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Astrocytes are no longer considered as passive support cells. In the hypothalamus, these glial cells actively participate in the control of appetite, energy expenditure, and the processes leading to obesity and its secondary complications. Here we briefly review studies supporting this conclusion and the advances made in understanding the underlying mechanisms.
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Astrocitos , Metabolismo Energético , Hipotálamo , Neuronas , Astrocitos/metabolismo , Astrocitos/fisiología , Hipotálamo/metabolismo , Hipotálamo/fisiología , Animales , Humanos , Neuronas/fisiología , Neuronas/metabolismo , Metabolismo Energético/fisiología , Obesidad/metabolismo , Obesidad/fisiopatologíaRESUMEN
Diets rich in saturated fats are more detrimental to health than those containing mono- or unsaturated fats. Fatty acids are an important source of energy, but they also relay information regarding nutritional status to hypothalamic metabolic circuits and when in excess can be detrimental to these circuits. Astrocytes are the main site of central fatty acid ß-oxidation, and hypothalamic astrocytes participate in energy homeostasis, in part by modulating hormonal and nutritional signals reaching metabolic neurons, as well as in the inflammatory response to high-fat diets. Thus, we hypothesized that how hypothalamic astrocytes process-specific fatty acids participates in determining the differential metabolic response and that this is sex dependent as males and females respond differently to high-fat diets. Male and female primary hypothalamic astrocyte cultures were treated with oleic acid (OA) or palmitic acid (PA) for 24 h, and an untargeted metabolomics study was performed. A clear predictive model for PA exposure was obtained, while the metabolome after OA exposure was not different from controls. The observed modifications in metabolites, as well as the expression levels of key metabolic enzymes, indicate a reduction in the activity of the Krebs and glutamate/glutamine cycles in response to PA. In addition, there were specific differences between the response of astrocytes from male and female mice, as well as between hypothalamic and cerebral cortical astrocytes. Thus, the response of hypothalamic astrocytes to specific fatty acids could result in differential impacts on surrounding metabolic neurons and resulting in varied systemic metabolic outcomes.
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Astrocitos , Hipotálamo , Ácido Oléico , Ácido Palmítico , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Ácido Oléico/farmacología , Femenino , Ácido Palmítico/farmacología , Hipotálamo/metabolismo , Hipotálamo/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Caracteres Sexuales , Células CultivadasRESUMEN
INTRODUCTION: Insulin-like growth factor (IGF)1 and IGF2 have neuroprotective effects, but less is known regarding how other members of the IGF system, including IGF binding proteins (IGFBPs) and the regulatory proteinase pappalysin-1 (PAPP-A) and its endogenous inhibitor stanniocalcin-2 (STC2) participate in this process. Here, we analyzed whether these members of the IGF system are modified in neurons and astrocytes in response to palmitic acid (PA), a fatty acid that induces cell stress when increased centrally. METHODS: Primary hypothalamic astrocyte cultures from male and female PND2 rats and the pro-opiomelanocortin (POMC) neuronal cell line, mHypoA-POMC/GFP-2, were treated with PA, IGF1 or both. To analyze the role of STC2 in astrocytes, siRNA assays were employed. RESULTS: In astrocytes of both sexes, PA rapidly increased cell stress factors followed by increased Pappa and Stc2 mRNA levels and then a decrease in Igf1, Igf2, and Igfbp2 expression and cell number. Exogenous IGF1 did not revert these effects. In mHypoA-POMC/GFP-2 neurons, PA reduced cell number and Pomc and Igf1 mRNA levels, and increased Igfbp2 and Stc2, again with no effect of exogenous IGF1. PA increased STC2 expression, but no effects of decreasing its levels by interference assays or exogenous STC2 treatment in astrocytes were found. CONCLUSIONS: The response of the IGF system to PA was cell and sex specific, but no protective effects of the IGFs were found. However, the modifications in hypothalamic PAPP-A and STC2 indicate that further studies are required to determine their role in the response to fatty acids and possibly in metabolic control.
