RESUMEN
Maternal obesity is an important risk factor for obesity, cardiovascular, and metabolic diseases in the offspring. Studies have shown that it leads to hypothalamic inflammation in the progeny, affecting the function of neurons regulating food intake and energy expenditure. In adult mice fed a high-fat diet, one of the hypothalamic abnormalities that contribute to the development of obesity is the damage of the blood-brain barrier (BBB) at the median eminence-arcuate nucleus (ME-ARC) interface; however, how the hypothalamic BBB is affected in the offspring of obese mothers requires further investigation. Here, we used confocal and transmission electron microscopy, transcript expression analysis, glucose tolerance testing, and a cross-fostering intervention to determine the impact of maternal obesity and breastfeeding on BBB integrity at the ME-ARC interface. The offspring of obese mothers were born smaller; conversely, at weaning, they presented larger body mass and glucose intolerance. In addition, maternal obesity-induced structural and functional damage of the offspring's ME-ARC BBB. By a cross-fostering intervention, some of the defects in barrier integrity and metabolism seen during development in an obesogenic diet were recovered. The offspring of obese dams breastfed by lean dams presented a reduction of body mass and glucose intolerance as compared to the offspring continuously exposed to an obesogenic environment during intrauterine and perinatal life; this was accompanied by partial recovery of the anatomical structure of the ME-ARC interface, and by the normalization of transcript expression of genes coding for hypothalamic neurotransmitters involved in energy balance and BBB integrity. Thus, maternal obesity promotes structural and functional damage of the hypothalamic BBB, which is, in part, reverted by lactation by lean mothers.NEW & NOTEWORTHY Maternal dietary habits directly influence offspring health. In this study, we aimed at determining the impact of maternal obesity on BBB integrity. We show that DIO offspring presented a leakier ME-BBB, accompanied by changes in the expression of transcripts encoding for endothelial and tanycytic proteins, as well as of hypothalamic neuropeptides. Breastfeeding in lean dams was sufficient to protect the offspring from ME-BBB disruption, providing a preventive strategy of nutritional intervention during early life.
Asunto(s)
Intolerancia a la Glucosa , Obesidad Materna , Humanos , Femenino , Animales , Ratones , Embarazo , Barrera Hematoencefálica/metabolismo , Eminencia Media/metabolismo , Obesidad Materna/metabolismo , Madres , Intolerancia a la Glucosa/metabolismo , Obesidad/metabolismo , Hipotálamo/metabolismo , Dieta Alta en Grasa/efectos adversos , Fenómenos Fisiologicos Nutricionales MaternosRESUMEN
Nescient helix-loop-helix 2 (NHLH2) is a hypothalamic transcription factor that controls the expression of prohormone convertase 1/3, therefore having an impact on the processing of proopiomelanocortin and thus on energy homeostasis. Studies have shown that KO of Nhlh2 results in increased body mass, reduced physical activity, and hypogonadism. In humans, a polymorphism of the NHLH2 gene is associated with obesity; and in Prader-Willi syndrome, a condition characterized by obesity, hypogonadism and behavioral abnormalities, the expression of NHLH2 is reduced. Despite clinical and experimental evidence suggesting that NHLH2 could be a good target for the treatment of obesity, no previous study has evaluated the impact of NHLH2 overexpression in obesity. Here, in mice fed a high-fat diet introduced right after the arcuate nucleus intracerebroventricular injection of a lentivirus that promoted 40% increase in NHLH2, there was prevention of the development of obesity by a mechanism dependent on the reduction of caloric intake. When hypothalamic overexpression of NHLH2 was induced in previously obese mice, the beneficial impact on obesity-associated phenotype was even greater; thus, there was an 80% attenuation in body mass gain, reduced whole-body adiposity, increased brown adipose tissue temperature, reduced hypothalamic inflammation, and reduced liver steatosis. In this setting, the beneficial impact of hypothalamic overexpression of NHLH2 was a result of combined effects on caloric intake, energy expenditure, and physical activity. Moreover, the hypothalamic overexpression of NHLH2 reduced obesity-associated anxiety/depression behavior. Thus, we provide an experimental proof of concept supporting that hypothalamic NHLH2 is a good target for the treatment of obesity.SIGNIFICANCE STATEMENT Obesity is a highly prevalent medical condition that lacks an effective treatment. The main advance provided by this study is the demonstration of the beneficial metabolic and behavioral outcomes resulting from the overexpression of NHLH2 in the hypothalamus. When NHLH2 was overexpressed simultaneously with the introduction of a high-fat diet, there was prevention of obesity by a mechanism dependent on reduced caloric intake. Conversely, when NHLH2 was overexpressed in previously obese mice, there was reduction of the obese phenotype because of a combination of reduced caloric intake, increased physical activity, and increased thermogenesis. In addition, the overexpression of NHLH2 reduced anxiety/depression-like behavior. Thus, NHLH2 emerges as a potential target for the combined treatment of obesity and its associated anxiety/depression-like behavior.
