RESUMEN
The α7nAChR is crucial to the anti-inflammatory reflex, and to the expression of neuropeptides that control food intake, but its expression can be decreased by environmental factors. We aimed to investigate whether microRNA modulation could be an underlying mechanism in the α7nAchR downregulation in mouse hypothalamus following a short-term exposure to an obesogenic diet. Bioinformatic analysis revealed Let-7 microRNAs as candidates to regulate Chrna7, which was confirmed by the luciferase assay. Mice exposed to an obesogenic diet for 3 days had increased Let-7a and decreased α7nAChR levels, accompanied by hypothalamic fatty acids and TNFα content. Hypothalamic neuronal cells exposed to fatty acids presented higher Let-7a and TNFα levels and lower Chrna7 expression, but when the cells were pre-treated with TLR4 inhibitor, Let-7a, TNFα, and Chrna7 were rescued to normal levels. Thus, the fatty acids overload trigger TNFα-induced Let-7 overexpression in hypothalamic neuronal cells, which negatively regulates α7nAChR, an event that can be related to hyperphagia and obesity predisposition in mice.
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Factor de Necrosis Tumoral alfa , Receptor Nicotínico de Acetilcolina alfa 7 , Animales , Ratones , Receptor Nicotínico de Acetilcolina alfa 7/genética , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Ácidos Grasos , Regulación hacia Abajo , Hipotálamo/metabolismoRESUMEN
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.
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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
The pathophysiology of the restless legs syndrome (RLS) is related to dopaminergic dysfunction, reduced iron and variations in gene expression, such as the protein tyrosine phosphatase receptor type delta gene (PTPRD). Animal models could be key to achieving a mechanistic understanding of RLS and to facilitate efficient platforms for evaluating new therapeutics. Thus, the aim of this study was to evaluate the expression of PTPRD, of genes and proteins associated with RLS, the sleep patterns and the cardiovascular parameters in an animal model of RLS (spontaneously hypertensive rat [SHR]). Rats were divided into two groups: (i) Wistar-Kyoto and (ii) SHR. Cardiovascular parameters were assessed by tail plethysmography. Polysomnography was used to analyse the sleep pattern (24 h). For the PTPRD analyses, quantitative polymerase chain reaction (qPCR) and indirect enzyme-linked immunosorbent assay (ELISA) techniques were used. To evaluate the tyrosine hydroxylase enzyme, dopamine transporter (DAT) and type 2 dopaminergic receptor, qPCR and Western Blotting techniques were used. For the quantification of iron, ferritin and transferrin, the ELISA method was used. SHRs had higher blood pressure, alterations in sleep pattern, lower expression of protein content of PTPRD, lower expression of DAT, and lower serum concentrations of ferritin. These data suggest that the behavioural, physiological, and molecular changes observed in SHRs provide a useful animal model of RLS, reinforcing the importance of this strain as an animal model of this sleep disorder.
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Síndrome de las Piernas Inquietas , Ratas , Animales , Síndrome de las Piernas Inquietas/genética , Ratas Endogámicas WKY , Hierro , Dopamina , Ferritinas , Modelos Animales , Ratas Endogámicas SHR , Proteínas Tirosina FosfatasasRESUMEN
KEY POINTS: Time-restricted feeding (TRF, in which energy intake is restricted to 8 h/day during the dark phase) alone or combined with aerobic exercise (AE) training can prevent weight gain and metabolic disorders in Swiss mice fed a high-fat diet. The benefits of TRF combined with AE are associated with improved hepatic metabolism and decreased hepatic lipid accumulation. TRF combined with AE training increased fatty acid oxidation and decreased expression of lipogenic and gluconeogenic genes in the liver of young male Swiss mice. TRF combined with AE training attenuated the detrimental effects of high-fat diet feeding on the insulin signalling pathway in the liver. ABSTRACT: Time-restricted feeding (TRF) or physical exercise have been shown to be efficient in the prevention and treatment of metabolic disorders; however, the additive effects of TRF combined with aerobic exercise (AE) training on liver metabolism have not been widely explored. In this study TRF (8 h in the active phase) and TRF combined with AE (TRF+Exe) were compared in male Swiss mice fed a high-fat diet, with evaluation of the effects on insulin sensitivity and expression of hepatic genes involved in fatty acid oxidation, lipogenesis and gluconeogenesis. As in previous reports, we show that TRF alone (eating only between zeitgeber time 16 and 0) was sufficient to reduce weight and adiposity gain, increase fatty acid oxidation and decrease lipogenesis genes in the liver. In addition, we show that mice of the TRF+Exe group showed additional adaptations such as increased oxygen consumption ( VÌO2${\dot V_{{{\rm{O}}_{\rm{2}}}}}$ ), carbon dioxide production ( VÌCO2${\dot V_{{\rm{C}}{{\rm{O}}_{\rm{2}}}}}$ ) and production of ketone bodies (ß-hydroxybutyrate). Also, TRF+Exe attenuated the negative effects of high-fat diet feeding on the insulin signalling pathway (insulin receptor, insulin receptor substrate, Akt), and led to increased fatty acid oxidation (Ppara, Cpt1a) and decreased gluconeogenic (Fbp1, Pck1, Pgc1a) and lipogenic (Srebp1c, Cd36) gene expression in the liver. These molecular results were accompanied by increased glucose metabolism, lower serum triglycerides and reduced hepatic lipid content in the TRF+Exe group. The data presented in this study show that TRF alone has benefits but TRF+Exe has additive benefits and can mitigate the harmful effects of consuming a high-fat diet on body adiposity, liver metabolism and glycaemic homeostasis in young male Swiss mice.
