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1.
Theranostics ; 11(14): 6983-7004, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34093866

RESUMEN

Rationale: We recently demonstrated that the 'Metabesity' factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes. HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1-CoREST complex but its expression pattern and function in adult brain remains unknown. Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues. Methods: HMG20A expression profile was assessed by quantitative PCR (QT-PCR), Western blotting and/or immunofluorescence in: 1) the hypothalamus of mice exposed or not to either a high-fat diet or a high-fat high-sucrose regimen, 2) human blood leukocytes and adipose tissue obtained from healthy or diabetic individuals and 3) primary mouse hypothalamic astrocytes exposed to either high glucose or palmitate. RNA-seq and cell metabolic parameters were performed on astrocytes treated or not with a siHMG20A. Astrocyte-mediated neuronal survival was evaluated using conditioned media from siHMG20A-treated astrocytes. The impact of ORY1001, an inhibitor of the LSD1-CoREST complex, on HMG20A expression, reactive astrogliosis and glucose metabolism was evaluated in vitro and in vivo in high-fat high-sucrose fed mice. Results: We show that Hmg20a is predominantly expressed in hypothalamic astrocytes, the main nutrient-sensing cell type of the brain. HMG20A expression was upregulated in diet-induced obesity and glucose intolerant mice, correlating with increased transcript levels of Gfap and Il1b indicative of inflammation and reactive astrogliosis. Hmg20a transcript levels were also increased in adipose tissue of obese non-diabetic individuals as compared to obese diabetic patients. HMG20A silencing in astrocytes resulted in repression of inflammatory, cholesterol biogenesis and epithelial-to-mesenchymal transition pathways which are hallmarks of reactive astrogliosis. Accordingly, HMG20A depleted astrocytes exhibited reduced mitochondrial bioenergetics and increased susceptibility to apoptosis. Neuron viability was also hindered in HMG20A-depleted astrocyte-derived conditioned media. ORY1001 treatment rescued expression of reactive astrogliosis-linked genes in HMG20A ablated astrocytes while enhancing cell surface area, GFAP intensity and STAT3 expression in healthy astrocytes, mimicking the effect of HMG20A. Furthermore, ORY1001 treatment protected against obesity-associated glucose intolerance in mice correlating with a regression of hypothalamic HMG20A expression, indicative of reactive astrogliosis attenuation with improved health status. Conclusion: HMG20A coordinates the astrocyte polarization state. Under physiological pressure such as obesity and insulin resistance that induces low grade inflammation, HMG20A expression is increased to induce reactive astrogliosis in an attempt to preserve the neuronal network and re-establish glucose homeostasis. Nonetheless, a chronic metabesity state or functional mutations will result in lower levels of HMG20A, failure to promote reactive astrogliosis and increase susceptibility of neurons to stress-induced apoptosis. Such effects could be reversed by ORY1001 treatment both in vitro and in vivo, paving the way for a new therapeutic approach for Type 2 Diabetes Mellitus.


Asunto(s)
Astrocitos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Gliosis/metabolismo , Proteínas del Grupo de Alta Movilidad/metabolismo , Hipotálamo/metabolismo , Neuronas/metabolismo , Obesidad/metabolismo , Tejido Adiposo/metabolismo , Adulto , Animales , Supervivencia Celular/efectos de los fármacos , Proteínas Co-Represoras/antagonistas & inhibidores , Dieta Alta en Grasa , Proteína Ácida Fibrilar de la Glía/metabolismo , Glucosa/metabolismo , Proteínas del Grupo de Alta Movilidad/antagonistas & inhibidores , Proteínas del Grupo de Alta Movilidad/genética , Histona Demetilasas/antagonistas & inhibidores , Humanos , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Mitocondrias/genética , Mitocondrias/metabolismo , Proteínas del Tejido Nervioso/antagonistas & inhibidores , ARN Interferente Pequeño , RNA-Seq
2.
Genes (Basel) ; 10(5)2019 05 08.
Artículo en Inglés | MEDLINE | ID: mdl-31072002

RESUMEN

The high prevalence of type 2 diabetes mellitus (T2DM), together with the fact that current treatments are only palliative and do not avoid major secondary complications, reveals the need for novel approaches to treat the cause of this disease. Efforts are currently underway to identify therapeutic targets implicated in either the regeneration or re-differentiation of a functional pancreatic islet ß-cell mass to restore insulin levels and normoglycemia. However, T2DM is not only caused by failures in ß-cells but also by dysfunctions in the central nervous system (CNS), especially in the hypothalamus and brainstem. Herein, we review the physiological contribution of hypothalamic neuronal and glial populations, particularly astrocytes, in the control of the systemic response that regulates blood glucose levels. The glucosensing capacity of hypothalamic astrocytes, together with their regulation by metabolic hormones, highlights the relevance of these cells in the control of glucose homeostasis. Moreover, the critical role of astrocytes in the response to inflammation, a process associated with obesity and T2DM, further emphasizes the importance of these cells as novel targets to stimulate the CNS in response to metabesity (over-nutrition-derived metabolic dysfunctions). We suggest that novel T2DM therapies should aim at stimulating the CNS astrocytic response, as well as recovering the functional pancreatic ß-cell mass. Whether or not a common factor expressed in both cell types can be feasibly targeted is also discussed.


