RESUMEN
Interleukin-17 (IL-17) is expressed in the intestine in response to changes in the gut microbiome landscape and plays an important role in intestinal and systemic inflammatory diseases. There is evidence that dietary factors can also modify the expression of intestinal IL-17. Here, we hypothesized that, similar to several other gut-produced factors, IL-17 may act in the hypothalamus to modulate food intake. We confirm that food intake increases IL-17 expression in the mouse ileum and human blood. There is no expression of IL-17 in the hypothalamus; however, IL-17 receptor A is expressed in both pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons. Upon systemic injection, IL-17 promoted a rapid increase in hypothalamic POMC expression, which was followed by a late increase in the expression of AgRP. Both systemic and intracerebroventricular injections of IL-17 reduced calorie intake without affecting whole-body energy expenditure. Systemic but not intracerebroventricular injection of IL-17 increase brown adipose tissue temperature. Thus, IL-17 is a gut-produced factor that is controlled by diet and modulates food intake by acting in the hypothalamus. Our findings provide the first evidence of a cytokine that is acutely regulated by food intake and plays a role in the regulation of eating.
Asunto(s)
Hipotálamo , Interleucina-17 , Proteína Relacionada con Agouti/metabolismo , Animales , Ingestión de Alimentos , Humanos , Hipotálamo/metabolismo , Ratones , Proopiomelanocortina/metabolismoRESUMEN
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
Obesity-associated hypothalamic inflammation plays an important role in the development of defective neuronal control of whole body energy balance. Because dietary fats are the main triggers of hypothalamic inflammation, we hypothesized that CD1, a lipid-presenting protein, may be involved in the hypothalamic inflammatory response in obesity. Here, we show that early after the introduction of a high-fat diet, CD1 expressing cells gradually appear in the mediobasal hypothalamus. The inhibition of hypothalamic CD1 reduces diet-induced hypothalamic inflammation and rescues the obese and glucose-intolerance phenotype of mice fed a high-fat diet. Conversely, the chemical activation of hypothalamic CD1 further increases diet-induced obesity and hypothalamic inflammation. A bioinformatics analysis revealed that hypothalamic CD1 correlates with transcripts encoding for proteins known to be involved in diet-induced hypothalamic abnormalities in obesity. Thus, CD1 is involved in at least part of the hypothalamic inflammatory response in diet-induced obesity and its modulation affects the body mass phenotype of mice.
Asunto(s)
Antígenos CD1/metabolismo , Hipotálamo/inmunología , Obesidad/metabolismo , Animales , Antígenos CD1/inmunología , Biología Computacional/métodos , Dieta Alta en Grasa , Grasas de la Dieta , Metabolismo Energético , Inflamación/metabolismo , Linfocitos/metabolismo , Masculino , Ratones , Obesidad/inmunologíaRESUMEN
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
BACKGROUND: Diet-induced hypothalamic inflammation is an important mechanism leading to dysfunction of neurons involved in controlling body mass. Studies have shown that polyunsaturated fats can reduce hypothalamic inflammation. Here, we evaluated the presence and function of RvD2, a resolvin produced from docosahexaenoic acid, in the hypothalamus of mice. METHODS: Male Swiss mice were fed either chow or a high-fat diet. RvD2 receptor and synthetic enzymes were evaluated by real-time PCR and immunofluorescence. RvD2 was determined by mass spectrometry. Dietary and pharmacological approaches were used to modulate the RvD2 system in the hypothalamus, and metabolic phenotype consequences were determined. RESULTS: All enzymes involved in the synthesis of RvD2 were detected in the hypothalamus and were modulated in response to the consumption of dietary saturated fats, leading to a reduction of hypothalamic RvD2. GPR18, the receptor for RvD2, which was detected in POMC and NPY neurons, was also modulated by dietary fats. The substitution of saturated by polyunsaturated fats in the diet resulted in increased hypothalamic RvD2, which was accompanied by reduced body mass and improved glucose tolerance. The intracerebroventricular treatment with docosahexaenoic acid resulted in increased expression of the RvD2 synthetic enzymes, increased expression of anti-inflammatory cytokines and improved metabolic phenotype. Finally, intracerebroventricular treatment with RvD2 resulted in reduced adiposity, improved glucose tolerance and increased hypothalamic expression of anti-inflammatory cytokines. CONCLUSIONS: Thus, RvD2 is produced in the hypothalamus, and its receptor and synthetic enzymes are modulated by dietary fats. The improved metabolic outcomes of RvD2 make this substance an attractive approach to treat obesity.