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Resistencia a la Insulina , Enfermedades Metabólicas , Animales , Dieta Alta en Grasa/efectos adversos , Hígado/metabolismo , Masculino , Enfermedades Metabólicas/metabolismo , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , Aumento de PesoRESUMEN
Acute metabolic and molecular response to exercise may vary according to exercise's intensity and duration. However, there is a lack regarding specific tissue alterations after acute exercise with aerobic or anaerobic predominance. The present study investigated the effects of acute exercise performed at different intensities, but with equal total load on molecular and physiological responses in swimming rats. Sixty male rats were divided into a control group and five groups performing an acute bout of swimming exercise at different intensities (80, 90, 100, 110 and 120% of anaerobic threshold [AnT]). The exercise duration of each group was balanced so all groups performed at the same total load. Gene expression (HIF-1α, PGC-1α, MCT1 and MCT4 mRNA), blood biomarkers and tissue glycogen depletion were analyzed after the exercise session. ANOVA One-Way was used to indicate statistical mean differences considering 5% significance level. Blood lactate concentration was the only biomarker sensitive to acute exercise, with a significant increase in rats exercised above AnT intensities (p < 0.000). Glycogen stores of gluteus muscle were significantly reduced in all exercised animals in comparison to control group (p = 0.02). Hepatic tissue presented significant reduction in glycogen in animals exercised above AnT (p = 0.000, as well as reduced HIF-1α mRNA and increased MCT1 mRNA, especially at the highest intensity (p = 0.002). Physiological parameters did not alter amongst groups for most tissues. Our results indicate the hepatic tissue alterations (glycogen stores and gene expressions) in response to different exercise intensities of exercise, even with the total load matched.
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Condicionamiento Físico Animal , Natación , Umbral Anaerobio , Animales , Glucógeno/metabolismo , Masculino , Músculo Esquelético/metabolismo , ARN Mensajero/metabolismo , Ratas , Natación/fisiologíaRESUMEN
INTRODUCTION: Metabolic alterations caused by an imbalance of macronutrient consumption are often related to the modulation of microRNAs (miRNAs), which could alter mRNAs expression profile and accelerate the development of non-alcoholic fatty liver disease (NAFLD). AIMS: This study aimed to investigate the contribution of miRNAs in modulating early stages of NAFLD in mice submitted to a high-fat diet (HFD). METHODS AND RESULTS: Male Swiss mice, fed either a control diet or an HFD for 1, 3, 7, 15, 30, 56 days, were assessed for metabolic alterations, gene expression and NAFLD markers. A hepatocyte cell line was used to investigate the effects of miR-370 modulation on enzymes involved in ß-oxidation. Body weight and adiposity were higher after 7 days of HFD. Fasting glucose and insulin increased after 3 and 7 days of HFD, respectively. While hepatic lipid content increased from the first day on, hepatic glycogen had a decrease after 3 days of HFD consumption. miR-370 and Let-7 expression increased with acute and chronic exposure to HFD, accompanied by carnitine palmitoyltransferase 1A (Cpt1a), acyl-CoA dehydrogenase very long chain (Acadvl) and protein kinase AMP-activated Catalytic Subunit 2 (Prkaa2) downregulation, while decreased miR-122 expression was accompanied by 1-acylglycerol-3-phosphate-O-acyltransferase (Agpat) upregulation after 56 days of HFD consumption, some of them confirmed by in vitro experiments. Despite fluctuations in TNFa and IL6 mRNA levels, molecular modulation was consistent with hepatic TG and NAFLD development. CONCLUSION: Hepatic miR-370-122-Let7 miRNA modulation could be the first insult to NAFLD development, preceding changes in glycemic homeostasis and adiposity.
