RESUMO
Reproduction is safeguarded by multiple, often cooperative, regulatory networks. Kisspeptin signaling, via KISS1R, plays a fundamental role in reproductive control, primarily by regulation of hypothalamic GnRH neurons. We disclose herein a pathway for direct kisspeptin actions in astrocytes that contributes to central reproductive modulation. Protein-protein interaction and ontology analyses of hypothalamic proteomic profiles after kisspeptin stimulation revealed that glial/astrocyte markers are regulated by kisspeptin in mice. This glial-kisspeptin pathway was validated by the demonstrated expression of Kiss1r in mouse astrocytes in vivo and astrocyte cultures from humans, rats, and mice, where kisspeptin activated canonical intracellular signaling-pathways. Cellular coexpression of Kiss1r with the astrocyte markers GFAP and S100-ß occurred in different brain regions, with higher percentage in Kiss1- and GnRH-enriched areas. Conditional ablation of Kiss1r in GFAP-positive cells in the G-KiR-KO mouse altered gene expression of key factors in PGE2 synthesis in astrocytes and perturbed astrocyte-GnRH neuronal appositions, as well as LH responses to kisspeptin and LH pulsatility, as surrogate marker of GnRH secretion. G-KiR-KO mice also displayed changes in reproductive responses to metabolic stress induced by high-fat diet, affecting female pubertal onset, estrous cyclicity, and LH-secretory profiles. Our data unveil a nonneuronal pathway for kisspeptin actions in astrocytes, which cooperates in fine-tuning the reproductive axis and its responses to metabolic stress.
Assuntos
Astrócitos , Hormônio Liberador de Gonadotropina , Kisspeptinas , Camundongos Knockout , Receptores de Kisspeptina-1 , Transdução de Sinais , Kisspeptinas/metabolismo , Kisspeptinas/genética , Animais , Astrócitos/metabolismo , Camundongos , Receptores de Kisspeptina-1/metabolismo , Receptores de Kisspeptina-1/genética , Humanos , Ratos , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Liberador de Gonadotropina/genética , Masculino , Hipotálamo/metabolismo , Neurônios/metabolismo , Dinoprostona/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100/genética , Proteína Glial Fibrilar Ácida/metabolismo , Proteína Glial Fibrilar Ácida/genética , ReproduçãoRESUMO
BACKGROUND: Children with pregnancy-associated plasma protein-A2 (PAPP-A2) mutations resulting in low levels of bioactive insulin-like growth factor-1 (IGF1) and progressive postnatal growth retardation have improved growth velocity and height following recombinant human (rh)IGF1 treatment. The present study aimed to evaluate whether Pappa2 deficiency and pharmacological manipulation of GH/IGF1 system are associated with sex-specific differences in growth-related signaling pathways. METHODS: Plasma, hypothalamus, pituitary gland and liver of Pappa2ko/ko mice of both sexes, showing reduced skeletal growth, and liver of these mice treated with rhGH, rhIGF1 and rhPAPP-A2 from postnatal day (PND) 5 to PND35 were analyzed. RESULTS: Reduced body and femur length of Pappa2ko/ko mice was associated with increases in: (1) components of IGF1 ternary complexes (IGF1, IGFBP5/Igfbp5, Igfbp3, Igfals) in plasma, hypothalamus and/or liver; and (2) key signaling regulators (phosphorylated PI3K, AKT, mTOR, GSK3ß, ERK1/2 and AMPKα) in hypothalamus, pituitary gland and/or liver, with Pappa2ko/ko females having a more prominent effect. Compared to rhGH and rhIGF1, rhPAPP-A2 specifically induced: (1) increased body and femur length, and reduced plasma total IGF1 and IGFBP5 concentrations in Pappa2ko/ko females; and (2) increased Igf1 and Igf1r levels and decreased Ghr, Igfbp3 and Igfals levels in the liver of Pappa2ko/ko females. These changes were accompanied by lower phospho-STAT5, phospho-AKT and phospho-ERK2 levels and higher phospho-AMPK levels in the liver of Pappa2ko/ko females. CONCLUSIONS: Sex-specific differences in IGF1 system and signaling pathways are associated with Pappa2 deficiency, pointing to rhPAPP-A2 as a promising drug to alleviate postnatal growth retardation underlying low IGF1 bioavailability in a female-specific manner.