Asunto(s)
Encéfalo/metabolismo , Glucosa/metabolismo , Islotes Pancreáticos/metabolismo , Enfermedades Metabólicas/metabolismo , Animales , Astrocitos/metabolismo , Metabolismo Energético , Homeostasis , Humanos
3.
Nat Commun ; 9(1): 1488, 2018 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-29662071

RESUMEN

Type 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by immune cells. Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative targets to dampen the immune process, while promoting beta cell survival and function. Liver receptor homologue-1 (LRH-1) is a nuclear receptor that represses inflammation in digestive organs, and protects pancreatic islets against apoptosis. Here, we show that BL001, a small LRH-1 agonist, impedes hyperglycemia progression and the immune-dependent inflammation of pancreas in murine models of T1DM, and beta cell apoptosis in islets of type 2 diabetic patients, while increasing beta cell mass and insulin secretion. Thus, we suggest that LRH-1 agonism favors a dialogue between immune and islet cells, which could be druggable to protect against diabetes mellitus.


Asunto(s)
Comunicación Celular/efectos de los fármacos , Diabetes Mellitus Experimental/terapia , Hipoglucemiantes/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Fenalenos/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Animales , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/patología , Femenino , Regulación de la Expresión Génica , Humanos , Inmunidad Innata , Insulina/metabolismo , Células Secretoras de Insulina/inmunología , Células Secretoras de Insulina/patología , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/inmunología , Islotes Pancreáticos/patología , Trasplante de Islotes Pancreáticos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/inmunología , Estreptozocina , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Trasplante Heterólogo
4.
Cell Death Dis ; 9(3): 279, 2018 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-29449530

RESUMEN

HMG20A (also known as iBRAF) is a chromatin factor involved in neuronal differentiation and maturation. Recently small nucleotide polymorphisms (SNPs) in the HMG20A gene have been linked to type 2 diabetes mellitus (T2DM) yet neither expression nor function of this T2DM candidate gene in islets is known. Herein we demonstrate that HMG20A is expressed in both human and mouse islets and that levels are decreased in islets of T2DM donors as compared to islets from non-diabetic donors. In vitro studies in mouse and human islets demonstrated that glucose transiently increased HMG20A transcript levels, a result also observed in islets of gestating mice. In contrast, HMG20A expression was not altered in islets from diet-induced obese and pre-diabetic mice. The T2DM-associated rs7119 SNP, located in the 3' UTR of the HMG20A transcript reduced the luciferase activity of a reporter construct in the human beta 1.1E7 cell line. Depletion of Hmg20a in the rat INS-1E cell line resulted in decreased expression levels of its neuronal target gene NeuroD whereas Rest and Pax4 were increased. Chromatin immunoprecipitation confirmed the interaction of HMG20A with the Pax4 gene promoter. Expression levels of Mafa, Glucokinase, and Insulin were also inhibited. Furthermore, glucose-induced insulin secretion was blunted in HMG20A-depleted islets. In summary, our data demonstrate that HMG20A expression in islet is essential for metabolism-insulin secretion coupling via the coordinated regulation of key islet-enriched genes such as NeuroD and Mafa and that depletion induces expression of genes such as Pax4 and Rest implicated in beta cell de-differentiation. More importantly we assign to the T2DM-linked rs7119 SNP the functional consequence of reducing HMG20A expression likely translating to impaired beta cell mature function.


Asunto(s)
Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/metabolismo , Proteínas del Grupo de Alta Movilidad/metabolismo , Células Secretoras de Insulina/metabolismo , Polimorfismo de Nucleótido Simple , Regiones no Traducidas 3' , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Glucemia/metabolismo , Línea Celular Tumoral , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Femenino , Predisposición Genética a la Enfermedad , Proteínas del Grupo de Alta Movilidad/genética , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Células Secretoras de Insulina/patología , Lípidos/sangre , Masculino , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Factores de Transcripción Paired Box/genética , Factores de Transcripción Paired Box/metabolismo , Fenotipo , Ratas
5.
Biol Sex Differ ; 7: 26, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27195103