Asunto(s)
Núcleo Arqueado del Hipotálamo/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Obesidad/metabolismo , Animales , Ansiedad/metabolismo , Índice de Masa Corporal , Depresión/metabolismo , Dieta Alta en Grasa/efectos adversos , Femenino , Masculino , Ratones , Obesidad/psicologíaRESUMEN
Selected neurons of the hypothalamus are equipped with molecules specialized in sensing the energy status of the organism. Upon activation or inhibition by central and systemic factors, such as neurotransmitters, hormones, cytokines, and nutrients, these molecules play important roles in the regulation of neuronal responses that control whole-body energy homeostasis. Dietary fats can control hypothalamic function by acting upon distinct energy sensing systems. They can be metabolized inside neurons, producing signals that control the expression of neurotransmitters involved in energy homeostasis; moreover, excessive amounts of certain fatty acids can activate inflammatory signaling in microglia, astrocytes, and neurons, leading to functional abnormalities and, eventually, neuronal apoptosis. In addition, recent studies have identified lipid-sensing G-protein-coupled receptors in the hypothalamus, revealing their involvement in the regulation of caloric intake and energy expenditure, as well as in the hypothalamic inflammatory response that occurs in obesity. Because of advances in the generation of synthetic ligands for this class of receptors, it is expected that pharmacological modulation of selected lipid-sensing G-protein-coupled receptors in the central nervous system could provide therapeutic advances in obesity and other metabolic diseases. Here we review seminal work in this field.
Asunto(s)
Ácidos Grasos , Hipotálamo , Metabolismo Energético , Homeostasis , Humanos , ObesidadRESUMEN
In experimental obesity, the hypothalamus is affected by an inflammatory response activated by dietary saturated fats. This inflammation is triggered as early as one day after exposure to a high-fat diet, and during its progression, there is recruitment of inflammatory cells from the systemic circulation. The objective of the present study was identifying chemokines potentially involved in the development of hypothalamic diet-induced inflammation. In order to identify chemokines potentially involved in this process, we performed a real-time PCR array that determined Ackr2 as one of the transcripts undergoing differential regulation in obese-prone as compared to obese-resistant mice fed a high-fat diet for three days. ACKR2 is a decoy receptor that acts as an inhibitor of the signals generated by several CC inflammatory chemokines. Our results show that Ackr2 expression is rapidly induced after exposure to dietary fats both in obese-prone and obese-resistant mice. In immunofluorescence studies, ACKR2 was detected in hypothalamic neurons expressing POMC and NPY and also in microglia and astrocytes. The lentiviral overexpression of ACKR2 in the hypothalamus reduced diet-induced hypothalamic inflammation; however, there was no change in spontaneous caloric intake and body mass. Nevertheless, the overexpression of ACKR2 resulted in improvement of glucose tolerance, which was accompanied by reduced insulin secretion and increased whole body insulin sensitivity. Thus, ACKR2 is a decoy chemokine receptor expressed in most hypothalamic cells that is modulated by dietary intervention and acts to reduce diet-induced inflammation, leading to improved glucose tolerance due to improved insulin action.