Understanding the physiological role of pregnancy-associated plasma protein-A2 (PAPP-A2), a proteinase involved in the insulin-like growth factor-1 (IGF1) availability to regulate growth, could provide insight into new treatments for patients with short stature and skeletal abnormalities. Although progressive postnatal growth retardation in patients with PAPP-A2 mutations can differ between males and females, we do not know the underlying differences in IGF1 system and signaling, and their response to treatment that contribute to growth improvement. The present study examines whether Pappa2 deficiency and pharmacological administration of rhGH, rhIGF1 and rhPAPP-A2 are associated with sex-specific differences in IGF1 ternary complexes and IGF1 signaling pathways. Reduced body and femur length of Pappa2-deficient mice was associated with sex- and tissue-specific alteration of IGF ternary/binary complexes and IGF1 signaling pathways. rhPAPP-A2 treatment induced female-specific increase in body and femur length and reduction in IGF ternary/binary complexes through STAT5-AKT-ERK2-AMPK signaling pathways in liver. The involvement of PAPP-A2 in sex-based growth physiology supports the use of promising drugs to alleviate postnatal growth retardation underlying low IGF1 bioavailability in a female-specific manner.
Assuntos
Piperazinas , Proteína Plasmática A Associada à Gravidez , Proteínas Proto-Oncogênicas c-akt , Humanos , Masculino , Criança , Camundongos , Feminino , Animais , Proteína Plasmática A Associada à Gravidez/genética , Proteína Plasmática A Associada à Gravidez/metabolismo , Transtornos do Crescimento/metabolismoRESUMO
CONTEXT: Anorexia nervosa (AN) can cause severe undernutrition associated with alterations in the IGF axis. Pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC-1, STC-2) modulate IGF binding-protein (IGFBP) cleavage and IGF bioavailability, but their implications in AN are unknown. OBJECTIVE: We determined serum levels of PAPP-As and STCs in relationship with classical IGF axis parameters in female adolescents with AN and their association with nutritional status and secondary amenorrhea. METHODS: Parameters of the IGF axis were determined in fasting serum samples of 68 female adolescents with AN at diagnosis and 62 sex- and age-matched controls. Standardized body mass index (BMI) and bone mineral density (BMD) were calculated. RESULTS: Patients with AN had lower concentrations of total and free IGF-I, total IGFBP-3, acid-labile subunit (ALS), insulin, PAPP-A2, STC-1, and STC-2 and higher levels of IGF-II and IGFBP-2. Their free/total IGF-I ratio was decreased and the intact/total IGFBP-3 and -4 ratios increased. BMI was directly related to total IGF-I and intact IGFBP-3 and inversely with IGFBP-2 and intact IGFBP-4. Weight loss was directly correlated with intact IGFBP-4 and negatively with intact IGFBP-3, ALS, STC-2, and PAPP-A2 concentrations. BMD was directly related to intact IGFBP-3 and inversely with intact IGFBP-4 and PAPP-A2 levels. Patients with amenorrhea had lower levels of total IGF-I and IGFBP-3 than those with menses. CONCLUSION: The reduction of PAPP-A2 in patients with AN may be involved in a decline in IGFBP cleavage, which could underlie the decrease in IGF-I bioavailability that is influenced by nutritional status and amenorrhea.
Assuntos
Anorexia Nervosa , Hormônios Peptídicos , Humanos , Feminino , Adolescente , Fator de Crescimento Insulin-Like I/metabolismo , Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina , Disponibilidade Biológica , Amenorreia , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina , Proteína Plasmática A Associada à Gravidez/metabolismoRESUMO
Leptin receptors (LepR) are expressed in brain areas controlling food intake homeostasis, such as the hypothalamus, the hippocampus and the prefrontal cortex. In a previous study we reported that long-term intake of saturated and monounsaturated fat alters hypothalamic LepR signalling. The current study aims at investigating the effect of foods high in either saturated (SOLF) or monounsaturated fat (UOLF) on LepR functionality in the hippocampus and the prefrontal cortex. Male mice were placed on SOLF/UOLF (eight weeks), then treated with recombinant murine leptin (1 mg/kg). After 60 min, brain regions were dissected and processed for western blot of phosphorylated STAT3 (pSTAT3), Akt (pAkt) and AMPK (pAMPK). Levels of SOCS3 were also quantified. SOLF itself increased basal levels of pSTAT3, while UOLF impaired leptin-induced phosphorylation of both Akt and AMPK. SOCS3 levels were specifically increased by UOLF within the prefrontal cortex. Our results show that SOLF and UOLF differently affect LepR signalling within the hippocampus and the prefrontal cortex, which points to the complex effect of saturated and unsaturated fat on brain function, particularly in areas regulating food intake.