RESUMEN

BACKGROUND: Males and females respond differently to diverse metabolic situations. Being raised in a small litter is reported to cause overnutrition that increases weight gain and predisposes an individual to metabolic disturbances in adulthood; however, existing data are inconsistent. Indeed, significant weight gain and/or metabolic disturbances, such as hyperinsulinemia and hyperleptinemia, are sometimes not encountered. We hypothesized that these inconsistencies could be due to the animal's sex and/or age at which metabolic parameters are measured. METHODS: To analyze the effects of neonatal overnutrition, male and female Wistar rats were raised in litters of 4 or 12 pups/dam and killed at postnatal days (PND) 10, 21, 30, 50, 85, or 150. In a second study to determine if neonatal sex steroid levels influence sex differences in metabolic parameters, female rats were treated with testosterone on PND1. Effects on weight, length, fat pads, adipokine production, and serum levels of glucose, metabolic hormones, and cytokines were analyzed in both studies. RESULTS: By PND10, both males and females raised in small litters had increased body weight, body length, adiposity, and serum glucose, insulin, leptin, and adiponectin levels. Females had a greater increase in inguinal fat, and males had higher expression of leptin messenger RNA (mRNA) and serum insulin, as well as increased testosterone levels. Most of the litter size effects diminished or disappeared after weaning and reappeared during adulthood in males, with sex differences in body size and adiposity being apparent postpubertally. Treatment of females with testosterone on PND1 tended to masculinize some metabolic parameters in adulthood such as increased body weight and serum leptin levels. CONCLUSIONS: Our results indicate that (1) both sex and age determine the response to neonatal overnutrition; (2) differences in neonatal sex steroid levels may participate in the development of sex differences in metabolic parameters in adulthood and possibly in the response to neonatal overnutrition; and (3) the comparison of circulating hormone and cytokine levels, even in normal control animals, should take into consideration the early neonatal nutritional environment.

6.
Nat Commun ; 7: 10782, 2016 Feb 29.
Artículo en Inglés | MEDLINE | ID: mdl-26923837

RESUMEN

Hypothalamic leptin signalling has a key role in food intake and energy-balance control and is often impaired in obese individuals. Here we identify histone deacetylase 5 (HDAC5) as a regulator of leptin signalling and organismal energy balance. Global HDAC5 KO mice have increased food intake and greater diet-induced obesity when fed high-fat diet. Pharmacological and genetic inhibition of HDAC5 activity in the mediobasal hypothalamus increases food intake and modulates pathways implicated in leptin signalling. We show HDAC5 directly regulates STAT3 localization and transcriptional activity via reciprocal STAT3 deacetylation at Lys685 and phosphorylation at Tyr705. In vivo, leptin sensitivity is substantially impaired in HDAC5 loss-of-function mice. Hypothalamic HDAC5 overexpression improves leptin action and partially protects against HFD-induced leptin resistance and obesity. Overall, our data suggest that hypothalamic HDAC5 activity is a regulator of leptin signalling that adapts food intake and body weight to our dietary environment.


Asunto(s)
Hipotálamo/metabolismo , Leptina/metabolismo , Animales , Glucemia , Línea Celular , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Prueba de Tolerancia a la Glucosa , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Infusiones Intraventriculares , Resistencia a la Insulina , Captura por Microdisección con Láser , Leptina/genética , Masculino , Hormonas Estimuladoras de los Melanocitos/farmacología , Ratones , Ratones Endogámicos , Ratones Noqueados , Neuronas/fisiología , Ratas , Ratas Wistar
7.
Sci Rep ; 6: 23673, 2016 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-27026049

RESUMEN

Hypothalamic astrocytes can respond to metabolic signals, such as leptin and insulin, to modulate adjacent neuronal circuits and systemic metabolism. Ghrelin regulates appetite, adiposity and glucose metabolism, but little is known regarding the response of astrocytes to this orexigenic hormone. We have used both in vivo and in vitro approaches to demonstrate that acylated ghrelin (acyl-ghrelin) rapidly stimulates glutamate transporter expression and glutamate uptake by astrocytes. Moreover, acyl-ghrelin rapidly reduces glucose transporter (GLUT) 2 levels and glucose uptake by these glial cells. Glutamine synthetase and lactate dehydrogenase decrease, while glycogen phosphorylase and lactate transporters increase in response to acyl-ghrelin, suggesting a change in glutamate and glucose metabolism, as well as glycogen storage by astrocytes. These effects are partially mediated through ghrelin receptor 1A (GHSR-1A) as astrocytes do not respond equally to desacyl-ghrelin, an isoform that does not activate GHSR-1A. Moreover, primary astrocyte cultures from GHSR-1A knock-out mice do not change glutamate transporter or GLUT2 levels in response to acyl-ghrelin. Our results indicate that acyl-ghrelin may mediate part of its metabolic actions through modulation of hypothalamic astrocytes and that this effect could involve astrocyte mediated changes in local glucose and glutamate metabolism that alter the signals/nutrients reaching neighboring neurons.