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MicroARNs , Enfermedad del Hígado Graso no Alcohólico , Animales , Dieta Alta en Grasa/efectos adversos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , MicroARNs/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Obesidad/metabolismoRESUMEN
BACKGROUND/AIMS: Cholinergic signalling mediated by the activation of muscarinic and nicotinic receptors has been described in the literature as a classic and important signalling pathway in the regulation of the inflammatory response. Recent research has investigated the role of acetylcholine, the physiological agonist of these receptors, in the control of energy homeostasis at the central level. Studies have shown that mice that do not express acetylcholine in brain regions regulating energy homeostasis present with excessive weight gain and hyperphagia. However, it has not yet been well-described in the literature which cholinergic receptor subunits are involved in this response; moreover, the signalling pathways responsible for the observed effects are not fully delineated. The hypothalamus is the regulating centre of energy homeostasis, and the α7 subunit of the nicotinic acetylcholine receptor (α7nAChR) is highly expressed in this region. When active, α7nAChR recruits proteins such as JAK2/STAT3 to mediate its signalling; the same intracellular components are required by leptin, an anorexigenic hormone. The aim of the present study was to evaluate the role of the hypothalamic α7nAChR in the control of energy homeostasis. METHODS: The work was performed on Swiss male mice. Initially, using immunofluorescent staining on brain sections, the presence of α7nAChR in hypothalamic cells regulating energy homeostasis was evaluated. Animals were submitted to stereotaxis in the lateral ventricle and intracerebroventricular stimulation (ICV) was used for the administration of an agonist (PNU) or antagonist (α-bungarotoxin) of α7nAChR. Metabolic parameters were evaluated and the expression of neuropeptides was evaluated in the hypothalamus by real-time PCR and western blot. The expression of hypothalamic neuropeptides was evaluated in mice treated with siRNA or inhibitors of JAK2/STAT3 (AG490 and STATTIC) proteins. We also evaluated food intake in α7nAChR knockout animals (α7KO). Additionally, in mouse hypothalamic cell culture (the mypHoA-POMC/GFP lineage), we evaluated the expression of neuropeptides and pSTAT3 after stimulation with PNU. RESULTS: Our results indicate co-localisation of α7nAChR with α-MSH, AgRP and NPY in hypothalamic cells. Pharmacological activation of α7nAChR reduced food intake and increased hypothalamic POMC expression and decreased NPY and AgRP mRNA levels and the protein content of pAMPK. Inhibition of α7nAChR with an antagonist increased the mRNA content of NPY and AgRP. Inhibition of α7nAChR with siRNA led to the suppression of POMC expression and an increase in AgRP mRNA levels. α7KO mice showed no changes in food intake. Inhibition of proteins involved in the JAK2/STAT3 signalling pathway reversed the effects observed after PNU stimulation. POMC-GFP cells, when treated with PNU, showed increased POMC expression and nuclear translocation of pSTAT3. CONCLUSION: Thus, selective activation of α7nAChR is able to modulate important markers of the response to food intake, suggesting that α7nAChR activation can suppress the expression of orexigenic markers and favour the expression of anorexics using the intracellular JAK2/STAT3 machinery.