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BACKGROUND: Development of obesity and its comorbidities is not only the result of excess energy intake, but also of dietary composition. Understanding how hypothalamic metabolic circuits interpret nutritional signals is fundamental to advance towards effective dietary interventions. OBJECTIVE: We aimed to determine the metabolic response to diets enriched in specific fatty acids. METHODS: Male mice received a diet enriched in unsaturated fatty acids (UOLF) or saturated fatty acids (SOLF) for 8 weeks. RESULTS: UOLF and SOLF mice gained more weight and adiposity, but with no difference between these two groups. Circulating leptin levels increased on both fatty acid-enriched diet, but were higher in UOLF mice, as were leptin mRNA levels in visceral adipose tissue. In contrast, serum non-esterified fatty acid levels only rose in SOLF mice. Hypothalamic mRNA levels of NPY decreased and of POMC increased in both UOLF and SOLF mice, but only SOLF mice showed signs of hypothalamic astrogliosis and affectation of central fatty acid metabolism. Exogenous leptin activated STAT3 in the hypothalamus of all groups, but the activation of AKT and mTOR and the decrease in AMPK activation in observed in controls and UOLF mice was not found in SOLF mice. CONCLUSIONS: Diets rich in fatty acids increase body weight and adiposity even if energy intake is not increased, while increased intake of saturated and unsaturated fatty acids differentially modify metabolic parameters that could underlie more long-term comorbidities. Thus, more understanding of how specific nutrients affect metabolism, weight gain, and obesity associated complications is necessary.
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Gliosis , Leptina , Ratones , Masculino , Animales , Gliosis/metabolismo , Grasas de la Dieta , Ácidos Grasos Insaturados/farmacología , Obesidad/metabolismo , Hipotálamo/metabolismo , Ácidos Grasos/metabolismo , ARN Mensajero/metabolismoRESUMEN
Aim: We aimed to investigate whether maternal malnutrition during gestation/lactation induces long-lasting changes on inflammation, lipid metabolism and endocannabinoid signaling in the adult offspring hypothalamus and the role of hypothalamic astrocytes in these changes.Methods: We analyzed the effects of a free-choice hypercaloric palatable diet (P) during (pre)gestation, lactation and/or post-weaning on inflammation, lipid metabolism and endogenous cannabinoid signaling in the adult offspring hypothalamus. We also evaluated the response of primary hypothalamic astrocytes to palmitic acid and anandamide.Results: Postnatal exposure to a P diet induced factors involved in hypothalamic inflammation (Tnfa and Il6) and gliosis (Gfap, vimentin and Iba1) in adult offspring, being more significant in females. In contrast, maternal P diet reduced factors involved in astrogliosis (vimentin), fatty acid oxidation (Cpt1a) and monounsaturated fatty acid synthesis (Scd1). These changes were accompanied by an increase in the expression of the genes for the cannabinoid receptor (Cnr1) and Nape-pld, an enzyme involved in endocannabinoid synthesis, in females and a decrease in the endocannabinoid degradation enzyme Faah in males. These changes suggest that the maternal P diet results in sex-specific alterations in hypothalamic endocannabinoid signaling and lipid metabolism. This hypothesis was tested in hypothalamic astrocyte cultures, where palmitic acid (PA) and the polyunsaturated fatty acid N-arachidonoylethanolamine (anandamide or AEA) were found to induce similar changes in the endocannabinoid system (ECS) and lipid metabolism.Conclusion: These results stress the importance of both maternal diet and sex in long term metabolic programming and suggest a possible role of hypothalamic astrocytes in this process.