Asunto(s)
Astrocitos/metabolismo , Ghrelina/fisiología , Transportador de Glucosa de Tipo 2/metabolismo , Receptores de Ghrelina/metabolismo , Animales , Células Cultivadas , Glucosa/metabolismo , Ácido Glutámico/metabolismo , Hipotálamo/citología , Masculino , Ratones Noqueados , Ratas Wistar , Receptores de Ghrelina/genética
8.
Diabetologia ; 59(4): 755-65, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26813254

RESUMEN

AIMS/HYPOTHESIS: A strategy to enhance pancreatic islet functional beta cell mass (BCM) while restraining inflammation, through the manipulation of molecular and cellular targets, would provide a means to counteract the deteriorating glycaemic control associated with diabetes mellitus. The aims of the current study were to investigate the therapeutic potential of such a target, the islet-enriched and diabetes-linked transcription factor paired box 4 (PAX4), to restrain experimental autoimmune diabetes (EAD) in the RIP-B7.1 mouse model background and to characterise putative cellular mechanisms associated with preserved BCM. METHODS: Two groups of RIP-B7.1 mice were genetically engineered to: (1) conditionally express either PAX4 (BPTL) or its diabetes-linked mutant variant R129W (mutBPTL) using doxycycline (DOX); and (2) constitutively express luciferase in beta cells through the use of RIP. Mice were treated or not with DOX, and EAD was induced by immunisation with a murine preproinsulin II cDNA expression plasmid. The development of hyperglycaemia was monitored for up to 4 weeks following immunisation and alterations in the BCM were assessed weekly by non-invasive in vivo bioluminescence intensity (BLI). In parallel, BCM, islet cell proliferation and apoptosis were evaluated by immunocytochemistry. Alterations in PAX4- and PAX4R129W-mediated islet gene expression were investigated by microarray profiling. PAX4 preservation of endoplasmic reticulum (ER) homeostasis was assessed using thapsigargin, electron microscopy and intracellular calcium measurements. RESULTS: PAX4 overexpression blunted EAD, whereas the diabetes-linked mutant variant PAX4R129W did not convey protection. PAX4-expressing islets exhibited reduced insulitis and decreased beta cell apoptosis, correlating with diminished DNA damage and increased islet cell proliferation. Microarray profiling revealed that PAX4 but not PAX4R129W targeted expression of genes implicated in cell cycle and ER homeostasis. Consistent with the latter, islets overexpressing PAX4 were protected against thapsigargin-mediated ER-stress-related apoptosis. Luminal swelling associated with ER stress induced by thapsigargin was rescued in PAX4-overexpressing beta cells, correlating with preserved cytosolic calcium oscillations in response to glucose. In contrast, RNA interference mediated repression of PAX4-sensitised MIN6 cells to thapsigargin cell death. CONCLUSIONS/INTERPRETATION: The coordinated regulation of distinct cellular pathways particularly related to ER homeostasis by PAX4 not achieved by the mutant variant PAX4R129W alleviates beta cell degeneration and protects against diabetes mellitus. The raw data for the RNA microarray described herein are accessible in the Gene Expression Omnibus database under accession number GSE62846.


Asunto(s)
Diabetes Mellitus Tipo 1/metabolismo , Retículo Endoplásmico/metabolismo , Proteínas de Homeodominio/metabolismo , Células Secretoras de Insulina/metabolismo , Factores de Transcripción Paired Box/metabolismo , Animales , Apoptosis/fisiología , Proliferación Celular/fisiología , Diabetes Mellitus Tipo 1/patología , Femenino , Células Secretoras de Insulina/patología , Masculino , Ratones , Ratones Mutantes
9.
Sci Rep ; 5: 15672, 2015 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-26503027

RESUMEN

PAX4 is a key regulator of pancreatic islet development whilst in adult acute overexpression protects ß-cells against stress-induced apoptosis and stimulates proliferation. Nonetheless, sustained PAX4 expression promotes ß-cell dedifferentiation and hyperglycemia, mimicking ß-cell failure in diabetic patients. Herein, we study mechanisms that allow stringent PAX4 regulation endowing favorable ß-cell adaptation in response to changing environment without loss of identity. To this end, PAX4 expression was monitored using a mouse bearing the enhanced green fluorescent protein (GFP) and cre recombinase construct under the control of the islet specific pax4 promoter. GFP was detected in 30% of islet cells predominantly composed of PAX4-enriched ß-cells that responded to glucose-induced insulin secretion. Lineage tracing demonstrated that all islet cells were derived from PAX4(+) progenitor cells but that GFP expression was confined to a subpopulation at birth which declined with age correlating with reduced replication. However, this GFP(+) subpopulation expanded during pregnancy, a state of active ß-cell replication. Accordingly, enhanced proliferation was exclusively detected in GFP(+) cells consistent with cell cycle genes being stimulated in PAX4-overexpressing islets. Under stress conditions, GFP(+) cells were more resistant to apoptosis than their GFP(-) counterparts. Our data suggest PAX4 defines an expandable ß-cell sub population within adult islets.