Asunto(s)
Perfilación de la Expresión Génica , Glucosa/metabolismo , Hipotálamo/metabolismo , Inflamación/genética , Obesidad/genética , Receptores de Quimiocina/genética , Animales , Astrocitos/metabolismo , Citocinas/genética , Citocinas/metabolismo , Dieta Alta en Grasa/efectos adversos , Prueba de Tolerancia a la Glucosa , Hipotálamo/citología , Inflamación/etiología , Inflamación/metabolismo , Resistencia a la Insulina/genética , Masculino , Ratones , Neuronas/metabolismo , Obesidad/etiología , Obesidad/metabolismo , Receptores de Quimiocina/metabolismoRESUMEN
BACKGROUND: The consumption of large amounts of dietary fats activates an inflammatory response in the hypothalamus, damaging key neurons involved in the regulation of caloric intake and energy expenditure. It is currently unknown why the mediobasal hypothalamus is the main target of diet-induced brain inflammation. We hypothesized that dietary fats can damage the median eminence blood/spinal fluid interface. METHODS: Swiss mice were fed on a high-fat diet, and molecular and structural studies were performed employing real-time PCR, immunoblot, immunofluorescence, transmission electron microscopy, and metabolic measurements. RESULTS: The consumption of a high fat diet was sufficient to increase the expression of inflammatory cytokines and brain-derived neurotrophic factor in the median eminence, preceding changes in other circumventricular regions. In addition, it led to an early loss of the structural organization of the median eminence ß1-tanycytes. This was accompanied by an increase in the hypothalamic expression of brain-derived neurotrophic factor. The immunoneutralization of brain-derived neurotrophic factor worsened diet-induced functional damage of the median eminence blood/spinal fluid interface, increased diet-induced hypothalamic inflammation, and increased body mass gain. CONCLUSIONS: The median eminence/spinal fluid interface is affected at the functional and structural levels early after introduction of a high-fat diet. Brain-derived neurotrophic factor provides an early protection against damage, which is lost upon a persisting consumption of large amounts of dietary fats.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Líquido Cefalorraquídeo/metabolismo , Dieta Alta en Grasa/efectos adversos , Grasas de la Dieta/efectos adversos , Eminencia Media/metabolismo , Eminencia Media/patología , Animales , Factor Neurotrófico Derivado del Encéfalo/antagonistas & inhibidores , Grasas de la Dieta/administración & dosificación , Masculino , Eminencia Media/ultraestructura , RatonesRESUMEN
BACKGROUND: The consumption of large amounts of dietary fats can trigger an inflammatory response in the hypothalamus and contribute to the dysfunctional control of caloric intake and energy expenditure commonly present in obesity. The objective of this study was to identify chemokine-related transcripts that could be involved in the early stages of diet-induced hypothalamic inflammation. METHODS: We used immunoblot, PCR array, real-time PCR, immunofluorescence staining, glucose and insulin tolerance tests, and determination of general metabolic parameters to evaluate markers of inflammation, body mass variation, and glucose tolerance in mice fed a high-fat diet. RESULTS: Using a real-time PCR array, we identified leukemia inhibitory factor as a chemokine/cytokine undergoing a rapid increase in the hypothalamus of obesity-resistant and a rapid decrease in the hypothalamus of obesity-prone mice fed a high-fat diet for 1 day. We hypothesized that the increased hypothalamic expression of leukemia inhibitory factor could contribute to the protective phenotype of obesity-resistant mice. To test this hypothesis, we immunoneutralized hypothalamic leukemia inhibitory factor and evaluated inflammatory and metabolic parameters. The immunoneutralization of leukemia inhibitory factor in the hypothalamus of obesity-resistant mice resulted in increased body mass gain and increased adiposity. Body mass gain was mostly due to increased caloric intake and reduced spontaneous physical activity. This modification in the phenotype was accompanied by increased expression of inflammatory cytokines in the hypothalamus. In addition, the inhibition of hypothalamic leukemia inhibitory factor was accompanied by glucose intolerance and insulin resistance. CONCLUSION: Hypothalamic expression of leukemia inhibitory factor may protect mice from the development of diet-induced obesity; the inhibition of this protein in the hypothalamus transforms obesity-resistant into obesity-prone mice.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Hipotálamo/metabolismo , Factor Inhibidor de Leucemia/antagonistas & inhibidores , Factor Inhibidor de Leucemia/biosíntesis , Obesidad/metabolismo , Fenotipo , Animales , Ingestión de Energía/efectos de los fármacos , Ingestión de Energía/fisiología , Hipotálamo/efectos de los fármacos , Inmunoglobulina G/farmacología , Masculino , Ratones , Obesidad/etiología , Distribución AleatoriaRESUMEN
Under physiological conditions, the brain consumes over 20% of the whole body energy supply. The blood-brain barrier (BBB) allows dynamic interactions between blood capillaries and the neuronal network in order to provide an adequate control of molecules that are transported in and out of the brain. Alterations in the BBB structure and function affecting brain accessibility to nutrients and exit of toxins are found in a number of diseases, which in turn may disturb brain function and nutrient signaling. In this review we explore the major advances obtained in the understanding of the BBB development and how its structure impacts on function. Furthermore, we focus on the particularities of the barrier permeability in the hypothalamus, its role in metabolic control and the potential impact of hypothalamic BBB abnormities in metabolic related diseases.