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Cannabinoides , Endocannabinoides , Hijos Adultos , Ácidos Araquidónicos , Astrocitos/metabolismo , Cannabinoides/metabolismo , Dieta , Femenino , Gliosis/metabolismo , Humanos , Hipotálamo/metabolismo , Inflamación/metabolismo , Metabolismo de los Lípidos , Masculino , Ácido Palmítico/metabolismo , Alcamidas Poliinsaturadas , Vimentina/metabolismoRESUMEN
Oxidative stress has been proposed to be a pathogenic mechanism to induce endothelial dysfunction and the onset of cardiovascular disease. Elevated levels of free fatty acids can cause oxidative stress by increasing mitochondrial uncoupling but, at physiological concentrations, they are essential for cell and tissue function and olive oil free fatty acids have proved to exhibit beneficial effects on risk factors for cardiovascular disease. We hypothesize that realistic concentrations within the physiological range of oleic (OA) and palmitic (PA) acids could be beneficial in the prevention of oxidative stress in vascular endothelium. Hence, pre-treatment and co-treatment with realistic physiological doses of palmitic and oleic acids were tested on cultured endothelial cells submitted to a chemically induced oxidative stress to investigate their potential chemo-protective effect. Cell viability and markers of oxidative status: reactive oxygen species (ROS), reduced glutathione (GSH), malondialdehyde (MDA), glutathione peroxidase (GPx) and glutathione reductase (GR) were evaluated. As a conclusion, the increased ROS generation induced by stress was significantly prevented by a pre- and co-treatment with PA or OA. Moreover, pre- and co-treatment of cells with FFAs recovered the stress-induced MDA concentration to control values and significantly recovered depleted GSH and normalized GPx and GR activities. Finally, pre- and co-treatment of cells with physiological concentrations of PA or OA in the low micromolar range conferred a substantial protection of cell viability against an oxidative insult.
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Células Endoteliales , Ácidos Palmíticos , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Ácidos Grasos no Esterificados/farmacología , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Humanos , Estrés Oxidativo , Ácidos Palmíticos/farmacología , Especies Reactivas de Oxígeno/farmacologíaRESUMEN
Long-term high-fat diet (HFD) consumption commonly leads to obesity, a major health concern of western societies and a risk factor for Alzheimer's disease (AD). Both conditions present glial activation and inflammation and show sex differences in their incidence, clinical manifestation, and disease course. HFD intake has an important impact on gut microbiota, the bacteria present in the gut, and microbiota dysbiosis is associated with inflammation and certain mental disorders such as anxiety. In this study, we have analyzed the effects of a prolonged (18 weeks, starting at 7 months of age) HFD on male and female mice, both wild type (WT) and TgAPP mice, a model for AD, investigating the behavioral profile, gut microbiota composition and inflammatory/phagocytosis-related gene expression in hippocampus. In the open-field test, no overt differences in motor activity were observed between male and female or WT and TgAPP mice on a low-fat diet (LFD). However, HFD induced anxiety, as judged by decreased motor activity and increased time in the margins in the open-field, and a trend towards increased immobility time in the tail suspension test, with increased defecation. Intriguingly, female TgAPP mice on HFD showed less immobility and defecation compared to female WT mice on HFD. HFD induced dysbiosis of gut microbiota, resulting in reduced microbiota diversity and abundance compared with LFD fed mice, with some significant differences due to sex and little effect of genotype. Gene expression of pro-inflammatory/phagocytic markers in the hippocampus were not different between male and female WT mice, and in TgAPP mice of both sexes, some cytokines (IL-6 and IFNγ) were higher than in WT mice on LFD, more so in female TgAPP (IL-6). HFD induced few alterations in mRNA expression of inflammatory/phagocytosis-related genes in male mice, whether WT (IL-1ß, MHCII), or TgAPP (IL-6). However, in female TgAPP, altered gene expression returned towards control levels following prolonged HFD (IL-6, IL-12ß, TNFα, CD36, IRAK4, PYRY6). In summary, we demonstrate that HFD induces anxiogenic symptoms, marked alterations in gut microbiota, and increased expression of inflammatory genes, except for female TgAPP that appear to be resistant to the diet effects. Lifestyle interventions should be introduced to prevent AD onset or exacerbation by reducing inflammation and its associated symptoms; however, our results suggest that the eventual goal of developing prevention and treatment strategies should take sex into consideration.