Asunto(s)
Apoptosis/fisiología , Regulación de la Expresión Génica/fisiología , Proteínas de Homeodominio/metabolismo , Células Secretoras de Insulina/citología , Factores de Transcripción Paired Box/metabolismo , Animales , Desdiferenciación Celular/fisiología , Linaje de la Célula , Proliferación Celular/fisiología , Diabetes Mellitus/patología , Proteínas Fluorescentes Verdes/genética , Proteínas de Homeodominio/genética , Hiperglucemia/patología , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/clasificación , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Factores de Transcripción Paired Box/genética , Regiones Promotoras Genéticas/genética
10.
Curr Gene Ther ; 15(4): 436-46, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26122098

RESUMEN

Successful normalization of blood glucose in patients transplanted with pancreatic islets isolated from cadaveric donors established the proof-of-concept that Type 1 Diabetes Mellitus is a curable disease. Nonetheless, major caveats to the widespread use of this cell therapy approach have been the shortage of islets combined with the low viability and functional rates subsequent to transplantation. Gene therapy targeted to enhance survival and performance prior to transplantation could offer a feasible approach to circumvent these issues and sustain a durable functional ß-cell mass in vivo. However, efficient and safe delivery of nucleic acids to intact islet remains a challenging task. Here we describe a simple and easy-to-use lentiviral transduction protocol that allows the transduction of approximately 80 % of mouse and human islet cells while preserving islet architecture, metabolic function and glucose-dependent stimulation of insulin secretion. Our protocol will facilitate to fully determine the potential of gene expression modulation of therapeutically promising targets in entire pancreatic islets for xenotransplantation purposes.


Asunto(s)
Vectores Genéticos , Islotes Pancreáticos/fisiología , Lentivirus/genética , Transducción Genética/métodos , Animales , Células Cultivadas , Citometría de Flujo , Glucagón/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Insulina/metabolismo , Islotes Pancreáticos/citología , Masculino , Ratones Endogámicos C57BL
11.
Endocrinology ; 156(4): 1272-82, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25574789

RESUMEN

Pubertal onset may be advanced by obesity, with leptin potentially acting as a permissive factor. We hypothesized that having increased body weight (BW) prepubertally affects the ability of leptin to activate intracellular signaling pathways and modulate the expression of hypothalamic neuropeptides involved in reproduction and metabolism. Because being raised in small litters (SLs) tends to increase BW at weaning, female rats were raised in litters of 4 or large litters (LLs) of 12 pups. Leptin (3 µg/g BW) or vehicle (saline) was injected sc at postnatal day (PND) 21 and 30. Rats raised in SLs weighed more at both ages, but relative visceral and subcutaneous fat was increased only on PND21. Serum leptin levels were not different at PND21 or PND30. At PND21, key elements of intracellular leptin signaling (phosphorylated signal transducer and activator of transcription 3 and phosphorylated Akt [p-Akt]) were lower in SL than in LL rats. Leptin injection stimulated phosphorylated signal transducer and activator of transcription 3 in both groups, with a greater increase in LL, whereas p-Akt rose only in SL rats. At PND30, basal leptin signaling did not differ between LL and SL rats. Leptin activation of Akt was similar at 45 minutes, but at 2 hours p-AKT levels were higher in SL than in LL rats, as was the decrease in neuropeptide Y mRNA and increase in pro-opiomelanocortin mRNA levels. No change in the reproductive axis was found. Thus, being raised in SLs increases BW and visceral body fat content, fails to increase plasma leptin concentrations, and increases the leptin responsiveness of both neuropeptide Y and pro-opiomelanocortin cells in the prepubertal hypothalamus.


Asunto(s)
Peso Corporal/fisiología , Leptina/farmacología , Neuronas/metabolismo , Neuropéptido Y/metabolismo , Proopiomelanocortina/metabolismo , Maduración Sexual/fisiología , Animales , Femenino , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Leptina/sangre , Neuronas/efectos de los fármacos , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Receptores de Leptina/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología
12.
Cell Rep ; 9(2): 633-45, 2014 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-25373903

RESUMEN

High-fat diets (HFDs) lead to obesity and inflammation in the central nervous system (CNS). Estrogens and estrogen receptor α (ERα) protect premenopausal females from the metabolic complications of inflammation and obesity-related disease. Here, we demonstrate that hypothalamic PGC-1α regulates ERα and inflammation in vivo. HFD significantly increased palmitic acid (PA) and sphingolipids in the CNS of male mice when compared to female mice. PA, in vitro, and HFD, in vivo, reduced PGC-1α and ERα in hypothalamic neurons and astrocytes of male mice and promoted inflammation. PGC-1α depletion with ERα overexpression significantly inhibited PA-induced inflammation, confirming that ERα is a critical determinant of the anti-inflammatory response. Physiologic relevance of ERα-regulated inflammation was demonstrated by reduced myocardial function in male, but not female, mice following chronic HFD exposure. Our findings show that HFD/PA reduces PGC-1α and ERα, promoting inflammation and decrements in myocardial function in a sex-specific way.


