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1.
Elife ; 72018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30079889

RESUMO

The neuropeptides tachykinin2 (Tac2) and kisspeptin (Kiss1) in hypothalamic arcuate nucleus Kiss1 (Kiss1ARH) neurons are essential for pulsatile release of GnRH and reproduction. Since 17ß-estradiol (E2) decreases Kiss1 and Tac2 mRNA expression in Kiss1ARH neurons, the role of Kiss1ARH neurons during E2-driven anorexigenic states and their coordination of POMC and NPY/AgRP feeding circuits have been largely ignored. Presently, we show that E2 augmented the excitability of Kiss1ARH neurons by amplifying Cacna1g, Hcn1 and Hcn2 mRNA expression and T-type calcium and h-currents. E2 increased Slc17a6 mRNA expression and glutamatergic synaptic input to arcuate neurons, which excited POMC and inhibited NPY/AgRP neurons via metabotropic receptors. Deleting Slc17a6 in Kiss1 neurons eliminated glutamate release and led to conditioned place preference for sucrose in E2-treated KO female mice. Therefore, the E2-driven increase in Kiss1 neuronal excitability and glutamate neurotransmission may play a key role in governing the motivational drive for palatable food in females.


Assuntos
Kisspeptinas/genética , Neurônios/metabolismo , Precursores de Proteínas/genética , Taquicininas/genética , Proteína Vesicular 2 de Transporte de Glutamato/genética , Animais , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Cálcio/metabolismo , Canais de Cálcio Tipo T/genética , Estradiol/administração & dosagem , Estradiol/metabolismo , Feminino , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Camundongos , Neurônios/patologia , Canais de Potássio/genética , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/genética
2.
Am J Physiol Regul Integr Comp Physiol ; 313(2): R169-R179, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28404581

RESUMO

Maternal high-fat-diet (HFD) consumption during pregnancy decreased fetal body weight and impacted development of hypothalamic melanocortin neural circuitry in nonhuman primate offspring. We investigated whether these impairments during gestation persisted in juvenile offspring and examined the interaction between maternal and early postnatal HFD consumption. Adult dams consumed either a control diet (CTR; 15% calories from fat) or a high-saturated-fat diet (HFD; 37% calories from fat) during pregnancy. Offspring were weaned onto a CTR or HFD at ~8 mo of age. Offspring from HFD-fed dams displayed early catch-up growth and elevated body weight at 6 and 13 mo of age. Maternal and postnatal HFD exposure reduced the amount of agouti-related peptide fibers in the paraventricular nucleus of the hypothalamus. Postnatal HFD consumption also decreased the amount of agouti-related peptide fibers in the arcuate nucleus of the hypothalamus. Postnatal HFD was associated with decreased food intake and increased activity. These results support and extend our previous findings of maternal diet effects on fetal development and reveal, for the first time in a nonhuman primate model, that maternal HFD-induced disturbances in offspring body weight regulation extended past gestation into the juvenile period. Maternal HFD consumption increases the risk for offspring developing obesity, with the developmental timing of HFD exposure differentially impacting the melanocortin system and energy balance regulation. The present findings provide translational insight into human clinical populations, suggesting that profound health consequences may await individuals later in life following intrauterine and postnatal HFD exposure.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos , Hipotálamo/fisiopatologia , Melanocortinas/metabolismo , Obesidade/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Animais , Metabolismo Energético , Comportamento Alimentar , Feminino , Desenvolvimento Fetal , Humanos , Macaca , Masculino , Obesidade/etiologia , Gravidez , Prenhez , Transdução de Sinais
3.
Obesity (Silver Spring) ; 23(11): 2157-64, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26530932

RESUMO

OBJECTIVE: To utilize a nonhuman primate model to examine the impact of maternal high-fat diet (HFD) consumption and pre-pregnancy obesity on offspring intake of palatable food and to examine whether maternal HFD consumption impaired development of the dopamine system, critical for the regulation of hedonic feeding. METHODS: The impact of exposure to maternal HFD and obesity on offspring consumption of diets of varying composition was assessed after weaning. The influence of maternal HFD consumption on the development of the prefrontal cortex-dopaminergic system at 13 months of age was also examined. RESULTS: During a preference test, offspring exposed to maternal HFD consumption and obesity displayed increased intake of food high in fat and sugar content relative to offspring from lean control mothers. Maternal HFD consumption suppressed offspring dopamine signaling (as assessed by immunohistochemistry) relative to control offspring. Specifically, there was decreased abundance of dopamine fibers and of dopamine receptor 1 and 2 proteins. CONCLUSIONS: This study reveals that offspring exposed to both maternal HFD consumption and maternal obesity during early development are at increased risk for obesity due to overconsumption of palatable energy-dense food, a behavior that may be related to reduced central dopamine signaling.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Dopamina/metabolismo , Ingestão de Alimentos/fisiologia , Fenômenos Fisiológicos da Nutrição Materna , Obesidade/metabolismo , Complicações na Gravidez/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Animais , Comportamento Alimentar/fisiologia , Feminino , Masculino , Modelos Animais , Obesidade/etiologia , Gravidez , Complicações na Gravidez/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Primatas , Transdução de Sinais , Paladar/fisiologia
4.
Front Neurosci ; 9: 194, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26150767