Assuntos
Encéfalo , Receptores para Leptina , Animais , Masculino , Camundongos , Proteínas Quinases Ativadas por AMP , Encéfalo/metabolismo , Gorduras Insaturadas/administração & dosagem , Hipotálamo/metabolismo , Leptina/metabolismo , Proteínas Proto-Oncogênicas c-akt , Receptores para Leptina/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismoRESUMO
Leptin is involved in the modulation of insulin signaling in peripheral tissues, being closely associated with changes in lipid metabolism. This adipokine modifies inflammatory pathways that can interact with insulin targets in peripheral organs; however, the mechanisms remain unclear. Inflammatory and insulin signaling targets, cytokines, adiponectin, irisin and non-esterified fatty acid (NEFA) levels and enzymes of fatty acid anabolism were studied in the gastrocnemius of chronic centrally infused leptin (L), pair-fed and control rats. The phosphorylation of signal transducer and activator of transcription 3 (STAT3) and c-Jun N-terminal kinase (JNK) was reduced in L rats (59% and 58%, respectively). The phosphorylation of the insulin receptor and Akt and adiponectin and irisin content was increased in L rats (154%, 157%, 308% and 329%, respectively). The levels of glucose-6-phosphate dehydrogenase, the mRNA content of acetyl Co-A carboxylase and NEFA concentrations were diminished in the muscles of L rats (59%, 50% and 61%, respectively). The activation of JNK correlated positively with STAT3 phosphorylation, tumoral necrosis factor-α and NEFA and negatively with irisin and Akt phosphorylation. These data suggest that the activation of insulin signaling targets and a decrease in NEFA content are associated with a reduction in muscle inflammation parameters, suggesting that leptin may integrate these pathways.
RESUMO
Long-term high-fat diet (HFD) consumption commonly leads to obesity, a major health concern of western societies and a risk factor for Alzheimer's disease (AD). Both conditions present glial activation and inflammation and show sex differences in their incidence, clinical manifestation, and disease course. HFD intake has an important impact on gut microbiota, the bacteria present in the gut, and microbiota dysbiosis is associated with inflammation and certain mental disorders such as anxiety. In this study, we have analyzed the effects of a prolonged (18 weeks, starting at 7 months of age) HFD on male and female mice, both wild type (WT) and TgAPP mice, a model for AD, investigating the behavioral profile, gut microbiota composition and inflammatory/phagocytosis-related gene expression in hippocampus. In the open-field test, no overt differences in motor activity were observed between male and female or WT and TgAPP mice on a low-fat diet (LFD). However, HFD induced anxiety, as judged by decreased motor activity and increased time in the margins in the open-field, and a trend towards increased immobility time in the tail suspension test, with increased defecation. Intriguingly, female TgAPP mice on HFD showed less immobility and defecation compared to female WT mice on HFD. HFD induced dysbiosis of gut microbiota, resulting in reduced microbiota diversity and abundance compared with LFD fed mice, with some significant differences due to sex and little effect of genotype. Gene expression of pro-inflammatory/phagocytic markers in the hippocampus were not different between male and female WT mice, and in TgAPP mice of both sexes, some cytokines (IL-6 and IFNγ) were higher than in WT mice on LFD, more so in female TgAPP (IL-6). HFD induced few alterations in mRNA expression of inflammatory/phagocytosis-related genes in male mice, whether WT (IL-1ß, MHCII), or TgAPP (IL-6). However, in female TgAPP, altered gene expression returned towards control levels following prolonged HFD (IL-6, IL-12ß, TNFα, CD36, IRAK4, PYRY6). In summary, we demonstrate that HFD induces anxiogenic symptoms, marked alterations in gut microbiota, and increased expression of inflammatory genes, except for female TgAPP that appear to be resistant to the diet effects. Lifestyle interventions should be introduced to prevent AD onset or exacerbation by reducing inflammation and its associated symptoms; however, our results suggest that the eventual goal of developing prevention and treatment strategies should take sex into consideration.
Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Comportamento Animal/fisiologia , Dieta Hiperlipídica , Disbiose/genética , Microbioma Gastrointestinal/fisiologia , Inflamação/genética , Estresse Psicológico/genética , Doença de Alzheimer/fisiopatologia , Animais , Modelos Animais de Doenças , Disbiose/fisiopatologia , Feminino , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Interleucina-1beta/genética , Interleucina-6/genética , Masculino , Camundongos , Camundongos Transgênicos , Fagocitose/genética , RNA Mensageiro/metabolismo , Caracteres Sexuais , Estresse Psicológico/fisiopatologiaRESUMO
Maternal nutritional imbalances, in addition to maternal overweight and obesity, can result in long-term effects on the metabolic health of the offspring, increasing the risk of common non-communicable disorders such as obesity, diabetes and cardiovascular disease. This increased disease risk may also be transmitted across generations. Unfortunately, lifestyle interventions have shown reduced compliancy and limited efficacy. Resveratrol is a natural polyphenolic compound reported to have pleiotropic beneficial actions including a possible protective effect against the metabolic programming induced by poor dietary habits during development. However, studies to date are inconclusive regarding the potential metabolic benefits of maternal resveratrol supplementation during pregnancy and lactation on the offspring. Moreover, the responses to metabolic challenges are suggested to be different in males and females, suggesting that the effectiveness of treatment strategies may also differ, but many studies have been performed only in males. Here we review the current evidence, both in humans and animal models, regarding the possible beneficial effects of maternal resveratrol intake on the metabolic health of the offspring and highlight the different effects of resveratrol depending on the maternal diet, as well as the differential responses of males and females.
Assuntos
Antioxidantes/farmacologia , Fenômenos Fisiológicos da Nutrição Materna , Resveratrol/farmacologia , Animais , Antioxidantes/administração & dosagem , Feminino , Humanos , Recém-Nascido , Lactação , Estilo de Vida , Masculino , Fenômenos Fisiológicos da Nutrição Materna/efeitos dos fármacos , Obesidade/metabolismo , Gravidez , Resveratrol/administração & dosagemRESUMO
The growth hormone (GH)/insulin-like growth factor I (IGF-I) axis is involved in metabolic control. Malnutrition reduces IGF-I and modifies the thermogenic capacity of brown adipose tissue (BAT). Leptin has effects on the GH/IGF-I axis and the function of BAT, but its interaction with IGF-I and the mechanisms involved in the regulation of thermogenesis remains unknown. We studied the GH/IGF-I axis and activation of IGF-I-related signaling and metabolism related to BAT thermogenesis in chronic central leptin infused (L), pair-fed (PF), and control rats. Hypothalamic somatostatin mRNA levels were increased in PF and decreased in L, while pituitary GH mRNA was reduced in PF. Serum GH and IGF-I concentrations were decreased only in PF. In BAT, the association between suppressor of cytokine signaling 3 and the IGF-I receptor was reduced, and phosphorylation of the IGF-I receptor increased in the L group. Phosphorylation of Akt and cyclic AMP response element binding protein and glucose transporter 4 mRNA levels were increased in L and mRNA levels of uncoupling protein-1 (UCP-1) and enzymes involved in lipid anabolism reduced in PF. These results suggest that modifications in UCP-1 in BAT and changes in the GH/IGF-I axis induced by negative energy balance are dependent upon leptin levels.
Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Hormônio do Crescimento/genética , Fator de Crescimento Insulin-Like I/genética , Leptina/farmacologia , Termogênese/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Metabolismo Energético/genética , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Hormônio do Crescimento/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Injeções Intraventriculares , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Fosforilação/efeitos dos fármacos , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Somatostatina/genética , Somatostatina/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Termogênese/genética , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMO
BACKGROUND: In obesity adipose tissue undergoes structural re-modelling leading to a chronic low-grade inflammatory state linked to insulin resistance (IR). OBJECTIVE: We aimed to develop a clinically relevant biomarker model for stratifying IR in adolescents with obesity. METHODS: Cytokines [tumour cell derived factor 1α, monocyte chemoattract protein (MCP) 1, eotaxin and fractalkine], growth factors [brain-derived neurotrophic factor, pro-fibrotic platelet-derived growth factor (PDGF-BB) and insulin-like growth factor 1] and biochemical/metabolic factors were analysed in serum of 143 pubertal patients with obesity (50% IR; 50% non-IR) and 33 controls. Factor analysis, correlation, binary logistic regression and receiver operating characteristic analysis were used to evaluate combinations of these biomarkers as possible diagnostic tools for IR. RESULTS: Two biomarker IR models combining levels of triglycerides (TG)/HDL, eotaxin, MCP-1 and PDGF-BB in pubertal patients with obesity of both sexes were defined. Altered levels of MCP-1, eotaxin, and PDGF-BB constitute a main component that determines 27.7% of the variance explaining IR. Growth and inflammatory factors comprise two other components linked to the first, together accounting for 59.2% of the variance determining IR. CONCLUSIONS: PDGF-BB, MCP-1, eotaxin, TG and cholesterol concentrations constitute a solid panel of biomarkers associated with IR in pubertal children with obesity that could be useful in their stratification in a clinical setting for stratification.