Asunto(s)
Dieta Alta en Grasa/efectos adversos , Receptor alfa de Estrógeno/metabolismo , Hipotálamo/metabolismo , Factores de Transcripción/metabolismo , Animales , Astrocitos/metabolismo , Línea Celular , Receptor alfa de Estrógeno/genética , Femenino , Hipotálamo/citología , Hipotálamo/efectos de los fármacos , Inflamación/etiología , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Ácido Palmítico/efectos adversos , Ácido Palmítico/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Factores Sexuales , Esfingolípidos/metabolismo , Factores de Transcripción/genética , Disfunción Ventricular/etiología , Disfunción Ventricular/metabolismo
13.
Endocrinology ; 155(8): 2868-80, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24848869

RESUMEN

Ghrelin is an endogenous hormone that stimulates appetite and adipose tissue accrual. Both the acylated (AG) and non-acylated (DAG) isoforms of this hormone are also reported to exert anti-inflammatory and protective effects systemically and in the central nervous system. As inflammatory processes have been implicated in obesity-associated secondary complications, we hypothesized that this natural appetite stimulator may protect against negative consequences resulting from excessive food intake. Adult male Wistar rats were treated icv (5 µg/day) with AG, DAG, the ghrelin mimetic GH-releasing peptide (GHRP)-6, AG, and pair-fed with controls (AG-pf) or saline for 14 days. Regardless of food intake AG increased visceral adipose tissue (VAT) and decreased circulating cytokine levels. However, AG reduced cytokine production in VAT only in rats fed ad libitum. Hypothalamic cytokine production was increased in AG-treated rats fed ad libitum and by DAG, but intracellular inflammatory signaling pathways associated with insulin and leptin resistance were unaffected. Gliosis was not observed in response to any treatment as glial markers were either reduced or unaffected. AG, DAG, and GHRP-6 stimulated production of hypothalamic insulin like-growth factor I that is involved in cell protective mechanisms. In hypothalamic astrocyte cell cultures AG decreased tumor necrosis factorα and DAG decreased interleukin-1ß mRNA levels, suggesting direct anti-inflammatory effects on astrocytes. Thus, whereas ghrelin stimulates food intake and weight gain, it may also induce mechanisms of cell protection that help to detour or delay systemic inflammatory responses and hypothalamic gliosis due to excess weight gain, as well as its associated pathologies.


Asunto(s)
Ingestión de Alimentos/fisiología , Ghrelina/fisiología , Hipotálamo/metabolismo , Mediadores de Inflamación/metabolismo , Aumento de Peso/fisiología , Acilación , Adiposidad , Animales , Citocinas/metabolismo , Hipotálamo/patología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Ratas , Ratas Wistar
14.
Adipocyte ; 2(3): 128-34, 2013 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-23991358

RESUMEN

Obesity and its associated secondary complications are active areas of investigation in search of effective treatments. As a result of this intensified research numerous differences between males and females at all levels of metabolic control have come to the forefront. These differences include not only the amount and distribution of adipose tissue, but also differences in its metabolic capacity and functions between the sexes. Here, we review some of the recent advances in our understanding of these dimorphisms and emphasize the fact that these differences between males and females must be taken into consideration in hopes of obtaining successful treatments for both sexes.

15.
Endocrinology ; 154(7): 2318-30, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23671260

RESUMEN

Hypothalamic inflammation and gliosis are proposed to participate in the pathogenesis of high-fat diet-induced obesity. Because other factors and nutrients also induce weight gain and adiposity, we analyzed the inflammatory and glial responses to a sucrose (S)-enriched diet. Neonatal overnutrition (NON) exacerbates weight gain in response to metabolic challenges; thus, we compared the inflammatory response of male Wistar rats with NON (4 pups/litter) and controls (12 pups/litter) to increased S intake. At weaning rats received water or a 33% sucrose solution and normal chow ad libitum for 2 months. Sucrose increased serum IL-1ß and -6 and hypothalamic IL-6 mRNA levels in NON and TNFα mRNA levels in control and NON rats, whereas NON alone had no effect. The astrocyte marker glial fibrillary acidic protein was increased by NON but decreased by S. This was associated with hypothalamic nuclei specific changes in glial fibrillary acidic protein-positive cell number and morphology. Sucrose increased the number of microglia and phosphorylation of inhibitor of -κB and c-Jun N-terminal kinase in control but not NON rats, with no effect on microglia activation markers. Proteins highly expressed in astrocytes (glutamate, glucose, and lactate transporters) were increased by NON but not S, with no increase in vimentin expression in astrocytes, further suggesting that S-induced adiposity is not associated with hypothalamic astrogliosis. Hence, activation of hypothalamic inflammatory processes and gliosis depend not only on weight gain but also on the diet inducing this weight gain and the early nutritional status. These diverse inflammatory processes could indicate a differential disposition to obesity-induced pathologies.