RESUMEN
BACKGROUND: The consumption of large amounts of dietary fats is one of the most important environmental factors contributing to the development of obesity and metabolic disorders. GPR120 and GPR40 are polyunsaturated fatty acid receptors that exert a number of systemic effects that are beneficial for metabolic and inflammatory diseases. Here, we evaluate the expression and potential role of hypothalamic GPR120 and GPR40 as targets for the treatment of obesity. METHODS: Male Swiss (6-weeks old), were fed with a high fat diet (HFD, 60% of kcal from fat) for 4 weeks. Next, mice underwent stereotaxic surgery to place an indwelling cannula into the right lateral ventricle. intracerebroventricular (icv)-cannulated mice were treated twice a day for 6 days with 2.0 µL saline or GPR40 and GPR120 agonists: GW9508, TUG1197, or TUG905 (2.0 µL, 1.0 mM). Food intake and body mass were measured during the treatment period. At the end of the experiment, the hypothalamus was collected for real-time PCR analysis. RESULTS: We show that both receptors are expressed in the hypothalamus; GPR120 is primarily present in microglia, whereas GPR40 is expressed in neurons. Upon intracerebroventricular treatment, GW9508, a non-specific agonist for both receptors, reduced energy efficiency and the expression of inflammatory genes in the hypothalamus. Reducing GPR120 hypothalamic expression using a lentivirus-based approach resulted in the loss of the anti-inflammatory effect of GW9508 and increased energy efficiency. Intracerebroventricular treatment with the GPR120- and GPR40-specific agonists TUG1197 and TUG905, respectively, resulted in milder effects than those produced by GW9508. CONCLUSIONS: GPR120 and GPR40 act in concert in the hypothalamus to reduce energy efficiency and regulate the inflammation associated with obesity. The combined activation of both receptors in the hypothalamus results in better metabolic outcomes than the isolated activation of either receptor alone.
Asunto(s)
Metabolismo Energético/fisiología , Ácidos Grasos Insaturados/biosíntesis , Homeostasis/fisiología , Hipotálamo/metabolismo , Receptores Acoplados a Proteínas G/biosíntesis , Animales , Línea Celular , Ácidos Grasos Insaturados/genética , Expresión Génica , Inflamación/genética , Inflamación/metabolismo , Masculino , Ratones , Microglía/metabolismo , Obesidad/genética , Obesidad/metabolismo , Receptores Acoplados a Proteínas G/genéticaRESUMEN
OBJECTIVE: This study aimed to investigate the effect of Passiflora edulis peel flour (PEPF) intake on hypothalamic neuropeptides messenger RNA expression, insulin sensitivity, and other metabolic parameters in Sprague-Dawley rats fed a high-fat (HF) diet. METHODS: Sprague-Dawley rats were divided in 3 groups: a control group, fed on a normal fat diet; a HF group, fed on a high-fat diet (35% fat [w/w]); and a high-fat Passiflora flour (HFPF) group, fed on a HF diet containing PEPF. The rats from the HFPF group as well as the HF group were kept on an HF diet for the first 4 wk to induce metabolic conditions related to obesity. Then the HFPF group was switched to a HF diet containing PEPF for additional 6 wk. Other groups were kept on normal-fat and HF diet without addition of PEPF during the whole period of experiment. The glucose tolerance and insulin sensitivity were evaluated through the glucose tolerance test (GTT) and the insulin tolerance test (ITT). Gut hormones and adipokines were measured through an immunoassay. The hypothalamic neuropeptides expression was assessed by real-time polymerase chain reaction. RESULTS: The PEPF intake increased the hypothalamic cocaine- and amphetamine-regulated transcript expression (CART) (P < 0.05), counteracted cumulative body weight gain (P < 0.001), decreased adiposity (P < 0.05) and leptin level (P < 0.01), whereas increased adiponectin (P < 0.01), glucose-dependent insulinotropic polypeptide (P < 0.01), and glucagon-like peptide-1 (GLP-1) (P < 0.001) improved the insulin sensitivity in diet-induced obesity rats by increasing the kITT (glucose disappearance rate) (P < 0.01), which was calculated during the ITT. Other gut hormones (peptide tyrosine tyrosine, pancreatic polypeptide, and amylin) and interleukins (IL) (IL-6, tumor necrosis factor-α, IL-1ß, and monocyte chemoattractant protein-1) were not changed by the PEPF intake. CONCLUSION: Our findings provide a further understanding of how the PEPF works as a dietary component to improve glucose homeostasis and demonstrate a molecular mechanism that may increase satiety by PEPF in diet-induced obesity.