Assuntos
Quimiocinas/sangue , Resistência à Insulina , Obesidade Infantil/fisiopatologia , Puberdade , Tecido Adiposo/metabolismo , Adolescente , Biomarcadores/sangue , Criança , Estudos Transversais , Análise Fatorial , Feminino , Humanos , Modelos Logísticos , Masculino , Obesidade Infantil/sangue , Curva ROCRESUMO
Maternal nutrition can affect the susceptibility of the offspring to metabolic disease later in life, suggesting that this period is a window of opportunity for intervention to reduce the risk of metabolic disease. Resveratrol, a natural polyphenol, has a wide range of beneficial properties including anti-obesogenic, anti-atherosclerotic, and anti-diabetic effects. We previously reported that maternal resveratrol intake during pregnancy and lactation has early metabolic effects in the offspring with these effects at weaning depending on the type of diet ingested by the mother and the offspring's sex. Here we analyzed whether these metabolic changes are maintained in the adult offspring and if they remain sex and maternal diet dependent. Wistar rats received a low-fat diet (LFD; 10.2% Kcal from fat) or high fat diet (HFD; 61.6% Kcal from fat) during pregnancy and lactation. Half of each group received resveratrol in their drinking water (50 mg/L). Offspring were weaned onto standard chow on postnatal day 21. Maternal resveratrol reduced serum cholesterol levels in all adult offspring from HFD mothers and increased it in adult female offspring from LFD mothers. Resveratrol increased visceral adipose tissue (VAT) in LFD offspring in both sexes but decreased it in male HFD offspring. Resveratrol shifted the distribution of VAT adipocyte size to a significantly higher incidence of large adipocytes, regardless of sex or maternal diet. These results clearly demonstrate that maternal resveratrol intake has long-lasting effects on metabolic health of offspring in a sex specific manner with these effects being highly dependent on the maternal diet.
Assuntos
Metabolismo Energético/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Resveratrol/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Feminino , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Masculino , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Doenças Metabólicas/sangue , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Ratos , Ratos Wistar , Caracteres SexuaisRESUMO
Microglia, the primary regulators of inflammatory responses in the brain, suffer deterioration during aging culminating in their inability to generate adequate adaptive responses to maintain physiological homeostasis in brain tissue. Microglia affect the function of other glial cells and neurons, including those involved in the hypothalamic control of body homeostasis. Microglial dysfunction with aging in cognitive areas such as the hippocampus is known to associate with cognitive decline; more recently, microglial alterations in the hypothalamus during midlife was suggested to participate in changes in the endocrine and metabolic control exerted by this brain region. Consequently, the feed-back loops between endocrine glands and the hypothalamus are altered. This generates a vicious circle in which the plasma levels of key neuroprotective hormones, such as gonadal hormones, insulin-like growth factor-1, growth hormone and leptin and their hypothalamic signaling are decreased, which further enhances microglial alterations and deterioration of hypothalamic function. Hypothalamic dysfunction is a risk factor for neurodegenerative diseases and these diseases in turn promote additional alterations in hypothalamic microglial cells, which are unable to cope with the neurodegenerative process, resulting in permanent damage of the neuronal-glial circuits controlling endocrine homeostasis, food intake and body metabolism. Thus, a "vicious cycle" may such be initiated.
