RESUMO
While the effects of progesterone on body weight and appetite in pre-menopausal conditions have been well elucidated, its effects in post-menopausal conditions have not been clarified. On the contrary, the effects of estrogen on body weight and appetite in post-menopausal conditions have been well established. In this study, the effects of progesterone treatment on body weight, appetite, and fat mass in ovariectomized rats were evaluated. In addition, the central and/or peripheral levels of oxytocin (OT), leptin, and their receptors, which are potent anorectic factors, were examined. Female rats were ovariectomized and divided into control, progesterone-treated, and estrogen-treated groups. Body weight, food intake, and subcutaneous fat mass were lower in both the progesterone and estrogen groups than in the control group. The estrogen group exhibited higher serum OT levels than the control group, whereas the OT levels of the progesterone and control groups did not differ. The serum leptin levels of both the progesterone and estrogen groups were lower than those of the control group. Gene expression analysis of OT, leptin, and their receptors in the hypothalamus and adipose tissue found few significant differences among the groups. Hypothalamic neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) mRNA levels involved in appetite regulation were slightly altered in the progesterone and estrogen groups. These findings suggest that progesterone treatment may have favorable effects on body weight, appetite, and fat mass regulation in post-menopausal conditions and that the mechanisms underlying these effects of progesterone differ from those underlying the effects of estrogen.
Assuntos
Leptina , Progesterona , Ratos , Animais , Feminino , Leptina/metabolismo , Progesterona/farmacologia , Progesterona/metabolismo , Ingestão de Alimentos , Peso Corporal , Hipotálamo , Proteínas de Transporte , Estrogênios/farmacologia , Estrogênios/metabolismo , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Pró-Opiomelanocortina/farmacologiaRESUMO
It has been well established that undernutrition and low energy availability disturb female reproductive functions in humans and many animal species. These reproductive dysfunctions are mainly caused by alterations of some hypothalamic factors, and consequent reduction of gonadotrophin-releasing hormone (GnRH) secretion. Evidence from literature suggests that increased activity of orexigenic factors and decreased activity of anorexigenic/satiety-related factors in undernourished conditions attenuate GnRH secretion in an integrated manner. Likewise, the activity of kisspeptin neurons, which is a potent stimulator of GnRH, is also reduced in undernourished conditions. In addition, it has been suggested that gonadotrophin-inhibitory hormone, which has anti-GnRH and gonadotrophic effects, may be involved in reproductive dysfunctions under several kinds of stress conditions. It should be remembered that these alterations, i.e., promotion of feeding behavior and temporary suppression of reproductive functions, are induced to prioritize the survival of individual over that of species, and that improvements in metabolic and nutritional conditions should be considered with the highest priority.
Assuntos
Hormônio Liberador de Gonadotropina , Desnutrição , Animais , Feminino , Humanos , Gonadotropinas , Hipotálamo/metabolismo , Kisspeptinas/fisiologiaRESUMO
In Japan, outcome measures for maternal and child health measures such as maternal, perinatal, and infant mortality have consistently shown a trend toward improvement. On the other hand, the problems of the declining birth rate, child abuse, and domestic violence have become evident since the 1990s. In terms of Japan's maternal and child health, it is necessary to take measures to preserve mental health of mothers and children, and also to respond to family issues such as abuse and violence. The services needed such as comprehensive support centers for families with children and new postpartum care programs have been established. It is necessary to further improve the competence of doctors, public health nurses, and midwives working in the maternal and child health field and to promptly construct a cooperation system in the community. J. Med. Invest. 69 : 159-164, August, 2022.