Asunto(s)
Gliosis/inducido químicamente , Hipotálamo/efectos de los fármacos , Hipotálamo/inmunología , Inflamación/inducido químicamente , Sacarosa/farmacología , Adiposidad/efectos de los fármacos , Animales , Animales Recién Nacidos , Astrocitos/citología , Astrocitos/efectos de los fármacos , Western Blotting , Hipotálamo/metabolismo , Inmunohistoquímica , Interleucina-1beta/sangre , Interleucina-6/sangre , Interleucina-6/genética , Masculino , Neuroglía/citología , Neuroglía/efectos de los fármacos , Ratas , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/genética , Aumento de Peso/efectos de los fármacos
16.
J Clin Invest ; 122(11): 3900-13, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23064363

RESUMEN

Glial cells perform critical functions that alter the metabolism and activity of neurons, and there is increasing interest in their role in appetite and energy balance. Leptin, a key regulator of appetite and metabolism, has previously been reported to influence glial structural proteins and morphology. Here, we demonstrate that metabolic status and leptin also modify astrocyte-specific glutamate and glucose transporters, indicating that metabolic signals influence synaptic efficacy and glucose uptake and, ultimately, neuronal function. We found that basal and glucose-stimulated electrical activity of hypothalamic proopiomelanocortin (POMC) neurons in mice were altered in the offspring of mothers fed a high-fat diet. In adulthood, increased body weight and fasting also altered the expression of glucose and glutamate transporters. These results demonstrate that whole-organism metabolism alters hypothalamic glial cell activity and suggest that these cells play an important role in the pathology of obesity.


Asunto(s)
Sistema de Transporte de Aminoácidos X-AG/metabolismo , Astrocitos/metabolismo , Grasas de la Dieta/efectos adversos , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Hipotálamo/metabolismo , Leptina/metabolismo , Obesidad/metabolismo , Animales , Astrocitos/patología , Grasas de la Dieta/farmacología , Hipotálamo/patología , Ratones , Neuronas/metabolismo , Neuronas/patología , Obesidad/inducido químicamente , Obesidad/patología , Proopiomelanocortina/metabolismo , Ratas , Ratas Wistar
17.
Am J Physiol Endocrinol Metab ; 302(12): E1586-98, 2012 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-22510708

RESUMEN

Both overnutrition and an incorrect nutrient balance have contributed to the rise in obesity. Moreover, it is now clear that poor nutrition during early life augments the possibility of excess weight gain in later years. Our aim was to determine how neonatal overnutrition affects later responses to a sucrose-enriched diet and whether this varies depending upon when the diet is introduced in postnatal life. Male Wistar rats raised in litters of four or 12 pups were given a 33% sucrose solution instead of water from weaning (day 21) or postnatal day (PND) 65. All rats received normal chow ad libitum until they were euthanized on PND 80. Body weight (BW) and food and liquid intake were monitored throughout the study. Fat mass, adipocyte morphology, serum biochemical and hormonal parameters, and hypothalamic neuropeptide mRNA levels were measured at study termination. Neonatal overnutrition increased food intake, BW, and leptin levels, induced adipocyte hypertrophy, and decreased total ghrelin levels. The sucrose-enriched diet increased total energy intake, adipose accrual, and leptin, adiponectin, and acylated ghrelin levels but decreased BW. Most of these responses were accentuated in neonatally overnourished rats, which also had increased insulin and triglyceride levels. However, long-term sucrose intake induced adipocyte hypertrophy in rats from normal-sized litters but not in neonatally overfed rats. The results reported here indicate that neonatal overnutrition increases the detrimental response to a diet rich in sucrose later in life. Moreover, the timing and duration of the exposure to a sucrose-enriched diet alter the adverse metabolic outcomes.