Assuntos
Envelhecimento/metabolismo , Doenças Hipotalâmicas/metabolismo , Inflamação/metabolismo , Microglia/metabolismo , Doenças Neurodegenerativas/metabolismo , Sistemas Neurossecretores/metabolismo , Animais , HumanosRESUMO
Obesity is one of the most important health problems facing developed countries because being overweight is associated with a higher incidence of type 2 diabetes, cardiovascular disease and cancer, as well as other comorbidities. Although increased weight gain results from a combination of poor dietary habits and decreased energy expenditure, not all individuals have equal propensities to gain weight or to develop secondary complications of obesity. This is partially a result not only of genetics, including sex, but also the time during which an individual is exposed to an obesogenic environment. In the present study, we have compared the response of male and female mice to short-term exposure to a high-fat diet (HFD) or a low-fat diet during the peripubertal period (starting at 42 days of age) because this is a stage of dramatic hormonal and metabolic modifications. After 1 week on a HFD, there was no significant increase in body weight, although females significantly increased their energy intake. Serum leptin levels increased in both sexes, even though no change in fat mass was detected. Glyceamia and homeostasis model assessment increased in males, suggesting a rapid change in glucose metabolism. Hypothalamic pro-opiomelanocortin mRNA levels were significantly higher in females on a HFD compared to all other groups, which may be an attempt to reduce their increased energy intake. Hypothalamic inflammation and gliosis have been implicated in the development of secondary complications of obesity; however, no indication of activation of inflammatory processes or gliosis was found in response to 1 week of HFD in the hypothalamus, hippocampus or cerebellum of these young mice. These results indicate that there are both sex and age effects in the response to poor dietary intake because peripubertal male and female mice respond differently to short-term dietary changes and this response is different from that reported in adult rodents.
Assuntos
Glicemia/metabolismo , Peso Corporal/fisiologia , Dieta Hiperlipídica , Hipotálamo/metabolismo , Maturidade Sexual/fisiologia , Adiposidade/fisiologia , Animais , Ingestão de Energia/fisiologia , Feminino , Insulina/sangue , Leptina/sangue , Masculino , Camundongos , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Fatores SexuaisRESUMO
Estradiol not only participates in the regulation of energy metabolism in adulthood, but also during the first stages of life as it modulates the alterations induced by under- and over-nutrition. The objectives of the present study were to determine: 1) If estradiol is involved in the normal programming of energy metabolism in rats; 2) If there is a specific window of time for this programming and 3) If males and females are differentially vulnerable to the action of this hormone. Estrogen receptors (ER) α, ERß and GPER were blocked by their specific antagonists MPP, PHTPP and G15, respectively, from postnatal day (P) 1 (the day of birth) to P5 or from P5 to P13. Physiological parameters such as body weight, fat depots and caloric intake were then analysed at P90. Hypothalamic AgRP, POMC, MC4R, ERα, ERß and GPER mRNA levels and plasma levels of estradiol, were also studied. We found that blocking ER receptors from P5 to P13 significantly decreases long-term body weight in males and hypothalamic POMC mRNA levels in females. The blocking of ERs from P1 to P5 only affected plasma estradiol levels in females. The present results indicate programming actions of estradiol from P5 to P13 on body weight in male and POMC expression in female rats and emphasize the importance of including both sexes in metabolic studies. It is necessary to unravel the mechanisms that underlie the actions of estradiol on food intake, both during development and in adulthood, and to determine how this programming differentially takes place in males and females.
Assuntos
Metabolismo Energético/efeitos dos fármacos , Receptor beta de Estrogênio/antagonistas & inibidores , Receptores de Estradiol/antagonistas & inibidores , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Metabolismo Energético/fisiologia , Estradiol/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Hipotálamo/metabolismo , Masculino , Receptores de Estrogênio/antagonistas & inibidores , Receptores de Estrogênio/metabolismoRESUMO