Assuntos
Maus-Tratos Infantis , Tocologia , Criança , Saúde da Criança , Família , Feminino , Humanos , Lactente , Japão , GravidezRESUMO
It is well known that undernourished conditions disturb female reproductive functions in many species, including humans. These alterations are mainly caused by a reduction in gonadotrophin-releasing hormone (GnRH) secretion from the hypothalamus. Evidence from the literature suggests that some hypothalamic factors play pivotal roles in the coordination of reproductive functions and energy homeostasis in response to environmental cues and internal nutritional status. Generally, anorexigenic/satiety-related factors, such as leptin, alpha-melanocyte-stimulating hormone, and proopiomelanocortin, promote GnRH secretion, whereas orexigenic factors, such as neuropeptide Y, agouti-related protein, orexin, and ghrelin, attenuate GnRH secretion. Conversely, gonadotrophin-inhibitory hormone, which exerts anti-GnRH and gonadotrophic effects, promotes feeding behavior in many species. In addition, the activity of kisspeptin, which is a potent stimulator of GnRH, is reduced by undernourished conditions. Under normal nutritional conditions, these factors are coordinated to maintain both feeding behavior and reproductive functions. However, in undernourished conditions their activity levels are markedly altered to promote feeding behavior and temporarily suppress reproductive functions, in order to prioritize the survival of the individual over that of the species.
Assuntos
Hormônio Liberador de Gonadotropina , Kisspeptinas , Feminino , Homeostase/fisiologia , Humanos , Hipotálamo/metabolismo , Kisspeptinas/fisiologia , Neuropeptídeo Y/metabolismoRESUMO
PURPOSE: We examined the mechanism by which neonatal immune stress reduces the sexual behavior of female rats in adulthood. METHODS: Neonatal female rats were randomly divided into 3 groups: control (n = 11), postnatal day 10 lipopolysaccharide (PND10LPS) (n = 23), and PND25LPS (n = 11) groups, which received intraperitoneal injections of LPS (100 µg/kg) or saline on PND10 and 25. Daily inspections of the vaginal opening (VO) were performed from PND27 to PND37. Thereafter, the frequency of estrus was assessed for 15 days. Female rats (at 11-12 weeks of age) were placed in a cage with male rats, and their sexual behavior was monitored for 30 min. The hypothalamic mRNA expression levels of factors related to sexual behavior were examined via real-time PCR. RESULTS: VO occurred later and the frequency of estrus was lower in the PND10LPS group compared to the control group. The number of lordosis behaviors and the total number of mounts performed by male partners were lower in the PND10LPS and PND25LPS groups than in the control group. Acceptability: The lordosis quotient and lordosis rating were lower in the PND10LPS group than in the control group. Proceptive behavior: the number of ear wiggling events was lower in the PND10LPS group than in the other groups, and the number of hops/darts was lower in the PND10LPS group than in the control group. The hypothalamic mRNA expression level of progesterone receptors (PR)A + B was lower in the PND10LPS group than in the control group, and the hypothalamic PRB mRNA expression level was lower in the PND10LPS and PND25LPS groups than in the control group. CONCLUSION: Neonatal immune stress impeded sexual behavior and hypothalamic PR mRNA expression in female rats. Decreased progesterone activity in the hypothalamus might explain the reduction in sexual behavior seen in these rats.
Assuntos
Hipotálamo/metabolismo , Lipopolissacarídeos/administração & dosagem , Receptores de Progesterona/genética , Comportamento Sexual Animal/efeitos dos fármacos , Comportamento Sexual Animal/fisiologia , Estresse Fisiológico/imunologia , Fatores Etários , Animais , Animais Recém-Nascidos , Regulação para Baixo/efeitos dos fármacos , Esquema de Medicação , Feminino , Expressão Gênica/efeitos dos fármacos , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/fisiopatologia , Lipopolissacarídeos/farmacologia , Masculino , Gravidez , Ratos , Ratos Sprague-Dawley , Receptores de Progesterona/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Fatores de TempoRESUMO
PURPOSE: To develop consensus-based components used in the first evidence-based cancer survivorship guidelines in Japan. METHODS: Purposive sampling was used to recruit a panel of experts in oncology clinical practice, nursing, health science, epidemiology, and patient advocacy. The panel engaged in a modified Delphi process to (1) generate consensus related to the definition of survivorship, (2) determine the aim and target users of the guideline, and (3) identify clinical issues for inclusion. A Web-based survey and panel meeting were conducted to obtain the panelists' feedback on the initial draft proposed by the secretariat. Multiple online votes were then completed until all elements of the proposed guidelines reached an approval rate of 80% or higher. Following each round, iterative refinements were made based on all panelists' feedback. RESULTS: Twenty-two experts were enrolled in the panel and participated in four rounds of online voting and two face-to-face meetings. Ultimately, the panel reached consensus on the definition of survivorship, the aim of the guidelines, and target users. Moreover, 11 of the original 17 clinical issues were retained. Finally, the panel selected two priority areas to implement immediately. CONCLUSION: The panel's consensus on the definition of survivorship, aim and target users of the guideline, and 11 clinical issues will serve as a compass for the development of comprehensive cancer survivorship guidelines in Japan. IMPLICATIONS FOR CANCER SURVIVORS: A culturally sensitive consensus approach was developed to improve the long term health and well- being of cancer survivors in Japan.