RESUMO

Recent evidence indicates that perinatal exposure to maternal obesity, metabolic disease, including diabetes and hypertension, and unhealthy maternal diet has a long-term impact on offspring behavior and physiology. During the past three decades, the prevalence of both obesity and neuropsychiatric disorders has rapidly increased. Epidemiologic studies provide evidence that maternal obesity and metabolic complications increase the risk of attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, anxiety, depression, schizophrenia, eating disorders (food addiction, anorexia nervosa, and bulimia nervosa), and impairments in cognition in offspring. Animal models of maternal high-fat diet (HFD) induced obesity also document persistent changes in offspring behavior and impairments in critical neural circuitry. Animals exposed to maternal obesity and HFD consumption display hyperactivity, impairments in social behavior, increased anxiety-like and depressive-like behaviors, substance addiction, food addiction, and diminished cognition. During development, these offspring are exposed to elevated levels of nutrients (fatty acids, glucose), hormones (leptin, insulin), and inflammatory factors (C-reactive protein, interleukin, and tumor necrosis factor). Such factors appear to permanently change neuroendocrine regulation and brain development in offspring. In addition, inflammation of the offspring brain during gestation impairs the development of neural pathways critical in the regulation of behavior, such as serotoninergic, dopaminergic, and melanocortinergic systems. Dysregulation of these circuits increases the risk of mental health disorders. Given the high rates of obesity in most developed nations, it is critical that the mechanisms by which maternal obesity programs offspring behavior are thoroughly characterized. Such knowledge will be critical in the development of preventative strategies and therapeutic interventions.

5.
Synapse ; 67(12): 897-908, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23959764

RESUMO

Estradiol (E) and progesterone (P) promote spinogenesis in several brain areas. Intracellular signaling cascades that promote spinogenesis involve RhoGTPases, glutamate signaling and synapse assembly. We found that in serotonin neurons, E ± P administration increases (a) gene and protein expression of RhoGTPases, (b) gene expression of glutamate receptors, and (c) gene expression of pivotal synapse assembly proteins. Therefore, in this study we determined whether structural changes in dendritic spines in the dorsal raphe follow the observed changes in gene and protein expression. Dendritic spines were examined with immunogold silver staining of a spine marker protein, postsynaptic density-95 (PSD-95) and with Golgi staining. In the PSD-95 study, adult Ovx monkeys received placebo, E, P, or E + P for 1 month (n = 3/group). Sections were immunostained for PSD-95 and the number of PSD-95-positive puncta was determined with stereology. E, P, and E + P treatment significantly increased the total number of PSD-95-positive puncta (ANOVA, P = 0.04). In the golgi study, adult Ovx monkeys received placebo, E or E + P for 1 month (n = 3-4) and the midbrain was golgi-stained. A total of 80 neurons were analyzed with Neurolucida software. There was a significant difference in spine density that depended on branch order (two-way ANOVA). E + P treatment significantly increased spine density in higher-order (3°-5°) dendritic branches relative to Ovx group (Bonferroni, P < 0.05). In summary, E + P leads to the elaboration of dendritic spines on dorsal raphe neurons. The ability of E to induce PSD-95, but not actual spines, suggests either a sampling or time lag issue. Increased spinogenesis on serotonin dendrites would facilitate excitatory glutamatergic input and, in turn, increase serotonin neurotransmission throughout the brain.


