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BACKGROUND: Neuropsychiatric sequelae of COVID-19 have been widely documented in patients with severe neurological symptoms during the chronic or subacute phase of the disease. However, it remains unclear whether subclinical changes in brain metabolism can occur early in the acute phase of the disease. The aim of this study was to identify and quantify changes in brain metabolism in patients hospitalized for acute respiratory syndrome due to COVID-19 with no or mild neurological symptoms. RESULTS: Twenty-three non-intubated patients (13 women; mean age 55.5 ± 12.1 years) hospitalized with positive nasopharyngeal swab test (RT-PCR) for COVID-19, requiring supplemental oxygen and no or mild neurological symptoms were studied. Serum C-reactive protein measured at admission ranged from 6.43 to 189.0 mg/L (mean: 96.9 ± 54.2 mg/L). The mean supplemental oxygen demand was 2.9 ± 1.4 L/min. [18F]FDG PET/CT images were acquired with a median of 12 (4-20) days of symptoms. After visual interpretation of the images, semiquantitative analysis of [18F]FDG uptake in multiple brain regions was evaluated using dedicated software and the standard deviation (SD) of brain uptake in each region was automatically calculated in comparison with reference values of a normal database. Evolutionarily ancient structures showed positive SD mean values of [18F]FDG uptake. Lenticular nuclei were bilaterally hypermetabolic (> 2 SD) in 21/23 (91.3%) patients, and thalamus in 16/23 (69.6%), bilaterally in 11/23 (47.8%). About half of patients showed hypermetabolism in brainstems, 40% in hippocampi, and 30% in cerebellums. In contrast, neocortical regions (frontal, parietal, temporal and occipital lobes) presented negative SD mean values of [18F]FDG uptake and hypometabolism (< 2 SD) was observed in up to a third of patients. Associations were found between hypoxia, inflammation, coagulation markers, and [18F]FDG uptake in various brain structures. CONCLUSIONS: Brain metabolism is clearly affected during the acute phase of COVID-19 respiratory syndrome in neurologically asymptomatic or oligosymptomatic patients. The most frequent finding is marked hypermetabolism in evolutionary ancient structures such as lenticular nucleus and thalami. Neocortical metabolism was reduced in up to one third of patients, suggesting a redistribution of brain metabolism from the neocortex to evolutionary ancient brain structures in these patients.
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Introduction: Cdc2-like kinase (CLK2) is a member of CLK kinases expressed in hypothalamic neurons and is activated in response to refeeding, leptin, or insulin. Diet-induced obesity and leptin receptor-deficient db/db mice lack CLK2 signal in the hypothalamic neurons. The neurotransmiter gamma-aminobutyric acid (GABA) is among the most prevalent in the central nervous system (CNS), particularly in the hypothalamus. Given the abundance of GABA-expressing neurons and their potential influence on regulating energy and behavioral homeostasis, we aimed to explore whether the deletion of CLK2 in GABAergic neurons alters energy homeostasis and behavioral and cognitive functions in both genders of mice lacking CLK2 in Vgat-expressing neurons (Vgat-Cre; Clk2loxP/loxP) on chow diet. Methods: We generated mice lacking Clk2 in Vgat-expressing neurons (Vgat-Cre; Clk2loxP/loxP) by mating Clk2loxP/loxP mice with Vgat-IRES-Cre transgenic mice and employed behavior, and physiological tests, and molecular approaches to investigate energy metabolism and behavior phenotype of both genders. Results and discussion: We showed that deletion of CLK2 in GABAergic neurons increased adiposity and food intake in females. The mechanisms behind these effects were likely due, at least in part, to hypothalamic insulin resistance and upregulation of hypothalamic Npy and Agrp expression. Besides normal insulin and pyruvate sensitivity, Vgat-Cre; Clk2loxP/loxP females were glucose intolerant. Male Vgat-Cre; Clk2loxP/loxP mice showed an increased energy expenditure (EE). Risen EE may account for avoiding weight and fat mass gain in male Vgat-Cre; Clk2loxP/loxP mice. Vgat-Cre; Clk2loxP/loxP mice had no alteration in cognition or memory functions in both genders. Interestingly, deleting CLK2 in GABAergic neurons changed anxiety-like behavior only in females, not males. These findings suggest that CLK2 in GABAergic neurons is critical in regulating energy balance and anxiety-like behavior in a gender-specific fashion and could be a molecular therapeutic target for combating obesity associated with psychological disorders in females.