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Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Conducta Animal/fisiología , Dieta Alta en Grasa , Disbiosis/genética , Microbioma Gastrointestinal/fisiología , Inflamación/genética , Estrés Psicológico/genética , Enfermedad de Alzheimer/fisiopatología , Animales , Modelos Animales de Enfermedad , Disbiosis/fisiopatología , Femenino , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Interleucina-1beta/genética , Interleucina-6/genética , Masculino , Ratones , Ratones Transgénicos , Fagocitosis/genética , ARN Mensajero/metabolismo , Caracteres Sexuales , Estrés Psicológico/fisiopatologíaRESUMEN
Maternal nutritional imbalances, in addition to maternal overweight and obesity, can result in long-term effects on the metabolic health of the offspring, increasing the risk of common non-communicable disorders such as obesity, diabetes and cardiovascular disease. This increased disease risk may also be transmitted across generations. Unfortunately, lifestyle interventions have shown reduced compliancy and limited efficacy. Resveratrol is a natural polyphenolic compound reported to have pleiotropic beneficial actions including a possible protective effect against the metabolic programming induced by poor dietary habits during development. However, studies to date are inconclusive regarding the potential metabolic benefits of maternal resveratrol supplementation during pregnancy and lactation on the offspring. Moreover, the responses to metabolic challenges are suggested to be different in males and females, suggesting that the effectiveness of treatment strategies may also differ, but many studies have been performed only in males. Here we review the current evidence, both in humans and animal models, regarding the possible beneficial effects of maternal resveratrol intake on the metabolic health of the offspring and highlight the different effects of resveratrol depending on the maternal diet, as well as the differential responses of males and females.
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Antioxidantes/farmacología , Fenómenos Fisiologicos Nutricionales Maternos , Resveratrol/farmacología , Animales , Antioxidantes/administración & dosificación , Femenino , Humanos , Recién Nacido , Lactancia , Estilo de Vida , Masculino , Fenómenos Fisiologicos Nutricionales Maternos/efectos de los fármacos , Obesidad/metabolismo , Embarazo , Resveratrol/administración & dosificaciónRESUMEN
Leptin has been suggested to play a role in amyotrophic lateral sclerosis (ALS), a fatal progressive neurodegenerative disease. This adipokine has previously been shown to be associated with a lower risk of ALS and to confer a survival advantage in ALS patients. However, the role of leptin in the progression of ALS is unknown. Indeed, our understanding of the mechanisms underlying leptin's effects in the pathogenesis of ALS is very limited, and it is fundamental to determine whether alterations in leptin's actions take place in this neurodegenerative disease. To characterize the association between leptin signaling and the clinical course of ALS, we assessed the mRNA and protein expression profiles of leptin, the long-form of the leptin receptor (Ob-Rb), and leptin-related signaling pathways at two different stages of the disease (onset and end-stage) in TDP-43A315T mice compared to age-matched WT littermates. In addition, at selected time-points, an immunoassay analysis was conducted to characterize plasma levels of total ghrelin, the adipokines resistin and leptin, and metabolic proteins (plasminogen activator inhibitor type 1 (PAI-1), gastric inhibitory peptide (GIP), glucagon-like peptide 1 (GLP-1), insulin and glucagon) in TDP-43A315T mice compared to WT controls. Our results indicate alterations in leptin signaling in the spinal cord and the hypothalamus on the backdrop of TDP-43-induced deficits in mice, providing new evidence about the pathways that could link leptin signaling to ALS.
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Esclerosis Amiotrófica Lateral/metabolismo , Leptina/metabolismo , Transducción de Señal/fisiología , Adipoquinas/metabolismo , Animales , Humanos , Masculino , Ratones , Neuronas Motoras/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Médula Espinal/metabolismoRESUMEN
The growth hormone (GH)/insulin-like growth factor I (IGF-I) axis is involved in metabolic control. Malnutrition reduces IGF-I and modifies the thermogenic capacity of brown adipose tissue (BAT). Leptin has effects on the GH/IGF-I axis and the function of BAT, but its interaction with IGF-I and the mechanisms involved in the regulation of thermogenesis remains unknown. We studied the GH/IGF-I axis and activation of IGF-I-related signaling and metabolism related to BAT thermogenesis in chronic central leptin infused (L), pair-fed (PF), and control rats. Hypothalamic somatostatin mRNA levels were increased in PF and decreased in L, while pituitary GH mRNA was reduced in PF. Serum GH and IGF-I concentrations were decreased only in PF. In BAT, the association between suppressor of cytokine signaling 3 and the IGF-I receptor was reduced, and phosphorylation of the IGF-I receptor increased in the L group. Phosphorylation of Akt and cyclic AMP response element binding protein and glucose transporter 4 mRNA levels were increased in L and mRNA levels of uncoupling protein-1 (UCP-1) and enzymes involved in lipid anabolism reduced in PF. These results suggest that modifications in UCP-1 in BAT and changes in the GH/IGF-I axis induced by negative energy balance are dependent upon leptin levels.