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Proteína Relacionada con Agouti/metabolismo , Janus Quinasa 2/metabolismo , Proopiomelanocortina/metabolismo , Factor de Transcripción STAT3/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Proteína Relacionada con Agouti/genética , Animales , Benzamidas/farmacología , Compuestos Bicíclicos con Puentes/farmacología , Bungarotoxinas/farmacología , Línea Celular , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/metabolismo , Proopiomelanocortina/genética , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/genética , Transducción de Señal/efectos de los fármacos , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Receptor Nicotínico de Acetilcolina alfa 7/antagonistas & inhibidores , Receptor Nicotínico de Acetilcolina alfa 7/genéticaRESUMEN
There is no consensus on the effects of omega-3 (ω-3) fatty acids (FA) on cutaneous repair. To solve this problem, we used 2 different approaches: (1) FAT-1 transgenic mice, capable of producing endogenous ω-3 FA; (2) wild-type (WT) mice orally supplemented with DHA-enriched fish oil. FAT-1 mice had higher systemic (serum) and local (skin tissue) ω-3 FA levels, mainly docosahexaenoic acid (DHA), in comparison with WT mice. FAT-1 mice had increased myeloperoxidase (MPO) activity and content of CXCL-1 and CXCL-2, and reduced IL-10 in the skin wound tissue three days after the wound induction. Inflammation was maintained by an elevated TNF-α concentration and presence of inflammatory cells and edema. Neutrophils and macrophages, isolated from FAT-1 mice, also produced increased TNF-α and reduced IL-10 levels. In these mice, the wound closure was delayed, with a wound area 6-fold bigger in relation with WT group, on the last day of analysis (14 days post-wounding). This was associated with poor orientation of collagen fibers and structural aspects in repaired tissue. Similarly, DHA group had a delay during late inflammatory phase. This group had increased TNF-α content and CD45+F4/80+ cells at the third day after skin wounding and increased concentrations of important metabolites derived from ω-3, like 18-HEPE, and reduced concentrations of those from ω-6 FA. In conclusion, elevated DHA content, achieved in both FAT-1 and DHA groups, slowed inflammation resolution and impaired the quality of healed skin tissue.
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Ácidos Docosahexaenoicos/fisiología , Cicatrización de Heridas , Animales , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Suplementos Dietéticos , Ácido Graso Desaturasas/genética , Inflamación , Macrófagos/fisiología , Masculino , Ratones Transgénicos , Neutrófilos/fisiología , Piel/metabolismoRESUMEN
Hypothalamic inflammation and metabolic changes resulting from the consumption of high-fat diets have been linked to low grade inflammation and obesity. Inflammation impairs the hypothalamic expression of α7 nicotinic acetylcholine receptor (α7nAChR). The α7nAChR is described as the main component of the anti-inflammatory cholinergic pathway in different inflammation models. To assess whether the reduction in α7nAChR expression exacerbates hypothalamic inflammation induced by a high-fat diet (HFD), were used male and female global α7nAChR knockout mouse line in normal or high-fat diet for 4 weeks. Body weight gain, adiposity, glucose homeostasis, hypothalamic inflammation, food intake, and energy expenditure were evaluated. Insulin sensitivity was evaluated in neuronal cell culture. Consumption of an HFD for 4 weeks resulted in body weight gain and adiposity in male Chrna7-/- mice and the hypothalamus of male Chrna7-/- mice showed neuroinflammatory markers, with increased gene expression of pro-inflammatory cytokines and dysregulation in the nuclear factor kappa B pathway. Moreover, male Chrna7-/- mice consuming an HFD showed alterations in glucose homeostasis and serum of Chrna7-/- mice that consumed an HFD impaired insulin signalling in neuronal cell culture experiments. In general, female Chrna7-/- mice that consumed an HFD did not show the phenotypic and molecular changes found in male mice, indicating that there is sexual dimorphism in the analysed parameters. Thus, receptor deletion resulted in increased susceptibility to hypothalamic inflammation and metabolic damage associated with HFD consumption in male mice.
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Dieta Alta en Grasa , Receptor Nicotínico de Acetilcolina alfa 7 , Masculino , Femenino , Animales , Ratones , Dieta Alta en Grasa/efectos adversos , Receptor Nicotínico de Acetilcolina alfa 7/genética , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Ratones Noqueados , Obesidad/genética , Obesidad/metabolismo , Inflamación/metabolismo , Aumento de Peso , Hipotálamo/metabolismo , Fenotipo , Glucosa/metabolismoRESUMEN
Maternal obesity and/or high-fat diet (HF) consumption can disrupt appetite regulation in their offspring, contributing to transgenerational obesity and metabolic diseases. As fatty acids (FAs) play a role in appetite regulation, we investigated the maternal and fetal levels of FAs as potential contributors to programmed hyperphagia observed in the offspring of obese dams. Female mice were fed either a control diet (CT) or HF prior to mating, and fetal and maternal blood and tissues were collected at 19 days of gestation. Elevated levels of linoleic acid were observed in the serum of HF dams as well as in the serum of their fetuses. An increased concentration of eicosadienoic acid was also detected in the hypothalamus of female HF-O fetuses. HF-O male fetuses showed increased hypothalamic neuropeptide Y (Npy) gene expression, while HF-O female fetuses showed decreased hypothalamic pro-opiomelanocortin (POMC) protein content. Both male and female fetuses exhibited reduced hypothalamic neurogenin 3 (NGN-3) gene expression. In vitro experiments confirmed that LA contributed to the decreased gene expression of Pomc and Ngn-3 in neuronal cells. During lactation, HF female offspring consumed more milk and had a higher body weight compared to CT. In summary, this study demonstrated that exposure to HF prior to and during gestation alters the FA composition in maternal serum and fetal serum and hypothalamus, particularly increasing n-6, which may play a role in the switch from POMC to NPY neurons, leading to increased weight gain in the offspring during lactation.