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Ansiedad , Metabolismo Energético , Neuronas GABAérgicas , Animales , Femenino , Masculino , Ratones , Ansiedad/genética , Metabolismo Energético/genética , Insulinas , Obesidad/genéticaRESUMEN
Metformin is the most prescribed drug for DM2, but its site and mechanism of action are still not well established. Here, we investigated the effects of metformin on basolateral intestinal glucose uptake (BIGU), and its consequences on hepatic glucose production (HGP). In diabetic patients and mice, the primary site of metformin action was the gut, increasing BIGU, evaluated through PET-CT. In mice and CaCo2 cells, this increase in BIGU resulted from an increase in GLUT1 and GLUT2, secondary to ATF4 and AMPK. In hyperglycemia, metformin increased the lactate (reducing pH and bicarbonate in portal vein) and acetate production in the gut, modulating liver pyruvate carboxylase, MPC1/2, and FBP1, establishing a gut-liver crosstalk that reduces HGP. In normoglycemia, metformin-induced increases in BIGU is accompanied by hypoglycemia in the portal vein, generating a counter-regulatory mechanism that avoids reductions or even increases HGP. In summary, metformin increases BIGU and through gut-liver crosstalk influences HGP.
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Tracto Gastrointestinal , Glucosa , Hígado , Metformina , Animales , Humanos , Ratones , Células CACO-2 , Diabetes Mellitus Tipo 2 , Glucosa/metabolismo , Hipoglucemiantes/farmacología , Hígado/metabolismo , Metformina/farmacología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tracto Gastrointestinal/metabolismoRESUMEN
Swiss mice belong to an outbred strain of mice largely used as a model for experimental obesity induced by high fat diet (HFD). We have previously demonstrated that a given cohort of age-matched Swiss mice is hallmarked by heterogeneous changes in body weight when exposed to HFD. The reasons underlying such variability, however, are not completely understood. Therefore we aimed to clarify the mechanisms underlying the variability in spontaneous weight gain in age-matched male swiss mice. To achieve that, individuals in a cohort of age-matched male Swiss mice were categorized as prone to body mass gain (PBMG) and resistant to body mass gain (RBMG). PBMG animals had higher caloric intake and body mass gain. RBMG and PBMG mice had a similar reduction in food intake when challenged with leptin but only RBMG exhibited a drop in ghrelin concentrations after refeeding. PBMG also showed increased midbrain levels of ghrelin receptor (Ghsr) and Dopamine receptor d2 (Drd2) mRNAs upon refeeding. Pharmacological blockade of GHSR with JMV3002 failed to reduce food intake in PMBG mice as it did in RBMG. On the other hand, the response to JMV3002 seen in PBMG was hallmarked by singular transcriptional response in the midbrain characterized by a simultaneous increase in both tyrosine hydroxylase (Th) and Proopiomelanocortin (Pomc) expressions. In conclusion, our data show that differences in the expression of genes related to the reward system in the midbrain as well as in ghrelin concentrations in serum correlate with spontaneous variability in body mass and food intake seen in age-matched male Swiss mice.
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Ghrelina , Receptores de Ghrelina , Animales , Peso Corporal , Dieta Alta en Grasa , Ingestión de Alimentos , Ghrelina/metabolismo , Humanos , Masculino , Ratones , Receptores de Ghrelina/genética , Receptores de Ghrelina/metabolismoRESUMEN
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.