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Tejido Adiposo Pardo/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Hormona del Crecimiento/genética , Factor I del Crecimiento Similar a la Insulina/genética , Leptina/farmacología , Termogénesis/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Metabolismo Energético/genética , Transportador de Glucosa de Tipo 4/genética , Transportador de Glucosa de Tipo 4/metabolismo , Hormona del Crecimiento/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Inyecciones Intraventriculares , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Fosforilación/efectos de los fármacos , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Somatostatina/genética , Somatostatina/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/genética , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Termogénesis/genética , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMEN
Deficiency of pregnancy-associated plasma protein-A2 (PAPP-A2), an IGF-1 availability regulator, causes postnatal growth failure and dysregulation of bone size and density. The present study aimed to determine the effects of recombinant murine IGF-1 (rmIGF-1) on bone composition and remodeling in constitutive Pappa2 knock-out (ko/ko) mice. To address this challenge, X-ray diffraction (XRD), attenuated total reflection-fourier transform infra-red (ATR-FTIR) spectroscopy and gene expression analysis of members of the IGF-1 system and bone resorption/formation were performed. Pappa2ko/ko mice (both sexes) had reduced body and bone length. Male Pappa2ko/ko mice had specific alterations in bone composition (mineral-to-matrix ratio, carbonate substitution and mineral crystallinity), but not in bone remodeling. In contrast, decreases in collagen maturity and increases in Igfbp3, osteopontin (resorption) and osteocalcin (formation) characterized the bone of Pappa2ko/ko females. A single rmIGF-1 administration (0.3 mg/kg) induced short-term changes in bone composition in Pappa2ko/ko mice (both sexes). rmIGF-1 treatment in Pappa2ko/ko females also increased collagen maturity, and Igfbp3, Igfbp5, Col1a1 and osteopontin expression. In summary, acute IGF-1 treatment modifies bone composition and local IGF-1 response to bone remodeling in mice with Pappa2 deficiency. These effects depend on sex and provide important insights into potential IGF-1 therapy for growth failure and bone loss and repair.
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Resorción Ósea/genética , Factor I del Crecimiento Similar a la Insulina/genética , Osteogénesis/efectos de los fármacos , Proteína Plasmática A Asociada al Embarazo/genética , Animales , Densidad Ósea/efectos de los fármacos , Remodelación Ósea/efectos de los fármacos , Remodelación Ósea/genética , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/patología , Proteínas Portadoras/genética , Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/farmacología , Ratones , Ratones Noqueados , Osteocalcina/genética , Osteopontina/genética , Caracteres SexualesRESUMEN
Maternal malnutrition in critical periods of development increases the risk of developing short- and long-term diseases in the offspring. The alterations induced by this nutritional programming in the hypothalamus of the offspring are of special relevance due to its role in energy homeostasis, especially in the endocannabinoid system (ECS), which is involved in metabolic functions. Since astrocytes are essential for neuronal energy efficiency and are implicated in brain endocannabinoid signaling, here we have used a rat model to investigate whether a moderate caloric restriction (R) spanning from two weeks prior to the start of gestation to its end induced changes in offspring hypothalamic (a) ECS, (b) lipid metabolism (LM) and/or (c) hypothalamic astrocytes. Monitorization was performed by analyzing both the gene and protein expression of proteins involved in LM and ECS signaling. Offspring born from caloric-restricted mothers presented hypothalamic alterations in both the main enzymes involved in LM and endocannabinoids synthesis/degradation. Furthermore, most of these changes were similar to those observed in hypothalamic offspring astrocytes in culture. In conclusion, a maternal low caloric intake altered LM and ECS in both the hypothalamus and its astrocytes, pointing to these glial cells as responsible for a large part of the alterations seen in the total hypothalamus and suggesting a high degree of involvement of astrocytes in nutritional programming.