Assuntos
Técnica Delphi , Neoplasias/mortalidade , Guias como Assunto , Humanos , Japão , Inquéritos e QuestionáriosRESUMO
PURPOSE: It is known that various types of stress in early life increase the incidence of diabetes, myocardial infarctions, and psychiatric disorders in adulthood. We examined the mechanism by which neonatal immune stress reduces sexual behavior in adult male rats. METHODS: Male rats were randomly divided into 3 groups: the control (n = 17), postnatal day 10 lipopolysaccharide (PND10LPS) (n = 31), and PND25LPS (n = 16) groups, which received intraperitoneal injections of LPS (100 µg/kg) or saline (injection volume: ≤0.1 ml/g) on postnatal days 10 and 25. In experiment 1, male rats (age: 11 to 12 weeks) were put together with female rats in a one-to-one setting for mating, and sexual behavior (mounting, intromission, and ejaculation) was monitored for 30 minutes. The serum levels of luteinizing hormone (LH) and testosterone (T) and the hypothalamic mRNA expression levels of factors related to sexual behavior were examined. After experiment 1 finished, the remaining 37 male rats were used for experiment 2: the control group (n = 8), PND10 LPS group (n = 21) and PND25LPS group (n = 8) these rats had been given an i.p. injection of the saline during the expriment1. All of the rats were orchidectomized at 14 weeks of age. After a 3-week recovery period, a silastic tube containing crystalline T was subcutaneously implanted into the back of each rat. The rats' sexual behavior, serum hormone concentrations, and hypothalamic mRNA expression levels were assessed. RESULTS: In experiment 1, preputial separation occurred significantly later in the PND10LPS group than in the control group. The frequency of sexual behavior was significantly lower in the PND10LPS group than in the control group. The serum T concentrations of the PND10LPS and PND25LPS groups were significantly lower than that of the control group, but the serum LH concentrations of the 3 groups did not differ significantly. The hypothalamic mRNA expression levels of progesterone receptor B (PRB) and gonadotropin-releasing hormone (GnRH) were significantly lower in the PND10LPS and PND25LPS groups than in the control group, whereas the hypothalamic PRA + B mRNA expression levels of the 3 groups did not differ significantly. In experiment 2, after T supplementation the frequency of sexual behavior was significantly lower in the PND10LPS and PND25LPS groups than in the control group, although there were no significant differences in the serum T or LH concentrations or the hypothalamic PRB, PRA + B, or GnRH mRNA expression levels of the 3 groups. CONCLUSION: In male rats, immune stress in the early neonatal period delayed sexual maturation, reduced sexual behavior, suppressed the serum T concentration, and downregulated the hypothalamic mRNA expression levels of GnRH and the PR in adulthood. The delayed sexual maturation was presumed to have been caused by the reduction in the serum T concentration. However, the rats that experienced neonatal stress exhibited reduced sexual behavior irrespective of their serum T concentrations.