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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
PURPOSE: Isolated case reports mention the uptake of radiolabeled PSMA in lymphoma. However, it is not clear if the intensity of 68Ga-PSMA expression varies among different histological subtypes or if it correlates with 18F-FDG uptake. This study compared both tracers in patients with diverse lymphoma subtypes. METHODS: Ten patients with biopsy-proven-lymphoma underwent 18F-FDG and 68Ga-PSMA-PET/CT (maximum time interval: 6 days). Lymphoma subtypes included Hodgkin's lymphoma (HL, three patients) and aggressive and indolent non-Hodgkin's lymphoma (NHL, seven patients). The intensity of PSMA uptake was classified visually as low, intermediate, or high, using blood pool, liver and parotid gland uptake as references. Maximum standardized-uptake value (SUVmax) of each affected site was measured in both sets of images. RESULTS: FDG detected 59/59 involved sites in 10 patients and PSMA 47/59 sites in nine patients. PSMA uptake was generally low, regardless of the intensity of FDG uptake, but it was classified as intermediate in two patients. The median SUVmax varied from 2.0 (2.0-8.2) to 30.9 for FDG and from 1.7 (1.7-1.7) to 4.4 for PSMA, P < 0.0001. The primary lesion of one patient had a marked intralesional mismatch uptake pattern of the tracers, with areas of higher PSMA expression than FDG uptake, and vice-versa. A brain lesion was more easily identified with PSMA than with FDG images. CONCLUSION: HL and several NHL subtypes may present PSMA uptake. The intensity of PSMA expression is generally lower than that of FDG uptake and seems to present less variation among the different histological subtypes of lymphomas.
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Tomografía Computarizada por Tomografía de Emisión de PositronesRESUMEN
SCOPE: Nutritional supplementation of the maternal diet can modify the cancer susceptibility in adult offspring. Therefore, the authors evaluate the effects of a fish-oil diet administered to a long-term, during pre-mating, gestation, and lactation, in reducing cancer-cachexia damages in adult Walker-256 tumor-bearing offspring. METHODS AND RESULTS: Female rats receive control or fish oil diet during pre-mating, gestation, and lactation. After weaning, male offspring are fed the control diet until adulthood and distributed in (C) control adult-offspring; (W) adult tumor-bearing offspring; (OC) adult-offspring of maternal fish oil diet; (WOC) adult tumor-bearing offspring of maternal fish oil diet groups. Fat body mass is preserved, muscle expression of mechanistic target of rapamicin (mTOR) and eukariotic binding protein of eukariotic factor 4E (4E-BP1) is modified, being associated with lower 20S proteasome protein expression, and the liver alanine aminotransferase (ALT) enzyme content maintained in the WOC group. Also, the OC group shows reduced triglyceridemia. CONCLUSION: In this experimental model of cachexia, the long-term maternal supplementation is a positive strategy to improve liver function and lipid metabolism, as well as to modify muscle proteins expression in the mTOR pathway and also reduce the 20S muscle proteasome protein, without altering the tumor development and muscle wasting in adult tumor-bearing offspring.
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Caquexia/prevención & control , Carcinoma 256 de Walker/complicaciones , Aceites de Pescado/administración & dosificación , Alanina Transaminasa/metabolismo , Animales , Composición Corporal , Carcinoma 256 de Walker/metabolismo , Suplementos Dietéticos , Femenino , Lactancia , Masculino , Proteínas Musculares/metabolismo , Ratas , Ratas Wistar , Serina-Treonina Quinasas TOR/fisiología , Triglicéridos/sangreRESUMEN
Leucine can stimulate protein synthesis in skeletal muscle, and recent studies have shown an increase in leucine-related mitochondrial biogenesis and oxidative phosphorylation capacity in muscle cells. However, leucine-related effects in tumour tissues are still poorly understood. Thus, we described the effects of leucine in both in vivo and in vitro models of a Walker-256 tumour. Tumour-bearing Wistar rats were randomly distributed into a control group (W; normoprotein diet) and leucine group (LW; leucine-rich diet [normoprotein + 3% leucine]). After 20 days of tumour evolution, the animals underwent 18-fludeoxyglucose positron emission computed tomography (18F-FDG PET-CT) imaging, and after euthanasia, fresh tumour biopsy samples were taken for oxygen consumption rate measurements (Oroboros Oxygraph), electron microscopy analysis and RNA and protein extraction. Our main results from the LW group showed no tumour size change, lower tumour glucose (18F-FDG) uptake, and reduced metastatic sites. Furthermore, leucine stimulated a shift in tumour metabolism from glycolytic towards oxidative phosphorylation, higher mRNA and protein expression of oxidative phosphorylation components, and enhanced mitochondrial density/area even though the leucine-treated tumour had a higher number of apoptotic nuclei with increased oxidative stress. In summary, a leucine-rich diet directed Walker-256 tumour metabolism to a less glycolytic phenotype profile in which these metabolic alterations were associated with a decrease in tumour aggressiveness and reduction in the number of metastatic sites in rats fed a diet supplemented with this branched-chain amino acid.