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Astrocitos/metabolismo , Restricción Calórica , Endocannabinoides/metabolismo , Hipotálamo/metabolismo , Metabolismo de los Lípidos , Transducción de Señal , Animales , Animales Recién Nacidos , Peso Corporal , Encéfalo/patología , Femenino , Regulación de la Expresión Génica , Gliosis/genética , Gliosis/patología , Inflamación/genética , Inflamación/patología , Metabolismo de los Lípidos/genética , Embarazo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Obesity is a very heterogeneous disorder at both the clinical and molecular levels and with high heritability. Several monogenic forms and genes with strong effects have been identified for non-syndromic severe obesity. Novel therapeutic interventions are in development for some genetic forms, emphasizing the importance of determining genetic contributions. OBJECTIVE: We aimed to define the contribution of rare single-nucleotide genetic variants (RSVs) in candidate genes to non-syndromic severe early-onset obesity (EOO; body mass index (BMI) >+3 standard deviation score, <3 years). METHODS: Using a pooled DNA-sequencing approach, we screened for RSVs in 15 obesity candidate genes in a series of 463 EOO patients and 480 controls. We also analysed exome data from 293 EOO patients from the "Viva la Familia" (VLF) study as a replication dataset. RESULTS: Likely or known pathogenic RSVs were identified in 23 patients (5.0%), with 7 of the 15 genes (BDNF, FTO, MC3R, MC4R, NEGR1, PPARG and SIM1) harbouring RSVs only in cases (3.67%) and none in controls. All were heterozygous changes, either de novo (one in BDNF) or inherited from obese parents (seven maternal, three paternal), and no individual carried more than one variant. Results were replicated in the VLF study, where 4.10% of probands carried RSVs in the overrepresented genes. RSVs in five genes were either absent (LEP) or more common in controls than in cases (ADRB3, LEPR, PCSK1 and PCSK2) in both obese datasets. CONCLUSIONS: Heterozygous RSVs in several candidate genes of the melanocortin pathway are found in ~5.0% patients with EOO. These results support the clinical utility of genetic testing to identify patients who might benefit from targeted therapeutic intervention.
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Variación Genética/genética , Obesidad Infantil/genética , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Heterocigoto , Humanos , Masculino , Mutación/genética , Adulto JovenRESUMEN
Many studies have shown the importance of an adequate nutritional environment during development to optimally establish the neurohormonal circuits that regulate feeding behavior. Under- or over-nutrition during early stages of life can lead to alterations in the physiology and brain networks that control food intake, resulting in a greater vulnerability to suffer maladjustments in energy metabolism in adulthood. These alterations produced by under- or over-nourishment during development differ between males and females, as does the modulatory action that estradiol exerts on the alterations produced by malnutrition. Estradiol regulates metabolism and brain metabolic circuits through the same transcription factor pathway, STAT3, that leptin and ghrelin use to program feeding circuits. Although more research is needed to disentangle the actual role of estradiol during development on the programming of feeding circuits, a synergistic role together with leptin and/or ghrelin might be hypothesized.
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Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Estradiol/metabolismo , Desnutrición/metabolismo , Caracteres Sexuales , Animales , Femenino , Masculino , RatasRESUMEN
Males and females have distinct propensities to develop obesity and its related comorbidities, partially due to gonadal steroids. There are sex differences in hypothalamic neuronal circuits, as well as in astrocytes, that participate in metabolic control and the development of obesity-associated complications. Astrocytes are involved in nutrient transport and metabolism, glucose sensing, synaptic remodeling and modulation of neuronal signaling. They express receptors for metabolic hormones and mediate effects of these metabolic signals on neurons, with astrogliosis occurring in response to high fat diet and excess weight gain. However, most studies of obesity have focused on males. Recent reports indicate that male and female astrocytes respond differently to metabolic signals and this could be involved in the differential response to high fat diet and the onset of obesity-associated pathologies. Here we focus on the sex differences in response to obesogenic paradigms and the possible role of hypothalamic astrocytes in this phenomenon.