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Neuropéptidos , Obesidad Materna , Efectos Tardíos de la Exposición Prenatal , Humanos , Femenino , Animales , Masculino , Embarazo , Ratones , Dieta Alta en Grasa/efectos adversos , Obesidad Materna/metabolismo , Ácidos Grasos/metabolismo , Proopiomelanocortina/metabolismo , Obesidad/metabolismo , Aumento de Peso , Neuropéptidos/metabolismo , Hipotálamo/metabolismo , Fenómenos Fisiologicos Nutricionales Maternos , Efectos Tardíos de la Exposición Prenatal/metabolismoRESUMEN
Interesterified fats have been used to replace trans-fat in ultra-processed foods. However, their metabolic effects are not completely understood. Hence, this study aimed to investigate the effects related to glucose homeostasis in response to interesterified palm oil or refined palm oil intake. Four-week-old male Swiss mice were randomly divided into four experimental groups and fed the following diets for 8 weeks: a normocaloric and normolipidic diet containing refined palm oil (PO group) or interesterified palm oil (IPO group); a hypercaloric and high-fat diet containing refined PO (POHF group) or interesterified PO (IPOHF group). Metabolic parameters related to body mass, adiposity and food consumption showed no significant differences. As for glucose homeostasis parameters, interesterified palm oil diets (IPO and IPOHF) resulted in higher glucose intolerance than unmodified palm oil diets (PO and POHF). Euglycemic-hyperinsulinemic clamp assessment showed a higher endogenous glucose production in the IPO group compared with the PO group. Moreover, the IPO group showed significantly lower p-AKT protein content (in the muscle and liver tissues) when compared with the PO group. Analysis of glucose-stimulated static insulin secretion (11.1 mmol/L glucose) in isolated pancreatic islets showed a higher insulin secretion in animals fed interesterified fat diets (IPO and IPOHF) than in those fed with palm oil (PO and POHF). Interesterified palm oil, including in normolipidic diets, can impair insulin signaling in peripheral tissues and increase insulin secretion by ß-cells, characterizing insulin resistance in mice.
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Resistencia a la Insulina , Masculino , Animales , Ratones , Aceite de Palma , Aceites de Plantas , Grasas de la Dieta , Secreción de Insulina , Ácidos Grasos/análisis , Dieta Alta en Grasa/efectos adversos , GlucosaRESUMEN
Developmental programming studies using mouse models have housed the animals at human thermoneutral temperatures (22°C) which imposes constant cold stress. As this impacts energy homeostasis, we investigated the effects of two housing temperatures (22°C and 30°C) on obesity development in male and female offspring of Control and FR dams. Pregnant mice were housed at 22°C (cold-exposed, CE) or 30°C (thermoneutrality, TN) room temperature. At gestational age e10, mice were fed either an ad libitum diet (Control) or were 30% food-restricted (FR) to produce low birth weight newborns. Following delivery, all dams were fed an ad libitum diet and maternal mice continued to nurse their own pups. At 3 weeks of age, offspring were weaned to an ad libitum diet and housed at similar temperatures as their mothers. Body weights and food intake were monitored. At 6 months of age, body composition and glucose tolerance test were determined, after which, brain and adipose tissue were collected for analysis. FR/CE and FR/TN offspring exhibited hyperphagia and were significantly heavier with increased adiposity as compared to their respective Controls. There was sex-specific effects of temperature in both groups. Male offspring at TN were heavier with increased body fat, though the food intake was decreased as compared to CE males. This was reflected by hypertrophic adipocytes and increased arcuate nucleus satiety/appetite ratio. In contrast, female offspring were not impacted by housing temperature. Thus, unlike female offspring, there was a significant interaction of diet and temperature evident in the male offspring with accentuated adverse effects evident in FR/TN males.