Assuntos
Espinhas Dendríticas/efeitos dos fármacos , Estradiol/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Progesterona/farmacologia , Núcleos da Rafe/efeitos dos fármacos , Animais , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/ultraestrutura , Estradiol/deficiência , Feminino , Complexo de Golgi/efeitos dos fármacos , Complexo de Golgi/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Macaca mulatta , Ovariectomia , Progesterona/deficiência , Núcleos da Rafe/citologia , Núcleos da Rafe/metabolismo , Neurônios Serotoninérgicos/citologia , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/metabolismo
6.
Physiol Behav ; 105(2): 188-94, 2012 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-21889523

RESUMO

Estradiol's inhibitory effect on food intake is mediated, in part, by its ability to increase the activity of meal-related signals, including serotonin (5-HT), which hastens satiation. The important role that postsynaptic 5-HT(2C) receptors play in mediating 5-HT's anorexigenic effect prompted us to investigate whether a regimen of acute estradiol treatment increases the anorexia associated with increased 5-HT(2C) receptor activation in ovariectomized (OVX) rats. We demonstrated that intraperitoneal and intracerebroventricular (i.c.v.) administration of low doses of the 5-HT(2C) receptor agonist meta-chlorophenylpiperazine (mCPP) decreased 1-h dark-phase food intake in estradiol-treated, but not oil-treated, OVX rats. During a longer feeding test, we demonstrated that i.c.v. administration of mCPP decreased 22-h food intake in oil-treated and, to a greater extent, estradiol-treated OVX rats. In a second study, we demonstrated that estradiol increased 5-HT(2C) receptor protein content in the caudal brainstem, but not hypothalamus, of OVX rats. We conclude that a physiologically-relevant regimen of acute estradiol treatment increases sensitivity to mCPP's anorexigenic effect. Our demonstration that this same regimen of estradiol treatment increases 5-HT(2C) receptor protein content in the caudal hindbrain of OVX rats provides a possible mechanism to explain our behavioral findings.


Assuntos
Anorexia/induzido quimicamente , Encéfalo/metabolismo , Estradiol/efeitos adversos , Estrogênios/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Receptor 5-HT2C de Serotonina/metabolismo , Análise de Variância , Animais , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Vias de Administração de Medicamentos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Ovariectomia , Piperazinas/farmacologia , Ratos , Ratos Long-Evans , Agonistas do Receptor de Serotonina/farmacologia , Fatores de Tempo
7.
Endocrinology ; 151(12): 5680-8, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21068154

RESUMO

Estradiol appears to exert its anorexigenic effect by activating nuclear estrogen receptors (ERs), which are expressed widely in peripheral tissues and in the brain. Here, we used ICI-182,780 (ICI), a pure antiestrogen with limited ability to cross the blood-brain barrier, to assess the relative involvement of peripheral vs. central ERs to estradiol's anorexigenic effect. Food intake was measured after peripheral (sc) administration of ICI or vehicle in ovariectomized rats treated with acute injections of estradiol benzoate and sesame oil over a 2-wk period. Uterine weight was assessed as a biological assay of peripheral ER activation. In a second experiment, food intake was measured after central (lateral ventricular) administration of ICI or vehicle in ovariectomized rats receiving acute injections of estradiol benzoate and oil over a period of 10 d. In order to assess the possible spread of ICI from the brain to the periphery, vaginal cytology samples were examined as a biological assay of peripheral ER activation. Peripherally administered ICI failed to attenuate estradiol's anorexigenic effect at a dose that was sufficient to block estradiol's uterotrophic effect. This suggests that peripheral activation of ERs is not necessary for estradiol's anorexigenic effect. Although central infusion of 4 nm ICI blocked estradiol's anorexigenic effect, it did not attenuate estradiol's ability to increase the presence of cornified cells in vaginal cytology samples, suggesting that ICI did not leak into the periphery. We conclude that activation of central, but not peripheral, ERs is necessary for estradiol's anorexigenic effect.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Estradiol/análogos & derivados , Receptores de Estrogênio/fisiologia , Animais , Encéfalo/metabolismo , Estradiol/administração & dosagem , Estradiol/farmacologia , Feminino , Infusões Intraventriculares , Ovariectomia , Ratos , Ratos Long-Evans
8.
Brain Res ; 1259: 51-8, 2009 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-19168037

RESUMO

Previous research has shown that estradiol increases the anorexia associated with serotonin (5-HT) neurotransmission. To examine further the putative relationship between estradiol and 5-HT, we investigated whether estradiol increases the expression of Pet-1 and the 5-HT transporter (5-HTT), two genes implicated in the development and regulation of the 5-HT system. Ovariectomized (OVX) rats (n=5-6/group) were treated with 0, 2, or 10 microg estradiol benzoate (EB) in sesame oil on 2 consecutive days. Food intake and body weight were recorded 2 days later when EB-treated rats typically display signs of behavioral estrus (e.g., reduced feeding). Following the collection of behavioral data, rats were perfused, brains were removed, and coronal sections were cut through the midbrain raphe nuclei. Pet-1 and 5-HTT mRNA levels were quantified throughout the dorsal and median raphe nuclei (DRN and MRN) by conducting in situ hybridization on free-floating tissue sections using (35)S-labeled cDNA probes. As expected, EB treatment decreased food intake and body weight on the day that modeled estrus. At this same time, EB treatment increased Pet-1 and 5-HTT mRNA levels within the DRN and MRN. We conclude that a physiologically relevant regimen of estradiol treatment in OVX rats increases Pet-1 and 5-HTT mRNA levels in the midbrain raphe nuclei at a time when the anorexigenic effect of estradiol is apparent. Further studies are required to determine whether the increased expression of Pet-1 and 5-HTT mRNA plays a causal role in the anorexigenic effect of estradiol.