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Astrocitos/metabolismo , Hormonas Esteroides Gonadales/metabolismo , Hipotálamo/metabolismo , Obesidad/metabolismo , Caracteres Sexuales , Animales , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: Overnutrition due to a high-fat diet (HFD) can increase the vulnerability of the metabolic system to maladjustments. Estradiol has an inhibitory role on food intake and this hormone has demonstrated to be a crucial organizer during brain development. OBJECTIVE: Our aim was to determine whether increased levels of estradiol in the early postnatal period modulate the alterations in metabolism and brain metabolic circuits produced by overnutrition. METHODS: Twenty-four male and 24 female Wistar rats were submitted to a HFD (34.9% fat) or a control diet (5% fat) from gestational day 6. From postnatal (P) 6 to P13, both control and HFD groups were administered a s.c. injection of vehicle or estradiol benzoate (0.4â mg/kg), resulting in eight experimental groups (n = 6 in each group). Body weight, food intake and subcutaneous, visceral, and brown fat pads were measured. Agouti-related peptide, neuropeptide Y, orexin, and proopiomelanocortin (POMC) were analyzed by quantitative real-time polymerase chain reaction assay and plasma estradiol levels were measured by ELISA. RESULTS: Males fed a HFD showed an increase in body weight and the amount of visceral and subcutaneous fat, which was coincident with an increase in the number of kilocalories ingested. Neonatal estradiol treatment restored the body weight and subcutaneous fat of HFD males to control levels. Hypothalamic POMC mRNA levels in HFD females were increased with respect to control females. This increase was reverted with estradiol treatment during development. DISCUSSION: HFD and estradiol treatment have different effects on males and females. Overnutrition affects physiological parameters, such as body weight, visceral, and subcutaneous fat content, in males, while females present alterations in hypothalamic POMC mRNA levels. Hence, the increase in estradiol levels during a period that is critical for the programing of the feeding system can modulate some of the alterations produced by the continuous intake of high-fat content food.
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Dieta Alta en Grasa/efectos adversos , Estradiol/análogos & derivados , Hipotálamo/patología , Hipernutrición/fisiopatología , Adiposidad , Animales , Peso Corporal , Dieta , Modelos Animales de Enfermedad , Estradiol/sangre , Estradiol/farmacología , Femenino , Hipotálamo/efectos de los fármacos , Masculino , Neuropéptido Y/metabolismo , Orexinas/metabolismo , Proopiomelanocortina/metabolismo , Ratas , Ratas Wistar , Factores SexualesRESUMEN
Sex differences in the incidence, clinical manifestation, disease course, and prognosis of neurological diseases, such as autism spectrum disorders or Alzheimer's disease, have been reported. Obesity has been postulated as a risk factor for cognitive decline and Alzheimer's disease and, during pregnancy, increases the risk of autism spectrum disorders in the offspring. Obesity is associated with increased serum and brain levels of free fatty acids, such as palmitic acid, which activate microglial cells triggering a potent inflammatory cascade. In this study, we have determined the effect of palmitic acid in the inflammatory profile, motility, and phagocytosis of primary male and female microglia, both in basal conditions and in the presence of a pro-inflammatory stimulus (interferon-γ). Male microglia in vitro showed higher migration than female microglia under basal and stimulated conditions. In contrast, female microglia had higher basal and stimulated phagocytic activity than male microglia. Palmitic acid did not affect basal migration or phagocytosis, but abolished the migration and phagocytic activity of male and female microglia in response to interferon-γ. These findings extend previous observations of sex differences in microglia and suggest that palmitic acid impairs the protective responses of these cells.
