabolismo , Masculino , Ratones , MicroARNs/genética , Modelos Biológicos , Especificidad de Órganos/genética , ARN Mensajero/genética , Ribonucleasa III/deficiencia , Ribonucleasa III/genética , Transcripción GenéticaRESUMEN
Insulin and IGF1 signaling are important for adipose tissue development and function; however, their role in mature adipocytes is unclear. Mice with a tamoxifen-inducible knockout of insulin and/or IGF1 receptors (IR/IGF1R) demonstrate a rapid loss of white and brown fat due to increased lipolysis and adipocyte apoptosis. This results in insulin resistance, glucose intolerance, hepatosteatosis, islet hyperplasia with hyperinsulinemia, and cold intolerance. This phenotype, however, resolves over 10-30 days due to a proliferation of preadipocytes and rapid regeneration of both brown and white adipocytes as identified by mTmG lineage tracing. This cycle can be repeated with a second round of receptor inactivation. Leptin administration prior to tamoxifen treatment blocks development of the metabolic syndrome without affecting adipocyte loss or regeneration. Thus, IR is critical in adipocyte maintenance, and this loss of adipose tissue stimulates regeneration of brown/white fat and reversal of metabolic syndrome associated with fat loss.
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Adipocitos/metabolismo , Eliminación de Gen , Síndrome Metabólico/metabolismo , Receptor de Insulina/metabolismo , Adipocitos/efectos de los fármacos , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/patología , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/patología , Animales , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Hígado Graso/complicaciones , Hígado Graso/metabolismo , Hígado Graso/patología , Intolerancia a la Glucosa/complicaciones , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/patología , Hiperglucemia/complicaciones , Hiperglucemia/metabolismo , Hiperglucemia/patología , Insulina/metabolismo , Resistencia a la Insulina , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Leptina/farmacología , Lipodistrofia/complicaciones , Lipodistrofia/metabolismo , Lipodistrofia/patología , Síndrome Metabólico/complicaciones , Ratones , Especificidad de Órganos/efectos de los fármacos , Receptor IGF Tipo 1/metabolismo , Regeneración/efectos de los fármacos , Tamoxifeno/farmacologíaRESUMEN
Angiogenesis is a central regulator for white (WAT) and brown (BAT) adipose tissue adaptation in the course of obesity. Here we show that deletion of hypoxia-inducible factor 2α (HIF2α) in adipocytes (by using Fabp4-Cre transgenic mice) but not in myeloid or endothelial cells negatively impacted WAT angiogenesis and promoted WAT inflammation, WAT dysfunction, hepatosteatosis, and systemic insulin resistance in obesity. Importantly, adipocyte HIF2α regulated vascular endothelial growth factor (VEGF) expression and angiogenesis of obese BAT as well as its thermogenic function. Consistently, obese adipocyte-specific HIF2α-deficient mice displayed BAT dysregulation, associated with reduced levels of uncoupling protein 1 (UCP1) and a dysfunctional thermogenic response to cold exposure. VEGF administration reversed WAT and BAT inflammation and BAT dysfunction in adipocyte HIF2α-deficient mice. Together, our findings show that adipocyte HIF2α is protective against maladaptation to obesity and metabolic dysregulation by promoting angiogenesis in both WAT and BAT and by counteracting obesity-mediated BAT dysfunction.
Asunto(s)
Adipocitos/patología , Tejido Adiposo Pardo/fisiopatología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Eliminación de Gen , Obesidad/genética , Obesidad/fisiopatología , Adipocitos/metabolismo , Tejido Adiposo Pardo/irrigación sanguínea , Tejido Adiposo Pardo/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Inflamación/complicaciones , Canales Iónicos/metabolismo , Masculino , Ratones , Ratones Noqueados , Proteínas Mitocondriales/metabolismo , Neovascularización Fisiológica , Obesidad/complicaciones , Obesidad/metabolismo , Termogénesis , Proteína Desacopladora 1 , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The neural crest-derived adrenal medulla is closely related to the sympathetic nervous system; however, unlike neural tissue, it is characterized by high plasticity which suggests the involvement of stem cells. Here, we show that a defined pool of glia-like nestin-expressing progenitor cells in the adult adrenal medulla contributes to this plasticity. These glia-like cells have features of adrenomedullary sustentacular cells, are multipotent, and are able to differentiate into chromaffin cells and neurons. The adrenal is central to the body's response to stress making its proper adaptation critical to maintaining homeostasis. Our results from stress experiments in vivo show the activation and differentiation of these progenitors into new chromaffin cells. In summary, we demonstrate the involvement of a new glia-like multipotent stem cell population in adrenal tissue adaptation. Our data also suggest the contribution of stem and progenitor cells in the adaptation of neuroendocrine tissue function in general.