Asunto(s)
Dieta Alta en Grasa , Hipotálamo/metabolismo , Incretinas/metabolismo , Resistencia a la Insulina/fisiología , Neuropéptidos/metabolismo , Passiflora , Adiponectina/metabolismo , Animales , Polipéptido Inhibidor Gástrico/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Hipotálamo/efectos de los fármacos , Leptina/metabolismo , Masculino , Ratones , Modelos Animales , Neuropéptidos/efectos de los fármacos , Reacción en Cadena de la Polimerasa , Ratas Sprague-DawleyRESUMEN
The peel of the native Brazilian fruit jaboticaba is rich in anthocyanins, which are known for their anti-obesity effects in animal models. The aim of the present study was to evaluate the effects of freeze-dried jaboticaba peel powder (FDJPP) on a number of metabolic parameters in a model of diet-induced obesity. Mice (n 8 per group) were initially fed on a high-fat diet (HFD, 35% w/w) for 4 weeks and then switched to a HFD supplemented with FDJPP (1, 2 or 4% w/w) for an additional 6 weeks. Energy intake, weight loss, glucose tolerance, insulin resistance and lipid profile were determined, and the results were evaluated using ANOVA and Tukey's tests. The FDJPP exerted no protective effect on HFD-induced weight gain, hyperleptinaemia and glucose intolerance. However, the supplementation was effective to reduce insulin resistance, as evidenced in the insulin tolerance test, and subsequently confirmed by improved signal transduction through the insulin receptor/insulin receptor substrate-1/Akt/forkhead box protein pathway and by the attenuation of HFD-induced inflammation in the liver, verified by lower expressions of IL-1b and IL-6 and decreased phosphorylated IkB-a protein levels in all jaboticaba-treated mice. These results suggest that FDJPP may exert a protective role against obesity-associated insulin resistance.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Resistencia a la Insulina , Insulina/metabolismo , Myrtaceae , Obesidad/tratamiento farmacológico , Fitoterapia , Preparaciones de Plantas/uso terapéutico , Análisis de Varianza , Animales , Antocianinas/farmacología , Antocianinas/uso terapéutico , Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/uso terapéutico , Suplementos Dietéticos , Frutas , Intolerancia a la Glucosa , Inflamación/tratamiento farmacológico , Inflamación/etiología , Inflamación/metabolismo , Leptina/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos , Myrtaceae/química , Obesidad/etiología , Obesidad/metabolismo , Preparaciones de Plantas/farmacología , Polvos , Receptor de Insulina/metabolismo , Transducción de Señal , Aumento de Peso/efectos de los fármacosRESUMEN
The goal of the this study was to evaluate the mutagenic/antimutagenic effects of conventional (BRS133) and transgenic (BRS 245 RR) soybeans (CS and TS, respectively) in vivo using the bone marrow micronucleus (MN) test, histopathological analysis, chromosome aberration test (CAT), and mitotic index (MI) determination. Six-week-old male Swiss mice were fed with pelleted commercial diet mixed with CS or TS at 10% or 20%. Two experimental designs (MN and CAT) were conducted simultaneously with 10 groups each during a 15-day period. Animals were treated with pelleted commercial diet, CS (10% or 20%), or TS (10% or 20%), and on day 14 they also received cyclophosphamide (CP) (50 mg/kg i.p.). The 10% and 20% CS and TS diets did not significantly decrease the frequencies of micronucleated polychromatic erythrocytes in bone marrow induced by CP. However, the CAT indicated that the 10% and 20% CS diets significantly (P < .05) protected nucleated bone marrow cells against chemical-induced mutagenesis and also produced a significant (P < .05) decrease in the total percentage of spontaneous aberrations. Among the treatments with TS, only the 10% TS diet reduced the percentage of total aberrations induced by CP. The results also indicated that the treatment with 20% TS alone significantly (P < .05) decreased the MI, indicating cytotoxic effects related to the treatment. Taken together, our results suggest that, under the tested conditions, TS and CS have antimutagenic properties and are not toxic.