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Carcinoma 256 de Walker/metabolismo , Glucosa/metabolismo , Glucólisis/efectos de los fármacos , Leucina/farmacología , Fosforilación Oxidativa/efectos de los fármacos , Animales , Carcinoma 256 de Walker/dietoterapia , Carcinoma 256 de Walker/patología , Femenino , Alimentos Formulados , Metástasis de la Neoplasia , Ratas , Ratas WistarRESUMEN
AIMS: The present investigation evaluated whether pregnancy followed by lactation exerts long-term impacts on maternal hepatic lipid metabolism. MAIN METHODS: Female mice were subjected to two pregnancies, after which they were either allowed to breastfeed their pups for 21â¯days (L21) or had their litter removed (L0). Age-matched virgin mice were used as controls (CTL). Three months after the second delivery, serum was collected for lipid profiling, and fragments of liver were used to assess lipid content and to evaluate the key steps of de novo non-esterified fatty acid (NEFA) synthesis, esterification and ß-oxidation, very low density lipoprotein (VLDL) assembly and secretion and autophagy. KEY FINDINGS: L0 exhibited a significant increase in hepatic TG and reduced apolipoprotein B-100 (ApoB-100) expression. L21 mice had increased ATP citrate lyase (ACLY) activity and reduced acetyl-CoA carboxylase (ACC) phosphorylation but no increased hepatic TG. On the other hand, L21 mice had reduced hepatic sequestosome 1 (SQSTM1/p62) levels. Increased high density lipoprotein (HDL) cholesterol and hepatic apolipoprotein A-1 (ApoA-1) expression were found exclusively in L21. SIGNIFICANCE: The present study reveals that long-term hepatic lipid accumulation is induced by the history of pregnancy without lactation. On the other hand, reduced SQSTM1/p62 levels indicate that increased autophagic flux during life may prevent hepatic fat in dams subjected to lactation. Lactation after pregnancy is also obligatory for a long-term increase in maternal HDL. The present data may contribute to the understanding of the mechanisms leading to elevated cardiometabolic risk in women limited to short periods of lactation.
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Lactancia , Metabolismo de los Lípidos , Hígado/metabolismo , Animales , Ácidos Grasos no Esterificados/análisis , Ácidos Grasos no Esterificados/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Oxidación-Reducción , Embarazo , Triglicéridos/análisis , Triglicéridos/metabolismoRESUMEN
OBJECTIVES: Insufficient protein ingestion may affect muscle and bone mass, increasing the risk of osteoporotic fractures in the elderly, and especially in postmenopausal women. We evaluated how a low-protein diet affects bone parameters under gonadal hormone deficiency and the improvement led by hormone replacement therapy (HRT) with 17ß-oestradiol. METHODS: Female Wistar rats were divided into control (C), ovariectomized (OVX), and 17ß-oestradiol-treated ovariectomized (OVX-HRT) groups, which were fed a control or an isocaloric low-protein diet (LP; 6.6% protein; seven animals per group). Morphometric, serum, and body composition parameters were assessed, as well as bone parameters, mechanical resistance, and mineralogy. RESULTS: The results showed that protein restriction negatively affected body chemical composition and bone metabolism by the sex hormone deficiency condition in the OVX group. The association between undernutrition and hormone deficiency led to bone and muscle mass loss and increased the fragility of the bone (as well as decreasing relative femoral weight, bone mineral density, femoral elasticity, peak stress, and stress at offset yield). Although protein restriction induced more severe adverse effects compared with the controls, the combination with HRT showed an improvement in minimizing these damaging effects, as it was seen that HRT had some efficacy in maintaining muscle and bone mass, preserving the bone resistance and minimizing some deleterious processes during the menopause. CONCLUSION: Protein restriction has adverse effects on metabolism, leading to more severe menopausal symptoms, and HRT could minimize these effects. Therefore, special attention should be given to a balanced diet during menopause and HRT.Cite this article: Bone Joint Res 2019;8:573-581.