Assuntos
Androgênios/metabolismo , Transtornos do Desenvolvimento Sexual/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hormônio Liberador de Gonadotropina/metabolismo , Receptores de Progesterona/metabolismo , Estresse Psicológico/metabolismo , Fatores Etários , Androgênios/genética , Animais , Animais Recém-Nascidos , Transtornos do Desenvolvimento Sexual/induzido quimicamente , Transtornos do Desenvolvimento Sexual/patologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/genética , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Lipopolissacarídeos/farmacologia , Hormônio Luteinizante/sangue , Hormônio Luteinizante/genética , Masculino , RNA Mensageiro/metabolismo , Ratos , Receptores de Progesterona/genética , Estresse Psicológico/patologia , Testosterona/sangue , Testosterona/genéticaRESUMO
Infectious, psychological and metabolic stresses in the prenatal and early neonatal period induce long-lasting effects in physiological function and increase the risk of metabolic disorders later in life. We examined the sexual behavior of female rats that were subjected to undernutrition in the prenatal period. Eight pregnant rats were divided into two groups: a maternal normal nutrition group (mNN; nâ¯=â¯4) and a maternal undernutrition group (mUN; nâ¯=â¯4), which received 50% of the daily food intake amount of the mNN group from gestation day 13 to delivery. Nine and seven female offspring were randomly selected from the mNN and mUN groups, respectively. Vaginal opening (VO), estrous cycle length, sexual behavior and mRNA expression levels of the factors that regulate sexual behavior were observed. In the mUN group, VO day was later, the estrous cycle was longer, and the lordosis quotient and lordosis rating were lower than in the mNN group; such differences were not seen in other sexual performances, such as ear wiggles, darts, kick bouts and box. The hypothalamic mRNA expression level of progesterone receptor (PR) Aâ¯+â¯B and oxytocin (OT) were significantly lower in the mUN group than in the mNN group. These findings indicated that prenatal undernutrition disrupted puberty onset, the estrous cycle, sexual behavior and hypothalamic mRNA expression of PR and OT in female rat pups.
Assuntos
Desnutrição/complicações , Efeitos Tardios da Exposição Pré-Natal/patologia , Comportamento Sexual , Tonsila do Cerebelo/metabolismo , Animais , Peso Corporal , Ingestão de Alimentos , Ciclo Estral , Feminino , Hipotálamo/metabolismo , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Maturidade SexualRESUMO
Prenatal undernutrition affects some physiological functions after birth, and such changes are associated with the pathogenesis of various diseases. Recently, we have reported that prenatally undernourished male rats exhibited stronger febrile and anorectic responses to immune stress induced by moderate-dose lipopolysaccharide (LPS) treatment in adulthood. In the present study, we evaluated the effects of prenatal undernutrition on stress responses to the administration of a septic dose (3â¯mg/kg) of LPS in later life, mainly focusing on changes in hypothalamic proinflammatory cytokine expression. We also evaluated the expression of hypothalamic and peripheral reproductive factors because it has been suggested that the stress responses of reproductive functions are affected by prenatal and neonatal stress and nutritional conditions. As a result, we found that prenatal undernutrition attenuated the anorectic response to septic-dose LPS treatment in adulthood in male rats. In addition, it attenuated the LPS-induced suppression of serum testosterone levels and the changes in hypothalamic proinflammatory cytokine (interleukin (IL)-1ß, tumor necrosis factor-α, and IL-6) expression induced by septic-dose LPS treatment in adulthood. These results suggest that prenatal undernutrition attenuates stress and reproductive responses under severe immune stress conditions. The downregulation of hypothalamic stress-related factor expression might be involved in such attenuated stress responses, which could be one of the protective mechanisms used to prevent excessive immune responses and aid survival.
Assuntos
Comportamento Alimentar/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Desnutrição/psicologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Sepse/psicologia , Animais , Animais Recém-Nascidos , Peso Corporal , Citocinas/metabolismo , Feminino , Hipotálamo/metabolismo , Hipotálamo/fisiopatologia , Masculino , Desnutrição/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Wistar , Sepse/induzido quimicamente , Estresse Psicológico/psicologiaRESUMO
Energy balance and reproductive functions are closely linked in some species. The sex hormones (estrogens and androgens) are involved in the regulation of appetite, metabolism, body weight (BW), and body composition in mammals. Previously, we showed that the effects of testosterone on BW, appetite, and fat weight were markedly affected by alterations to the gonadal hormonal milieu. In this study, we examined whether testosterone administration changes food preferences and whether these effects of testosterone depend on gonadal status in female rats. We also evaluated the underlying mechanisms responsible for these effects, focusing on hypothalamic inflammation and endoplasmic reticulum (ER) stress. In gonadal-intact (sham) female rats, chronic testosterone administration promoted a preference for a high-fat diet (HFD) and increased BW gain, fat weight, and adipocyte size, whereas no such effects were observed in ovariectomized (OVX) rats. Testosterone administration increased hypothalamic interleukin-1 mRNA expression in the sham rats, but not the OVX rats. On the contrary, testosterone administration decreased the hypothalamic mRNA levels of ER stress-response genes in the OVX rats, but not the sham rats. These testosterone-induced alterations in OVX rats might represent a regulatory mechanism for preventing hypothalamic inflammation and the overconsumption of a HFD. In conclusion, testosterone's effects on food preferences and the subsequent changes were affected by gonadal status. Testosterone-induced changes in hypothalamic inflammatory cytokine production and ER stress might be related to these findings.