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Tejido Adiposo , Obesidad , Embarazo , Humanos , Animales , Masculino , Femenino , Ratones , Obesidad/etiología , Obesidad/metabolismo , Tejido Adiposo/metabolismo , Dieta , Adiposidad , DesteteRESUMEN
Introduction: High-fat diet (HFD) consumption is associated with various metabolic disorders and diseases. Both pre-pregnancy and maternal obesity can have long-term consequences on offspring health. Furthermore, consuming an HFD in adulthood significantly increases the risk of obesity and metabolic disorders. However, an intriguing phenomenon known as the obesity paradox suggests that obesity may confer a protective effect on mortality outcomes in sepsis. In sepsis, activation of the cholinergic anti-inflammatory pathway (CAP) can help mitigate systemic inflammation. We employed a metabolic programming model to explore the relationship between maternal HFD consumption and offspring response to sepsis. Methods: We fed female mice either a standard diet (SC) or an HFD during the pre-pregnancy, pregnancy, and lactation periods. Subsequently, we evaluated 28-day-old male offspring. Results: Notably, we discovered that offspring from HFD-fed dams (HFD-O) exhibited a higher survival rate compared with offspring from SC-fed dams (SC-O). Importantly, inhibition of the m1 muscarinic acetylcholine receptor (m1mAChR), involved in the CAP, in the hypothalamus abolished this protection. The expression of m1mAChR in the hypothalamus was higher in HFD-O at different ages, peaking on day 28. Treatment with an m1mAChR agonist could modulate the inflammatory response in peripheral tissues. Specifically, CAP activation was greater in the liver of HFD-O following agonist treatment. Interestingly, lipopolysaccharide (LPS) challenge failed to induce a more inflammatory state in HFD-O, in contrast to SC-O, and agonist treatment had no additional effect. Analysis of spleen immune cells revealed a distinct phenotype in HFD-O, characterized by elevated levels of CD4+ lymphocytes rather than CD8+ lymphocytes. Moreover, basal Il17 messenger RNA (mRNA) levels were lower while Il22 mRNA levels were higher in HFD-O, and we observed the same pattern after LPS challenge. Discussion: Further examination of myeloid cells isolated from bone marrow and allowed to differentiate showed that HFD-O macrophages displayed an anti-inflammatory phenotype. Additionally, treatment with the m1mAChR agonist contributed to reducing inflammatory marker levels in both groups. In summary, our findings demonstrate that HFD-O are protected against LPS-induced sepsis, and this protection is mediated by the central m1mAChR. Moreover, the inflammatory response in the liver, spleen, and bone marrow-differentiated macrophages is diminished. However, more extensive analysis is necessary to elucidate the specific mechanisms by which m1mAChR modulates the immune response during sepsis.
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Enfermedades Metabólicas , Sepsis , Humanos , Embarazo , Femenino , Masculino , Animales , Ratones , Receptor Muscarínico M1 , Dieta Alta en Grasa/efectos adversos , Lipopolisacáridos , Acetilcolina , Obesidad/etiología , ARN MensajeroRESUMEN
Purpose: Considering that the CHRNA7 and CHRFAM7A genes can be modulated by acute or chronic inflammation, and exercise modulates inflammatory responses, the question that arises is whether physical exercise could exert any effect on the expression of these genes. Thus, the aim of this work is to identify the effects of different types of exercises on the expression of the CHRNA7, CHRFAM7A and tumor necrosis factor-α (TNF-α) in leukocytes of healthy normal weight (HNW), and overweight with type 2 diabetes (OT2D) individuals. Methods: 15 OT2D and 13 HNW participants (men and women, from 40 to 60 years old) performed in a randomized crossover design three exercise sessions: aerobic exercise (AE), resistance exercise (RE) and combined exercise (CE). Blood samples were collected at rest and post-60-min of the exercise sessions. The leukocytes were the analysis of the CHRNA7, CHRFAM7A and (TNF-α) gene expression. Results: At baseline, OT2D had higher CHRFAM7A and TNF-α expression compared to HNW. No statistical differences were observed between groups for CHRNA7; however, the HNW group presented almost twice as many subjects with the expression of this gene (24% vs. 49%). Post exercise, the CHRFAM7A increased in AE, RE and CE for HNW, and in AE and CE for OT2D. There was no significant difference for TNF-α and CHRNA7 expression between any type of exercise and group. Conclusions: Our study shows that OT2D individuals presented higher baseline expression of TNF-α and CHRFAM7A, besides evidence of decreased CHRNA7A expression in leukocytes when compared with HNW. On the other hand, acutely physical exercise induces increased CHRFAM7A expression, especially when the aerobic component is present.