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Obesity and type 2 diabetes are characterized by subclinical inflammatory process. Changes in composition or modulation of the gut microbiota may play an important role in the obesity-associated inflammatory process. In the current study, we evaluated the effects of probiotics (Lactobacillus rhamnosus, L. acidophilus and Bifidobacterium bifidumi) on gut microbiota, changes in permeability, and insulin sensitivity and signaling in high-fat diet and control animals. More importantly, we investigated the effects of these gut modulations on hypothalamic control of food intake, and insulin and leptin signaling. Swiss mice were submitted to a high-fat diet (HFD) with probiotics or pair-feeding for 5 weeks. Metagenome analyses were performed on DNA samples from mouse feces. Blood was drawn to determine levels of glucose, insulin, LPS, cytokines and GLP-1. Liver, muscle, ileum and hypothalamus tissue proteins were analyzed by Western blotting and real-time polymerase chain reaction. In addition, liver and adipose tissues were analyzed using histology and immunohistochemistry. The HFD induced huge alterations in gut microbiota accompanied by increased intestinal permeability, LPS translocation and systemic low-grade inflammation, resulting in decreased glucose tolerance and hyperphagic behavior. All these obesity-related features were reversed by changes in the gut microbiota profile induced by probiotics. Probiotics also induced an improvement in hypothalamic insulin and leptin resistance. Our data demonstrate that the intestinal microbiome is a key modulator of inflammatory and metabolic pathways in both peripheral and central tissues. These findings shed light on probiotics as an important tool to prevent and treat patients with obesity and insulin resistance.
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Diabetes Mellitus Tipo 2/prevención & control , Disbiosis/prevención & control , Microbioma Gastrointestinal , Resistencia a la Insulina , Mucosa Intestinal/fisiopatología , Obesidad/dietoterapia , Probióticos/uso terapéutico , Tejido Adiposo Blanco/inmunología , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/patología , Animales , Regulación del Apetito , Bifidobacterium bifidum/clasificación , Bifidobacterium bifidum/crecimiento & desarrollo , Bifidobacterium bifidum/inmunología , Bifidobacterium bifidum/aislamiento & purificación , Permeabilidad de la Membrana Celular , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/microbiología , Dieta Alta en Grasa/efectos adversos , Disbiosis/etiología , Disbiosis/inmunología , Disbiosis/microbiología , Heces/microbiología , Microbioma Gastrointestinal/inmunología , Técnica de Clampeo de la Glucosa , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Lactobacillus acidophilus/clasificación , Lactobacillus acidophilus/crecimiento & desarrollo , Lactobacillus acidophilus/inmunología , Lactobacillus acidophilus/aislamiento & purificación , Lacticaseibacillus rhamnosus/clasificación , Lacticaseibacillus rhamnosus/crecimiento & desarrollo , Lacticaseibacillus rhamnosus/inmunología , Lacticaseibacillus rhamnosus/aislamiento & purificación , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Tipificación Molecular , Obesidad/metabolismo , Obesidad/patología , Obesidad/fisiopatología , Distribución AleatoriaRESUMEN
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.
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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
OBJECTIVE: Protein tyrosine phosphatase 1B (PTP1B) has been extensively implicated in the regulation of body weight, food intake, and energy expenditure. The role of PTP1B appears to be cell and brain region dependent. RESULTS: Herein, we demonstrated that chronic high-fat feeding enhanced PTP1B expression in the central nucleus of the amygdala (CeA) of rats compared to rats on chow. Knocking down PTP1B with oligonucleotide antisense (ASO) decreased its expression and was sufficient to improve the anorexigenic effect of insulin through IR/Akt signaling in the CeA. ASO treatment reduces body weight, fat mass, serum leptin levels, and food intake and also increases energy expenditure, without altering ambulatory activity. These changes were explained, at least in part, by the improvement of insulin sensitivity in the CeA, decreasing NPY and enhancing oxytocin expression. There was a slight decline in fasting blood glucose and serum insulin levels possibly due to leanness in rats treated with ASO. Surprisingly, the elevated plus maze test revealed an anxiolytic behavior after reduction of PTP1B in the CeA. CONCLUSIONS: Thus, the present study highlights the deleterious role that the amygdalar PTP1B has on energy homeostasis in obesity states. The reduction of PTP1B in the CeA may be a strategy for the treatment of obesity, insulin resistance and anxiety disorders.