Assuntos
Peso Corporal/fisiologia , Dieta Hiperlipídica , Comportamento Alimentar/fisiologia , Testosterona/metabolismo , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Feminino , Hipotálamo/citologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Interleucina-1/metabolismo , Leptina/sangue , Ovariectomia , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Testosterona/administração & dosagemRESUMO
To clarify the direct effects of androgens, the changes in the hypothalamic levels of reproductive and appetite regulatory factors induced by chronic dihydrotestosterone (DHT) administration were evaluated in female rats. DHT treatment increased the BW and food intake of the ovariectomized rats, but not the estradiol (E2)-treated rats. DHT administration suppressed the expression of a hypothalamic anorexigenic factor. Although the kisspeptin (Kiss1) mRNA levels of the anterior hypothalamic block (the anteroventral periventricular nucleus, AVPV) were increased in the E2-treated rats, DHT administration did not affect the Kiss1 mRNA levels of the AVPV in the ovariectomized or E2-treated rats. Conversely, DHT administration reduced the Kiss1 mRNA levels of the posterior hypothalamic block (the arcuate nucleus, ARC) in the ovariectomized rats. Although the Kiss1 mRNA levels of the posterior hypothalamic block (ARC) were decreased in the E2-treated rats, DHT administration did not affect the Kiss1 mRNA levels of the ARC in these rats. Serum luteinizing hormone levels of these groups exhibited similar patterns to the Kiss1 mRNA levels of the ARC. These results showed that DHT affects the production of hypothalamic reproductive and appetite regulatory factors, and that these effects of DHT differ according to the estrogen milieu.
Assuntos
Peso Corporal/efeitos dos fármacos , Di-Hidrotestosterona/administração & dosagem , Estradiol/administração & dosagem , Ovariectomia , Reprodução/efeitos dos fármacos , Animais , Núcleo Arqueado do Hipotálamo/química , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Hipotálamo/química , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Kisspeptinas/genética , RNA Mensageiro/análise , Ratos , Ratos WistarRESUMO
The effects of androgens on gonadotropin-releasing hormone (GnRH) secretion in females have not been fully established. To clarify the direct effects of androgens on hypothalamic reproductive factors, we evaluated the effects of chronic testosterone administration on hypothalamic GnRH regulatory factors in ovariectomized (OVX) female rats. Both testosterone and estradiol reduced the serum luteinizing hormone levels of OVX female rats, indicating that, as has been found for estrogen, testosterone suppresses GnRH secretion via negative feedback. Similarly, the administration of testosterone or estradiol suppressed the hypothalamic mRNA levels of kisspeptin and neurokinin B, both of which are positive regulators of GnRH, whereas it did not affect the hypothalamic mRNA levels of the kisspeptin receptor or neurokinin-3 receptor. On the contrary, the administration of testosterone, but not estradiol, suppressed the hypothalamic mRNA expression of prodynorphin, which is a negative regulator of GnRH. The administration of testosterone did not alter the rats' serum estradiol levels, indicating that testosterone's effects on hypothalamic factors might be induced by its androgenic activity. These findings suggest that as well as estrogen, androgens have negative feedback effects on GnRH in females and that the underlying mechanisms responsible for these effects are similar, but do not completely correspond, to the mechanisms underlying the effects of estrogen on GnRH.