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Maternal obesity results in programmed offspring hyperphagia and obesity. The increased offspring food intake is due in part to the preferential differentiation of hypothalamic neuroprogenitor cells (NPCs) to orexigenic (AgRP) vs. anorexigenic (POMC) neurons. The altered neurogenesis may involve hypothalamic bHLH (basic helix-loop-helix) neuroregulatory factors (Hes1, Mash1, and Ngn3). Whilst the underlying mechanism remains unclear, it is known that mitochondrial function is critical for neurogenesis and is impacted by proinflammatory cytokines such as TNFα. Obesity is associated with the activation of inflammation and oxidative stress pathways. In obese pregnancies, increased levels of TNFα are seen in maternal and cord blood, indicating increased fetal exposure. As TNFα influences neurogenesis and mitochondrial function, we tested the effects of TNFα and reactive oxidative species (ROS) hydrogen peroxide (H2O2) on hypothalamic NPC cultures from newborn mice. TNFα treatment impaired NPC mitochondrial function, increased ROS production and NPC proliferation, and decreased the protein expression of proneurogenic Mash1/Ngn3. Consistent with this, AgRP protein expression was increased and POMC was decreased. Notably, treatment with H2O2 produced similar effects as TNFα and also reduced the protein expression of antioxidant SIRT1. The inhibition of STAT3/NFκB prevented the effects of TNFα, suggesting that TNFα mediates its effects on NPCs via mitochondrial-induced oxidative stress that involves both signaling pathways.
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In the last decades, obesity and nonalcoholic fatty liver disease (NAFLD) have become increasingly prevalent in wide world. Fatty liver can be detrimental to liver regeneration (LR) and offspring of obese dams (HFD-O) are susceptible to NAFLD development. Here we evaluated LR capacity in HFD-O after partial hepatectomy (PHx). HFD-O re-exposed or not to HFD in later life were evaluated for metabolic parameters, inflammation, proliferation, tissue repair markers and survival rate after PHx. Increasing adiposity and fatty liver were observed in HFD-O. Despite lower IL-6 levels, Ki67 labeling, cells in S phase and Ciclin D1/PCNA protein content, a lower impact on survival rate was found after PHx, even when re-exposed to HFD. However, no difference was observed between offspring of control dams (SC-O) and HFD-O after surgery. Although LR impairment is dependent of steatosis development, offspring of obese dams are programmed to be protected from the damage promoted by HFD.
Asunto(s)
Dieta Alta en Grasa , Enfermedad del Hígado Graso no Alcohólico , Animales , Dieta Alta en Grasa/efectos adversos , Hígado/metabolismo , Regeneración Hepática , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Obesidad/etiologíaRESUMEN
Obesity has become a public health problem in recent decades, and during pregnancy, it can lead to an increased risk of gestational complications and permanent changes in the offspring resulting from a process known as metabolic programming. The offspring of obese dams are at increased risk of developing non-alcoholic fatty liver disease (NAFLD), even in the absence of high-fat diet consumption. NAFLD is a chronic fatty liver disease that can progress to extremely severe conditions that require surgical intervention with the removal of the injured tissue. Liver regeneration is necessary to preserve organ function. A range of pathways is activated in the liver regeneration process, including the Hippo, TGFß, and AMPK signaling pathways that are under epigenetic control. We investigated whether microRNA modulation in the liver of the offspring of obese dams would impact gene expression of Hippo, TGFß, and AMPK pathways and tissue regeneration after partial hepatectomy (PHx). Female Swiss mice fed a standard chow or a high-fat diet (HFD) before and during pregnancy and lactation were mated with male control mice. The offspring from control (CT-O) and obese (HF-O) dams weaned to standard chow diet until day 56 were submitted to PHx surgery. Prior to the surgery, HF-O presented alterations in miR-122, miR-370, and Let-7a expression in the liver compared to CT-O, as previously shown, as well as in its target genes involved in liver regeneration. However, after the PHx (4 h or 48 h post-surgery), differences in gene expression between CT-O and HF-O were suppressed, as well as in microRNA expression in the liver. Furthermore, both CT-O and HF-O presented a similar regenerative capacity of the liver within 48 h after PHx. Our results suggest that survival and regenerative mechanisms induced by the partial hepatectomy may overcome the epigenetic changes in the liver of offspring programmed by maternal obesity.