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Amígdala del Cerebelo/enzimología , Ansiedad/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Oligonucleótidos Antisentido/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 1/efectos de los fármacos , Adiposidad/genética , Animales , Ansiedad/genética , Dieta , Técnicas de Silenciamiento del Gen/métodos , Homeostasis , Insulina/metabolismo , Resistencia a la Insulina , Obesidad/etiología , Oligonucleótidos Antisentido/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 1/genética , Ratas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
Obesity and insulin resistance have been associated with deterioration in asthma outcomes. High oxidative stress and deficient activation of AMP-activated protein kinase (AMPK) have emerged as important regulators linking insulin resistance and inflammation. This study aimed to evaluate the effects of resveratrol on obesity-associated allergic pulmonary inflammation. Male C57/Bl6 mice fed with high-fat diet to induce obesity (obese group) or standard-chow diet (lean group) were treated or not with resveratrol (100mg/kg/day, two weeks). Mice were sensitized and challenged with ovalbumin (OVA). At 48h thereafter, bronchoalveolar lavage fluid was performed, and lungs collected for morphological studies and Western blot analysis. Treatment of obese mice with resveratrol significantly reduced hyperglycemia and insulin resistance, as well as the body measures (body mass, fat mass, % fat, and body area). OVA-challenge promoted a higher increase in pulmonary eosinophil infiltration in obese compared with lean mice, which was nearly abrogated by resveratrol treatment. Resveratrol markedly increased the phosphorylated AMPK expression in lung tissues of obese compared with lean mice. Resveratrol reduced the p47phox expression and reactive-oxygen species (ROS) production, and elevated the superoxide dismutase (SOD) levels in lung tissues of obese mice. The increased pulmonary levels of TNF-α and inducible nitric oxide synthase (iNOS) in obese mice were also normalized after resveratrol treatment. In lean mice, resveratrol failed to affect the levels of fasting glucose, p47phox, ROS levels, TNF-α, iNOS and phosphorylated AMPK. Resveratrol exhibits protective effects in obesity-associated lung inflammation that is accompanied by local AMPK activation and antioxidant property.
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Antioxidantes/uso terapéutico , Asma/tratamiento farmacológico , Eosinófilos/fisiología , Pulmón/efectos de los fármacos , Obesidad/tratamiento farmacológico , Neumonía/tratamiento farmacológico , Estilbenos/uso terapéutico , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Progresión de la Enfermedad , Pulmón/patología , Ratones , Ratones Endogámicos , ResveratrolRESUMEN
Recently, we demonstrated that the hypothalamic S1PR1/STAT3 axis plays a critical role in the control of food consumption and energy expenditure in rodents. Here, we found that reduction of hypothalamic S1PR1 expression occurs in an age-dependent manner, and was associated with defective thermogenic signaling and weight gain. To address the physiological relevance of these findings, we investigated the effects of chronic and acute exercise on the hypothalamic S1PR1/STAT3 axis. Chronic exercise increased S1PR1 expression and STAT3 phosphorylation in the hypothalamus, restoring the anorexigenic and thermogenic signals in middle-aged mice. Acutely, exercise increased sphingosine-1-phosphate (S1P) levels in the cerebrospinal fluid (CSF) of young rats, whereas the administration of CSF from exercised young rats into the hypothalamus of middle-aged rats at rest was sufficient to reduce the food intake. Finally, the intracerebroventricular (ICV) administration of S1PR1 activators, including the bioactive lipid molecule S1P, and pharmacological S1PR1 activator, SEW2871, induced a potent STAT3 phosphorylation and anorexigenic response in middle-aged rats. Overall, these results suggest that hypothalamic S1PR1 is important for the maintenance of energy balance and provide new insights into the mechanism by which exercise controls the anorexigenic and thermogenic signals in the central nervous system during the aging process.