BACKGROUND: Overnutrition due to a high-fat diet (HFD) can increase the vulnerability of the metabolic system to maladjustments. Estradiol has an inhibitory role on food intake and this hormone has demonstrated to be a crucial organizer during brain development. OBJECTIVE: Our aim was to determine whether increased levels of estradiol in the early postnatal period modulate the alterations in metabolism and brain metabolic circuits produced by overnutrition. METHODS: Twenty-four male and 24 female Wistar rats were submitted to a HFD (34.9% fat) or a control diet (5% fat) from gestational day 6. From postnatal (P) 6 to P13, both control and HFD groups were administered a s.c. injection of vehicle or estradiol benzoate (0.4â mg/kg), resulting in eight experimental groups (n = 6 in each group). Body weight, food intake and subcutaneous, visceral, and brown fat pads were measured. Agouti-related peptide, neuropeptide Y, orexin, and proopiomelanocortin (POMC) were analyzed by quantitative real-time polymerase chain reaction assay and plasma estradiol levels were measured by ELISA. RESULTS: Males fed a HFD showed an increase in body weight and the amount of visceral and subcutaneous fat, which was coincident with an increase in the number of kilocalories ingested. Neonatal estradiol treatment restored the body weight and subcutaneous fat of HFD males to control levels. Hypothalamic POMC mRNA levels in HFD females were increased with respect to control females. This increase was reverted with estradiol treatment during development. DISCUSSION: HFD and estradiol treatment have different effects on males and females. Overnutrition affects physiological parameters, such as body weight, visceral, and subcutaneous fat content, in males, while females present alterations in hypothalamic POMC mRNA levels. Hence, the increase in estradiol levels during a period that is critical for the programing of the feeding system can modulate some of the alterations produced by the continuous intake of high-fat content food.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Estradiol/análogos & derivados , Hipotálamo/patologia , Hipernutrição/fisiopatologia , Adiposidade , Animais , Peso Corporal , Dieta , Modelos Animais de Doenças , Estradiol/sangue , Estradiol/farmacologia , Feminino , Hipotálamo/efeitos dos fármacos , Masculino , Neuropeptídeo Y/metabolismo , Orexinas/metabolismo , Pró-Opiomelanocortina/metabolismo , Ratos , Ratos Wistar , Fatores SexuaisRESUMO
Somatostatin (SRIF), a neuropeptide highly distributed in the hippocampus and involved in learning and memory, is markedly reduced in the brain of Alzheimer's disease patients. The effects of insulin-like growth factor-I (IGF-I) against ß amyloid (Aß)-induced neuronal death and associated cognitive disorders have been extensively reported in experimental models of this disease. Here, we examined the effect of IGF-I on the hippocampal somatostatinergic system in Aß-treated rats and the molecular mechanisms associated with changes in this peptidergic system. Intracerebroventricular Aß25-35 administration during 14â¯days (300â¯pmol/day) to male rats increased Aß25-35 levels and cell death and markedly reduced SRIF and SRIF receptor 2 levels in the hippocampus. These deleterious effects were associated with reduced Akt and cAMP response element-binding protein (CREB) phosphorylation and activation of c-Jun N-terminal kinase (JNK). Subcutaneous IGF-I co-administration (50⯵g/kg/day) reduced hippocampal Aß25-35 levels, cell death and JNK activation. In addition, IGF-I prevented the reduction in the components of the somatostatinergic system affected by Aß infusion. Its co-administration also augmented protein kinase A (PKA) activity, as well as Akt and CREB phosphorylation. These results suggest that IGF-I co-administration may have protective effects on the hippocampal somatostatinergic system against Aß insult through up-regulation of PKA activity and Akt and CREB phosphorylation.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Fármacos Neuroprotetores/farmacologia , Somatostatina/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Fragmentos de Peptídeos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Receptores de Somatostatina/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Astrocytes participate in both physiological and pathophysiological responses to metabolic and nutrient signals. Although most studies have focused on the astrocytic response to weight gain due to high-fat/high-carbohydrate intake, surplus intake of a balanced diet also induces excess weight gain. We have accessed the effects of neonatal overnutrition, which has both age- and sex-dependent effects on weight gain, on hypothalamic inflammation/gliosis. Although both male and female Wistar rats accumulate excessive fat mass as early as postnatal day (PND) 10 with neonatal overnutrition, no increase in hypothalamic cytokine levels, markers of astrocytes or microglia, or inflammatory signaling pathways were observed. At PND 50, no effect of neonatal overnutriton was found in either sex, whereas at PND 150, males again weighed significantly more than their controls, and this was coincident with an increase in markers of inflammation and astrogliosis in the hypothalamus. Circulating triglycerides and free fatty acids were also elevated in these males, but not in females or in either sex at PND 10. Thus, the effects of fatty acids and estrogens on astrocytes in vitro were analyzed. Our results indicate that changes in circulating fatty acid levels may be involved in the induction of hypothalamic inflammation/gliosis in excess weight gain, even on a normal diet, and that estrogens could participate in the protection of females from these processes. In conclusion, the interaction of developmental influences, dietary composition, age, and sex determines the central inflammatory response and the associated long-term outcomes of excess weight gain.