Assuntos
Dinorfinas/metabolismo , Hipotálamo/efeitos dos fármacos , Kisspeptinas/metabolismo , Neurocinina B/metabolismo , Testosterona/farmacologia , Animais , Dinorfinas/genética , Estradiol/farmacologia , Feminino , Hipotálamo/metabolismo , Kisspeptinas/genética , Leptina/sangue , Hormônio Luteinizante/sangue , Neurocinina B/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Wistar , Receptores de Kisspeptina-1/genética , Receptores de Kisspeptina-1/metabolismo , Receptores da Neurocinina-3/genética , Receptores da Neurocinina-3/metabolismoRESUMO
Estrogen plays pivotal roles in body weight regulation through its effects on central estrogen receptor-α (ERα) expression. ERα is found on neurons that express the hypothalamic anorexigenic factors steroidogenic factor-1 (SF-1) and pro-opiomelanocortin (POMC) mediate these effects of estrogen. As the gonadal hormonal milieu is drastically altered during the developmental period, the expression levels of SF-1 and POMC might also change during this period. In this study, we showed that hypothalamic SF-1 and ERα mRNA expression did not change during the neonatal to pre-pubertal period (from postnatal day 10 to 30), and there were no significant differences in the hypothalamic mRNA expression levels of these molecules between males and females at any examined age. On the other hand, hypothalamic POMC mRNA expression and the serum estradiol (E2) level increased during development in both males and females. Significant positive correlations were detected between the serum E2 level and hypothalamic POMC mRNA expression in both males and females. Hypothalamic ERα and POMC mRNA expression were decreased by fasting in male rats at all examined ages, whereas fasting had no effect on hypothalamic ERα or POMC mRNA expression in the female rats. These results indicate that the regulatory system involving E2 and hypothalamic POMC expression might already be established in the neonatal period and that the roles of POMC and ERα in body weight regulation during development might differ slightly between males and females.
Assuntos
Receptor alfa de Estrogênio/metabolismo , Jejum/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Hipotálamo/metabolismo , Pró-Opiomelanocortina/metabolismo , Caracteres Sexuais , Fator Esteroidogênico 1/metabolismo , Animais , Peso Corporal/fisiologia , Estradiol/sangue , Receptor alfa de Estrogênio/genética , Feminino , Masculino , Neurônios/metabolismo , Pró-Opiomelanocortina/genética , Ratos , Fator Esteroidogênico 1/genéticaRESUMO
In females, estrogens play pivotal roles in preventing excess body weight (BW) gain. On the other hand, the roles of androgens in female BW, appetite, and energy metabolism have not been fully examined. We hypothesized that androgens' effects on food intake (FI) and BW regulation change according to the estrogens' levels. To evaluate this hypothesis, the effects of chronic testosterone administration in ovariectomized (OVX) female rats with or without estradiol supplementation were examined in this study. Chronic testosterone administration decreased BW, FI, white adipose tissue (WAT) weight, and adipocyte size in OVX rats, whereas it increased BW, WAT weight, and adipocyte size in OVX with estradiol-administered rats. In addition, chronic testosterone administration increased hypothalamic CYP19a1 mRNA levels in OVX rats, whereas it did not alter CYP19a1 mRNA levels in OVX with estradiol-administered rats, indicating that conversion of testosterone to estrogens in the hypothalamus may be activated in testosterone-administered OVX rats. Furthermore, chronic testosterone administration decreased hypothalamic TNF-α mRNA levels in OVX rats, whereas it increased hypothalamic IL-1ß mRNA levels in OVX with estradiol-administered rats. On the other hand, IL-1ß and TNF-α mRNA levels in visceral and subcutaneous WAT and liver were not changed by chronic testosterone administration in both groups. These data indicate that the effects of chronic testosterone administration on BW, FI, WAT weight, and adipocyte size were changed by estradiol treatment in female rats. Testosterone has facilitative effects on BW gain, FI, and adiposity under the estradiol-supplemented condition, whereas it has inhibitory effects in the non-supplemented condition. Differences in the responses of hypothalamic factors, such as aromatase and inflammatory cytokines, to testosterone might underlie these opposite effects.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Estrogênios/farmacologia , Testosterona/farmacologia , Tecido Adiposo/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Estradiol/farmacologia , Feminino , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Ovariectomia , Ratos , Ratos Wistar , Testosterona/administração & dosagem , Aumento de Peso/efeitos dos fármacosRESUMO