RESUMEN
Neuronal hypothalamic insulin resistance is implicated in energy balance dysregulation and contributes to the pathogenesis of several neurodegenerative diseases. Its development has been intimately associated with a neuroinflammatory process mainly orchestrated by activated microglial cells. In this regard, our study aimed to investigate a target that is highly expressed in the hypothalamus and involved in the regulation of the inflammatory process, but still poorly investigated within the context of neuronal insulin resistance: the α7 nicotinic acetylcholine receptor (α7nAchR). Herein, we show that mHypoA-2/29 neurons exposed to pro-inflammatory microglial conditioned medium (MCM) showed higher expression of the pro-inflammatory cytokines IL-6, IL-1ß, and TNF-α, in addition to developing insulin resistance. Activation of α7nAchR with the selective agonist PNU-282987 prevented microglial-induced inflammation by inhibiting NF-κB nuclear translocation and increasing IL-10 and tristetraprolin (TTP) gene expression. The anti-inflammatory role of α7nAchR was also accompanied by an improvement in insulin sensitivity and lower activation of neurodegeneration-related markers, such as GSK3 and tau. In conclusion, we show that activation of α7nAchR anti-inflammatory signaling in hypothalamic neurons exerts neuroprotective effects and prevents the development of insulin resistance induced by pro-inflammatory mediators secreted by microglial cells.
Asunto(s)
Resistencia a la Insulina , Receptor Nicotínico de Acetilcolina alfa 7 , Animales , Benzamidas , Compuestos Bicíclicos con Puentes , Glucógeno Sintasa Quinasa 3/metabolismo , Hipotálamo/metabolismo , Inflamación/patología , Ratones , Microglía/metabolismo , Neuronas/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/metabolismoRESUMEN
The aim of this study was to investigate certain parameters regarding the maternal-fetal outcomes in a diet-induced obesity model. Obese, glucose-intolerant females who were exposed to a high-fat diet prior to pregnancy had lower placental efficiency and lower birth weight pups compared to the controls. Simple linear regression analyses showed that maternal obesity disrupts the proportionality between maternal and fetal outcomes during pregnancy. Maternal obesity is correlated with fetal outcomes, perhaps because of problems with hormonal signaling and exacerbation of inflammation in the maternal metabolic environment. The maternal obese phenotype altered the thickness of the placental layer, the transport of fatty acids, and the expression of growth factors. For example, lower expression of epidermal growth factor receptor (EGFR) mRNA in the obesity-prone group may have contributed to the rupture of the placental layers, leading to adverse fetal outcomes. Furthermore, maintenance of maternal glucose homeostasis and overexpression of placental growth factor (PGF) in the obesity-resistant group likely protected the placenta and fetuses from morphological and functional damage.
Asunto(s)
Dieta Alta en Grasa , Obesidad Materna , Animales , Dieta Alta en Grasa/efectos adversos , Femenino , Desarrollo Fetal , Retardo del Crecimiento Fetal/genética , Glucosa/metabolismo , Humanos , Ratones , Obesidad/metabolismo , Fenotipo , Placenta/metabolismo , Factor de Crecimiento Placentario/genética , Factor de Crecimiento Placentario/metabolismo , EmbarazoRESUMEN
High-fat diets seem to have a negative influence on the development of obesity and the processes associated with low-grade chronic systemic inflammation. In recent years, partial hydrogenated oil, rich in trans isomers, has been associated with deleterious health effects. It has been replaced by interesterified fat (IF). However, there is no evidence whether IF ingestion can exert adverse effects on the intestinal mucosa. Thus, this study aimed to evaluate the effect of IF on the intestinal mucosa of male Swiss mice fed a normal or high-fat diet, focusing on its effects on intestinal permeability and bacterial translocation and its possible damage to the intestinal epithelium. The animals were divided into 4 groups: Control (C) and Interesterified Control (IC) groups (10 En% lipids from unmodified fat or interesterified fat, respectively) and High Fat (HF) and Interesterified High Fat (IHF) groups (45 En% lipids from unmodified fat or interesterified fat, respectively). Compare to C, the IC, HF, and IHF groups presented flattened epithelium, a shorter villi length and a lower percentage of goblet cells, less mucin 2, an increased oxidative stress and more inflammatory cells, higher IL-1ß, IL-17, and IL-23 levels. These groups also presented increased intestinal permeability and gene expression of the protein claudin 2, while JAM-A and claudin 1 gene expression was reduced. IC and IHF increased IL-6 levels while reducing occludin expression. In addition, the IC group also presented a mucosa with lesions of low intensity in the ileum, an increased mucin 5ac, TNF-α levels, and reduced occludin expression in the distal jejunum. Moreover, there was a significant increase in bacterial translocation in the IC group to blood, liver, and lungs, while HF and IHF groups presented bacterial translocation which was restricted to the mesenteric lymph nodes. In summary, our results supported the hypothesis that IF added to a normolipidic diet can be considered harmful or even worse when compared to a HF.