Assuntos
Estradiol/análogos & derivados , Ovariectomia , Núcleos da Rafe/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Fatores de Transcrição/metabolismo , Análise de Variância , Animais , Depressores do Apetite/administração & dosagem , Depressores do Apetite/farmacologia , Peso Corporal , Ingestão de Alimentos/efeitos dos fármacos , Estradiol/administração & dosagem , Estradiol/farmacologia , Estro/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Hibridização In Situ , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Núcleos da Rafe/efeitos dos fármacos , Ratos , Ratos Long-Evans , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Fatores de Transcrição/genética
9.
Physiol Behav ; 86(3): 331-7, 2005 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-16139852

RESUMO

The emergence of sex- and estrous cycle-related differences in the anorectic effect of fenfluramine, a serotonin (5-HT) agonist, prompted us to investigate whether these behavioral changes are mediated by estradiol. Rats were ovariectomized and housed in cages that permitted the analysis of feeding and locomotor activity via an automated, computerized system. Using a within-subjects design, we investigated the effects of 1 mg/kg d-fenfluramine and saline vehicle on food intake and wheel running in ovariectomized rats following estradiol benzoate (EB) and oil vehicle treatment. A cyclic regimen of EB treatment was used to mimic the changes in endogenous estradiol secretion over the rat's 4-day estrous cycle. The decrease in food intake following fenfluramine treatment was greater in EB-treated rats, relative to oil-treated rats. Fenfluramine also produced a small but significant decrease in wheel running in ovariectomized rats that was not modulated by EB treatment. Thus, EB's ability to increase the anorectic effect of this dose of fenfluramine appears behaviorally specific. Although the inhibition of food intake by fenfluramine is largely attributed to its ability to increase synaptic levels of 5-HT, additional research involving selective 5-HT receptor agonists and antagonists is necessary to determine whether estradiol interacts with the endogenous 5-HT system to control food intake in the female rat.


Assuntos
Anorexia/tratamento farmacológico , Estradiol/análogos & derivados , Fenfluramina , Animais , Anorexia/induzido quimicamente , Interações Medicamentosas , Ingestão de Alimentos/efeitos dos fármacos , Estradiol/administração & dosagem , Feminino , Atividade Motora/efeitos dos fármacos , Ovariectomia/métodos , Ratos , Ratos Long-Evans , Inibidores Seletivos de Recaptação de Serotonina , Fatores de Tempo
10.
Am J Physiol Regul Integr Comp Physiol ; 288(6): R1486-91, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15637164

RESUMO

The controls of food intake differ in male and female rats. Daily food intake is typically greater in male rats, relative to female rats, and a decrease in food intake, coincident with the estrous stage of the ovarian reproductive cycle, is well documented in female rats. This estrous-related decrease in food intake has been attributed to a transient increase in the female rat's sensitivity to satiety signals generated during feeding bouts. Here, we investigated whether sex or stage of the estrous cycle modulate the satiety signal generated by fenfluramine, a potent serotonin (5-HT) releasing agent. To examine this hypothesis, food intake was monitored in male, diestrous female, and estrous female rats after intraperitoneal injections of 0, 0.25, and 1.0 mg/kg D-fenfluramine. The lower dose of fenfluramine decreased food intake only in diestrous and estrous females, suggesting that the minimally effective anorectic dose of fenfluramine is lower in female rats, relative to male rats. Although the larger dose of fenfluramine decreased food intake in both sexes, the duration of anorexia was greater in diestrous and estrous female rats, relative to male rats. Moreover, the magnitude of the anorectic effect of the larger dose of fenfluramine was greatest in estrous rats, intermediate in diestrous rats, and least in male rats. Thus our findings indicate that the anorectic effect of fenfluramine is modulated by gonadal hormone status.


Assuntos
Depressores do Apetite/farmacologia , Ciclo Estral/fisiologia , Fenfluramina/farmacologia , Animais , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Estrogênios/sangue , Feminino , Masculino , Ratos , Ratos Long-Evans , Caracteres Sexuais , Sacarose
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