Prenatal undernutrition and postnatal overnutrition increase the risk of some peripheral and central metabolic disorders in adulthood. We speculated that disturbances of appetite/metabolic regulatory factors might already have been established in the early stages of life and contribute to obesity later in life. The effects of a high-fat diet on the levels of peripheral and central appetite/metabolic regulatory factors were compared between the offspring of normally nourished dams and those of undernourished dams in the peri-pubertal period. In the offspring of the normally nourished dams (control), the consumption of the high-fat diet resulted in lower hypothalamic mRNA levels of orexigenic factors (neuropeptide Y (NPY) and prepro-orexin (pporexin)), whereas no such changes were seen in the offspring of the undernourished dams (subjected to intrauterine growth restriction). These results indicate that in high-energy conditions either the adaptive response does not function properly or has not been established in the offspring of undernourished dams. Because NPY and pporexin are negatively regulated by leptin, these findings suggest that in the intrauterine growth restriction group, the leptin resistance of hypothalamic functions, which is usually caused by diet-induced obesity in adulthood, had already been established in the peri-pubertal period.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Desenvolvimento Fetal , Regulação da Expressão Gênica no Desenvolvimento , Hipotálamo/metabolismo , Desnutrição/fisiopatologia , Fenômenos Fisiológicos da Nutrição Materna , Obesidade/etiologia , Animais , Regulação do Apetite , Feminino , Retardo do Crescimento Fetal/etiologia , Retardo do Crescimento Fetal/fisiopatologia , Gordura Intra-Abdominal/metabolismo , Lactação , Leptina/sangue , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Obesidade/sangue , Obesidade/metabolismo , Orexinas/genética , Orexinas/metabolismo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Ratos Sprague-Dawley , DesmameRESUMO
The actions and responses of hypothalamic appetite regulatory factors change markedly during the neonatal to pre-pubertal period in order to maintain appropriate metabolic and nutritional conditions. In this study, we examined the developmental changes in the hypothalamic mRNA levels of brain-derived neurotrophic factor (BDNF), which is a potent anorectic factor and the changes in the sensitivity of the hypothalamic expression of this factor to fasting during the neonatal to pre-pubertal period. Under fed conditions, hypothalamic BDNF mRNA expression decreased during development in both male and female rats. Similarly, the serum levels of leptin, which is a positive regulator of hypothalamic BDNF expression, also tended to fall during the developmental period. The serum leptin level and the hypothalamic BDNF mRNA level were found to be positively correlated in both sexes under the fed conditions. Hypothalamic BDNF mRNA expression was decreased by 24h fasting (separating the rats from their mothers) in the early neonatal period (postnatal day 10) in both males and females, but no such changes were seen at postnatal day 20. Twenty-four hours' fasting (food deprivation) did not affect hypothalamic BDNF mRNA expression in the pre-pubertal period (postnatal day 30). On the other hand, the rats' serum leptin levels were decreased by 24h fasting (separating the rats from their mothers at postnatal day 10 and 20, and food deprivation at postnatal day 30) throughout the early neonatal to pre-pubertal period. The correlation between serum leptin and hypothalamic BDNF mRNA levels was not significant under the fasted conditions. It can be speculated that leptin partially regulates hypothalamic BDNF mRNA levels, but only in fed conditions. Such changes in hypothalamic BDNF expression might play a role in maintaining appropriate metabolic and nutritional conditions and promoting normal physical development. In addition, because maternal separation induces a negative energy balance and short- and long-term stress responses, it is also possible that reductions in hypothalamic BDNF mRNA levels in the early neonatal period (postnatal day 10) may be partially induced by stress responses of the maternal deprivation.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Jejum/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hipotálamo/crescimento & desenvolvimento , Hipotálamo/metabolismo , Leptina/sangue , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Feminino , Masculino , Gravidez , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores SexuaisRESUMO
In females, estrogens play pivotal roles in preventing excessive body weight gain. On the other hand, the roles of androgen in female appetite and body weight regulation have not been fully studied. In this study, whether the roles of androgen in the regulation of body weight and appetite were different among ages and/or the estrogen milieu in females was evaluated. Body weight gain and food intake were increased by chronic testosterone administration in pre-pubertal and gonadal-intact female rats, but not in ovariectomized female rats. Testosterone administration also affected the serum leptin level and adipose leptin gene expression levels differently in each experimental condition. Hypothalamic mRNA levels of ERα, which plays pivotal roles in regulation of body weight and metabolism, were decreased by chronic testosterone administration in pre-pubertal and gonadal-intact female rats, but not in ovariectomized female rats. These results indicate that the effects of testosterone on body weight and appetite differed among ages and/or estrogen milieu in female rats, and that attenuation of estrogens' actions on the hypothalamus might be partly involved in the androgen-induced increases of body weight gain and food intake in females.