Asunto(s)
Tejido Adiposo/patología , Dieta , Sacarosa en la Dieta/farmacología , Hipernutrición/patología , Adiponectina/metabolismo , Animales , Animales Recién Nacidos , Proteínas Sanguíneas/metabolismo , Composición Corporal/fisiología , Colesterol/sangre , Corticosterona/metabolismo , Ingestión de Alimentos/fisiología , Ensayo de Inmunoadsorción Enzimática , Ácidos Grasos no Esterificados/sangre , Femenino , Ghrelina/metabolismo , Prueba de Tolerancia a la Glucosa , Glicerol/sangre , Insulina/metabolismo , Leptina/metabolismo , Masculino , Hipernutrición/psicología , Embarazo , Radioinmunoensayo , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Aumento de Peso/fisiología
18.
Obes Facts ; 5(1): 138-50, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22433625

RESUMEN

Leptin levels during the perinatal period are important for the development of metabolic systems involved in energy homeostasis. In rodents, there is a postnatal leptin surge, with circulating leptin levels increasing around postnatal day (PND) 5 and peaking between PND 9 and PND 10. At this time circulating leptin acts as an important trophic factor for the development of hypothalamic circuits that control energy homeostasis and food seeking and reward behaviors. Blunting the postnatal leptin surge results in long-term leptin insensitivity and increased susceptibility to diet-induced obesity during adulthood. Pharmacologically increased leptin levels in the postnatal period also have long-term effects on metabolism. Nevertheless, this effect is controversial as postnatal hyperleptinemia is reported to both increase and decrease the predisposition to obesity in adulthood. The different effects reported in the literature could be explained by the different moments at which this hormone was administered, suggesting that modifications of the neonatal leptin surge at specific time points could selectively affect the development of central and peripheral systems that are undergoing modifications at this moment resulting in different metabolic and behavioral outcomes. In addition, maternal nutrition and the hormonal environment during pregnancy and lactation may also modulate the offspring's response to postnatal modifications in leptin levels. This review highlights the importance of leptin levels during the perinatal period in the development of metabolic systems that control energy homeostasis and how modifications of these levels may induce long-lasting and potentially irreversible effects on metabolism.


Asunto(s)
Metabolismo Energético/fisiología , Hipotálamo , Leptina/sangre , Fenómenos Fisiologicos Nutricionales Maternos , Obesidad/etiología , Animales , Femenino , Humanos , Recién Nacido , Leptina/farmacología , Metaboloma , Obesidad/metabolismo , Embarazo
19.
Metabolism ; 61(6): 812-22, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22209665

RESUMEN

Long-term metabolic effects induced by early nutritional changes are suspected to differ between males and females, but few studies have analyzed both sexes simultaneously. We analyzed the consequences of neonatal nutritional changes on body weight (BW) and the adult response to a sucrose-enriched diet in both male and female rats. Litter size was manipulated at birth to induce over- and undernutrition (4 pups: L4; 12 pups: L12; 20 pups: L20). From 50 to 65 days of age, half of each group received a 33% sucrose solution instead of water. Serum leptin, insulin, and ghrelin levels were analyzed at day 65. At weaning, rats from L4 weighed more and those from L20 weighed less than controls (L12). Body weight was greater in L4 rats throughout the study and increased further compared with controls in adult life. L20 males ate less and gained less weight throughout the study, but L20 females had a significant catch-up in BW. Sucrose intake increased total energy consumption in all groups, but not BW gain, with L4 males and L4 and L20 females reducing weight gain. Yet, sucrose intake increased serum leptin levels, with this increase being significant in L4 and L20 males. Our results suggest that females are more capable than males of recuperating and maintaining a normal BW after reduced neonatal nutrition. Furthermore, increased sucrose intake does not increase BW, but could alter body composition as reflected by leptin levels, with the percentage of calories consumed in the form of sucrose being affected by sex and neonatal nutrition.


Asunto(s)
Peso Corporal/efectos de los fármacos , Carbohidratos de la Dieta/farmacología , Desnutrición/metabolismo , Estado Nutricional/fisiología , Hipernutrición/metabolismo , Sacarosa/farmacología , Animales , Animales Recién Nacidos/metabolismo , Peso Corporal/fisiología , Ingestión de Energía/efectos de los fármacos , Ingestión de Energía/fisiología , Femenino , Ghrelina/sangre , Insulina/sangre , Leptina/sangre , Masculino , Ratas , Factores Sexuales
20.
Mol Metab ; 1(1-2): 37-46, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-24024117

RESUMEN

Glia are the most abundant cell type in the brain and are indispensible for the normal execution of neuronal actions. They protect neurons from noxious insults and modulate synaptic transmission through affectation of synaptic inputs, release of glial transmitters and uptake of neurotransmitters from the synaptic cleft. They also transport nutrients and other circulating factors into the brain thus controlling the energy sources and signals reaching neurons. Moreover, glia express receptors for metabolic hormones, such as leptin and insulin, and can be activated in response to increased weight gain and dietary challenges. However, chronic glial activation can be detrimental to neurons, with hypothalamic astrocyte activation or gliosis suggested to be involved in the perpetuation of obesity and the onset of secondary complications. It is now accepted that glia may be a very important participant in metabolic control and a possible therapeutical target. Here we briefly review this rapidly advancing field.

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