Assuntos
Astrócitos/metabolismo , Gliose/etiologia , Hiperfagia/fisiopatologia , Doenças Hipotalâmicas/etiologia , Hipotálamo/metabolismo , Microglia/metabolismo , Adiposidade , Fatores Etários , Animais , Animais Recém-Nascidos , Astrócitos/imunologia , Astrócitos/patologia , Biomarcadores/metabolismo , Células Cultivadas , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Gliose/imunologia , Gliose/metabolismo , Gliose/patologia , Doenças Hipotalâmicas/imunologia , Doenças Hipotalâmicas/metabolismo , Doenças Hipotalâmicas/patologia , Hipotálamo/imunologia , Hipotálamo/patologia , Mediadores da Inflamação/metabolismo , Masculino , Microglia/imunologia , Microglia/patologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Ratos Wistar , Caracteres Sexuais , Transdução de Sinais , Aumento de PesoRESUMO
Many studies have shown the importance of an adequate nutritional environment during development to optimally establish the neurohormonal circuits that regulate feeding behavior. Under- or over-nutrition during early stages of life can lead to alterations in the physiology and brain networks that control food intake, resulting in a greater vulnerability to suffer maladjustments in energy metabolism in adulthood. These alterations produced by under- or over-nourishment during development differ between males and females, as does the modulatory action that estradiol exerts on the alterations produced by malnutrition. Estradiol regulates metabolism and brain metabolic circuits through the same transcription factor pathway, STAT3, that leptin and ghrelin use to program feeding circuits. Although more research is needed to disentangle the actual role of estradiol during development on the programming of feeding circuits, a synergistic role together with leptin and/or ghrelin might be hypothesized.
Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Estradiol/metabolismo , Desnutrição/metabolismo , Caracteres Sexuais , Animais , Feminino , Masculino , RatosRESUMO
The importance of the neonatal leptin surge in rodents in neurodevelopmental processes has aroused curiosity in its implication in other physiological systems. Given the role of leptin in neuro-immune interactions, we hypothesized that the neonatal leptin surge could have an effect on the oxidative and inflammatory stress situations of both systems. We blocked the neonatal leptin surge by a leptin antagonist and measured several parameters of oxidative and inflammatory stress in the spleen, hypothalamus and adipose tissue of peripubertal/adolescent rats. The treated rats showed lower activity of several antioxidant enzymes in the spleen and their leukocytes released lower levels of mitogen-stimulated IL-10 and IL-13 and higher levels of TNF-alpha. In conclusion, the neonatal leptin surge may have a key role in the establishment of adequate redox and inflammatory states in the immune system, which is important for the generation of adequate immune responses and to obtain and maintain good health.
Assuntos
Inflamação/metabolismo , Inflamação/patologia , Leptina/antagonistas & inibidores , Maturidade Sexual , Tecido Adiposo Branco/metabolismo , Animais , Animais Recém-Nascidos , Peso Corporal , Catalase/metabolismo , Citocinas/metabolismo , Feminino , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Hipotálamo/metabolismo , Masculino , Tamanho do Órgão , Oxirredução , Estresse Oxidativo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Superóxido Dismutase/metabolismoRESUMO
PURPOSE: Our aim was to characterize the effect of an unfamiliar high-fat diet (HFD) on circadian feeding behaviour, plasma parameters, body weight (BW), and gene expression in the prefrontal cortex (PFC) of adolescent male mice. To this end, mice were allowed to consume a HFD during 48 h, but one group was allowed a free choice of HFD or normal chow (FC-HFD), while the other was restricted to a non-optional unfamiliar HFD feeding (NOP-HFD). METHODS: Energy intake was monitored at 6-h intervals during 48 h. Mice cohorts were killed at 6-h intervals after 48-h dietary treatment, and PFC samples dissected for RT-PCR analysis. RESULTS: Mice on the FC-HFD protocol avoided eating the standard chow, showed lower energy intake and lower BW increase than NOP-HFD mice. All animals with access to HFD exhibited nocturnal overeating, but diurnal hyperphagia was more prominent in the FC-HFD cohort. A robust increase in tyrosine hydroxylase (Th) gene expression was detected specifically during the light period of the circadian cycle in FC-HFD mice. In contrast, both protocols similarly up-regulated the expression of cytosolic malic enzyme (Me1), which is very sensitive to HFD. CONCLUSION: Our data show that the PFC participates in driving motivational feeding during HFD-evoked hyperphagia and also suggest that sensory neural pathways might be relevant for the onset of eating disorders and overweight. Moreover, we have observed that animals that had the possibility of choosing between standard chow and HFD were more hyperphagic and specifically displayed an overexpression of the tyrosine hydroxylase gene.