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Movimiento Celular/fisiología , Microglía/metabolismo , Ácido Palmítico/toxicidad , Fagocitosis/fisiología , Caracteres Sexuales , Animales , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Femenino , Inflamación/metabolismo , Inflamación/patología , Interferón gamma/administración & dosificación , Interferón gamma/metabolismo , Masculino , Microglía/efectos de los fármacos , Microglía/patología , Fagocitosis/efectos de los fármacos , Prosencéfalo/efectos de los fármacos , Prosencéfalo/metabolismo , Prosencéfalo/patología , ARN Mensajero/metabolismo , Ratas WistarRESUMEN
PURPOSE: Our aim was to characterize the effect of an unfamiliar high-fat diet (HFD) on circadian feeding behaviour, plasma parameters, body weight (BW), and gene expression in the prefrontal cortex (PFC) of adolescent male mice. To this end, mice were allowed to consume a HFD during 48 h, but one group was allowed a free choice of HFD or normal chow (FC-HFD), while the other was restricted to a non-optional unfamiliar HFD feeding (NOP-HFD). METHODS: Energy intake was monitored at 6-h intervals during 48 h. Mice cohorts were killed at 6-h intervals after 48-h dietary treatment, and PFC samples dissected for RT-PCR analysis. RESULTS: Mice on the FC-HFD protocol avoided eating the standard chow, showed lower energy intake and lower BW increase than NOP-HFD mice. All animals with access to HFD exhibited nocturnal overeating, but diurnal hyperphagia was more prominent in the FC-HFD cohort. A robust increase in tyrosine hydroxylase (Th) gene expression was detected specifically during the light period of the circadian cycle in FC-HFD mice. In contrast, both protocols similarly up-regulated the expression of cytosolic malic enzyme (Me1), which is very sensitive to HFD. CONCLUSION: Our data show that the PFC participates in driving motivational feeding during HFD-evoked hyperphagia and also suggest that sensory neural pathways might be relevant for the onset of eating disorders and overweight. Moreover, we have observed that animals that had the possibility of choosing between standard chow and HFD were more hyperphagic and specifically displayed an overexpression of the tyrosine hydroxylase gene.
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Conducta de Elección , Ritmo Circadiano , Dieta Alta en Grasa/efectos adversos , Ingestión de Energía , Corteza Prefrontal/fisiología , Animales , Glucemia/metabolismo , Peso Corporal , Carbohidratos de la Dieta/administración & dosificación , Grasas de la Dieta/administración & dosificación , Proteínas en la Dieta/administración & dosificación , Regulación de la Expresión Génica , Hiperfagia , Insulina/sangre , Leptina/sangre , Leptina/genética , Malato Deshidrogenasa/genética , Malato Deshidrogenasa/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Sobrepeso/etiología , Sobrepeso/genética , Receptores de Leptina/sangre , Receptores de Leptina/genética , Tirosina 3-Monooxigenasa/genética , Tirosina 3-Monooxigenasa/metabolismo , Aumento de PesoRESUMEN
Although astrocytes are the most abundant cells in the mammalian brain, much remains to be learned about their molecular and functional features. Astrocytes express receptors for numerous hormones and metabolic factors, including the appetite-promoting hormone ghrelin. The metabolic effects of ghrelin are largely opposite to those of leptin, as it stimulates food intake and decreases energy expenditure. Ghrelin is also involved in glucose-sensing and glucose homeostasis. The widespread expression of the ghrelin receptor in the central nervous system suggests that this hormone is not only involved in metabolism, but also in other essential functions in the brain. In fact, ghrelin has been shown to promote cell survival and neuroprotection, with some studies exploring the use of ghrelin as a therapeutic agent against metabolic and neurodegenerative diseases. In this review, we highlight the possible role of glial cells as mediators of ghrelin's actions within the brain.
Asunto(s)
Astrocitos/fisiología , Ghrelina/metabolismo , Receptores de Ghrelina/metabolismo , Animales , Ingestión de Alimentos , Metabolismo Energético , Homeostasis , HumanosRESUMEN
The incidence of obesity and type diabetes 2 has increased dramatically resulting in an increased interest in its biomedical relevance. However, the mechanisms that trigger the development of diabetes type 2 in obese patients remain largely unknown. Scientific, clinical and pharmaceutical communities are dedicating vast resources to unravel this issue by applying different omics tools. During the last decade, the advances in proteomic approaches and the Human Proteome Organization have opened and are opening a new door that may be helpful in the identification of patients at risk and to improve current therapies. Here, we briefly review some of the advances in our understanding of type 2 diabetes that have occurred through the application of proteomics. We also review, in detail, the current improvements in proteomic methodologies and new strategies that could be employed to further advance our understanding of this pathology. By applying these new proteomic advances, novel therapeutic and/or diagnostic protein targets will be discovered in the obesity/Type 2 diabetes area.