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Metabolismo Energético/fisiología , Hipotálamo/metabolismo , Lisofosfolípidos/metabolismo , Condicionamiento Físico Animal/fisiología , Receptores de Lisoesfingolípidos/metabolismo , Transducción de Señal/fisiología , Esfingosina/análogos & derivados , Absorciometría de Fotón , Tejido Adiposo Pardo/diagnóstico por imagen , Envejecimiento/fisiología , Animales , Homeostasis/fisiología , Interleucina-6/sangre , Masculino , Ratones , Consumo de Oxígeno/fisiología , Ratas , Ratas Wistar , Esfingosina/metabolismo , Receptores de Esfingosina-1-Fosfato , Proteína Desacopladora 1/metabolismoRESUMEN
The liver regeneration is an important clinical issue after major hepatectomies. Unfortunately, many organs (including the liver) exhibit age-related impairments regarding their regenerative capacity. Recent studies found that low-power laser irradiation (LPLI) has a stimulatory effect on the liver regeneration process. However, its effects in elderly remain unknown. Thus, this study aimed to investigate the main molecular mechanisms involved in liver regeneration of partially hepatectomized elderly rats exposed to LPLI. The effects of 15 min of LPLI (wavelength of 632.8 nm; fluence of 0.97 J/cm(2); total energy delivered of 3.6 J) were evaluated in hepatectomized elderly Wistar male rats. Afterwards, through immunoblotting approaches, the protein expression and phosphorylation levels of hepatocyte growth factor (HGF), Met, Akt and Erk 1/2 signaling pathways as well as the proliferating cell nuclear antigen (PCNA) were investigated. It was observed that LPLI was not able to improve liver regeneration in elderly rats as evidenced by the lack of improvement of HGF and PCNA protein expression or phosphorylation levels of Met, Akt and Erk 1/2 in the remnant livers. In sum, this study demonstrated that the main molecular pathway, i.e. HGF/Met â Akt and Erk 1/2 â PCNA, involved in the hepatic regeneration process was not improved by LPLI in elderly hepatectomized rats, which in turn rules out LPLI as an adjuvant therapy, as observed in this protocol of liver regeneration evaluation (i.e. at 48 h after 70 % resection), in elderly.
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Envejecimiento , Regeneración Hepática/efectos de la radiación , Terapia por Luz de Baja Intensidad , Animales , Factor de Crecimiento de Hepatocito/metabolismo , Hígado/metabolismo , Hígado/fisiopatología , Hígado/efectos de la radiación , Sistema de Señalización de MAP Quinasas , Masculino , Antígeno Nuclear de Célula en Proliferación , Ratas , Ratas WistarRESUMEN
Hypothalamic inflammation is a common feature of experimental obesity. Dietary fats are important triggers of this process, inducing the activation of toll-like receptor-4 (TLR4) signaling and endoplasmic reticulum stress. Microglia cells, which are the cellular components of the innate immune system in the brain, are expected to play a role in the early activation of diet-induced hypothalamic inflammation. Here, we use bone marrow transplants to generate mice chimeras that express a functional TLR4 in the entire body except in bone marrow-derived cells or only in bone marrow-derived cells. We show that a functional TLR4 in bone marrow-derived cells is required for the complete expression of the diet-induced obese phenotype and for the perpetuation of inflammation in the hypothalamus. In an obesity-prone mouse strain, the chemokine CX3CL1 (fractalkine) is rapidly induced in the neurons of the hypothalamus after the introduction of a high-fat diet. The inhibition of hypothalamic fractalkine reduces diet-induced hypothalamic inflammation and the recruitment of bone marrow-derived monocytic cells to the hypothalamus; in addition, this inhibition reduces obesity and protects against diet-induced glucose intolerance. Thus, fractalkine is an important player in the early induction of diet-induced hypothalamic inflammation, and its inhibition impairs the induction of the obese and glucose intolerance phenotypes.