Asunto(s)
Ácidos Docosahexaenoicos/uso terapéutico , Encefalitis/tratamiento farmacológico , Encefalitis/etiología , Hipotálamo/metabolismo , Obesidad/complicaciones , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Proteínas de Unión al Calcio/metabolismo , Citocinas/genética , Citocinas/metabolismo , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/química , Ácidos Docosahexaenoicos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Hipotálamo/patología , Masculino , Ratones , Proteínas de Microfilamentos/metabolismo , Neuronas/metabolismo , Neuropéptido Y/metabolismo , Obesidad/inducido químicamente , Consumo de Oxígeno/fisiología , Proopiomelanocortina/metabolismo , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
O cerrado brasileiro é um bioma detentor de grande diversidade biológica. No entanto, são escassas as pesquisas de espécies vegetais, especialmente do cerrado mato-grossense, com potencial para serem utilizadas como filtros solares naturais. O objetivo desta pesquisa foi estudar o potencial fotoprotetor de espécies de diferentes famílias (Apocynaceae, Lythraceae, Oxalidaceae) do cerrado da região do Rio Manso, Chapada dos Guimarães - MT. A absorbância dos extratos etanólicos secos foram medidas em diferentes concentrações entre os comprimentos de onda de 260 a 400nm para verificar a absorção nas regiões ultravioleta A e B (UVA e UVB). As plantas que apresentaram absorbância na região estudada foram submetidas a uma análise fitoquímica qualitativa preliminar para determinar a presença de polifenóis e alcalóides, constituintes característicos de plantas que absorvem a radiação UV. Os extratos etanólicos secos que apresentaram absorção em UVB foram submetidos ao teste de determinação in vitro do Fator de Proteção Solar (FPS) desenvolvido por Mansur. M. Velame apresentou absorção na região UVB com absorbância máxima em 318nm, enquanto que a L. pacari e O. hirsutissima apresentaram absorbância na região UVA. Na concentração utilizada e padronizada, nenhuma das espécies apresentou FPS >2, sendo assim não podem ser consideradas plantas com potencial fotoprotetor.
The Brazilian savanna is a holding biome of large biological diversity. However, the researches of plants species are scarce, especially at the Mato Grosso's savanna; which have potential to be used as natural sunscreen. The objective of this research was to study the photoprotector potential of several species (Apocynaceae, Lythraceae, Oxalidaceae) from the savanna's region at the Manso River, Chapada dos Guimarães - MT. The absorbance of dry ethanolic extracts were measured in different concentrations, between waves from 260nm until 400 nm in length. Just to check the absorption in the A and B ultraviolet regions (UVA and UVB). The plants that presented absorbance by the studied area were submitted to a preliminary qualitative phytochemical analysis to determine if there are polyphenols and alkaloids inside, because they are typical constituents of plants that absorber the UV radiation. The dry ethanolic extracts, that presented absorption in UVB, were submitted to a in vitro Sun Protection Factor (SPF) determination test, developed by Mansur. M.velame presented absorption in the UVB region with maximal absorbance at 318 nm, while L. pacari and O. hirsutissima presented absorbance in the UVA region. At the used and standardized concentration, no species presented SPF > 2, so they cannot be considered plants with photoprotector potential.