Assuntos
Androgênios/farmacologia , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Estrogênios/metabolismo , Testosterona/farmacologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Animais , Peso Corporal/fisiologia , Ingestão de Alimentos/fisiologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Hipotálamo/efeitos dos fármacos , Hipotálamo/crescimento & desenvolvimento , Hipotálamo/metabolismo , Leptina/sangue , Ovariectomia , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos Sprague-DawleyRESUMO
The actions and responses of hypothalamic appetite regulatory and factors change markedly during the neonatal to pre-pubertal period. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been found to play pivotal roles in the regulation of metabolic and nutritional status through its specific receptor PAC1. PACAP/PAC1 have anorectic roles, and their functions are regulated by leptin in adulthood. In the present study, we showed that hypothalamic PACAP mRNA expression decreases during the neonatal to pre-pubertal period (from postnatal day 10-30) in both male and female rats. During this period, hypothalamic PACAP mRNA expression was not affected by 24h fasting in either sex, while the serum leptin levels (leptin is a positive regulator of hypothalamic PACAP expression in adulthood) of both sexes were decreased by fasting. On the other hand, hypothalamic PAC1 mRNA expression did not change during the neonatal to pre-pubertal period in either sex; however, its levels were consistently higher in males than in females. Hypothalamic PAC1 mRNA expression was decreased by 24h fasting in males, but no such changes were observed in females. These results indicate while hypothalamic PACAP expression is sensitive to a negative energy state and the serum leptin level in adulthood, no such relationships are seen in the pre-pubertal period. In addition, we speculate that differences in the gonadal steroidal milieu might induce sexual dimorphism in the basal hypothalamic PAC1 mRNA level and its response to fasting. The mechanisms responsible for and the physiological effects of such changes in hypothalamic PACAP and PAC1 expression during the developmental period remain to be clarified.
Assuntos
Jejum/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hipotálamo/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , RNA Mensageiro/metabolismo , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Caracteres Sexuais , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Feminino , Hipotálamo/crescimento & desenvolvimento , Leptina/sangue , Masculino , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismoRESUMO
The neonatal and/or prepubertal androgen milieu affects sexual maturation and reproductive function in adulthood. However, the effects of chronic dehydroepiandrosterone (DHEA) treatment on reproductive functions have not been fully elucidated. Therefore, the reproductive phenotypes and parameters of rats that had been subjected to chronic DHEA treatment were evaluated in this study. The chronic DHEA-treated (from postnatal day 23-12 weeks of age) rats exhibited earlier vaginal opening, indicating that DHEA treatment promotes sexual maturation. In addition, the estrus phase lasted longer in the DHEA-treated rats, suggesting that their estrous cycles had been disrupted. As the DHEA-treated rats' serum luteinizing hormone levels and hypothalamic Kiss1 mRNA expression levels were decreased and their uterine weight was increased, DHEA and/or estrogen might directly affect reproductive phenotypes. While DHEA treatment caused changes in body weight and body composition in chronic testosterone-treated models in previous studies, no such changes were seen in the present study.
Assuntos
Desidroepiandrosterona/farmacologia , Ciclo Estral/efeitos dos fármacos , Hormônios Esteroides Gonadais/farmacologia , Kisspeptinas/efeitos dos fármacos , Hormônio Luteinizante/efeitos dos fármacos , Maturidade Sexual/efeitos dos fármacos , Vagina/efeitos dos fármacos , Animais , Desidroepiandrosterona/administração & dosagem , Feminino , Hormônios Esteroides Gonadais/administração & dosagem , Hipotálamo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Vagina/crescimento & desenvolvimentoRESUMO
Nesfatin-1 is a central anorectic peptide derived from the precursor protein nucleobindin-2 (NUCB2). In the present study, the changes in hypothalamic NUCB2 mRNA expression and their responses to food deprivation during the neonatal to pre-pubertal period (postnatal days 10, 20, and 30) were evaluated in male and female rats. The rats' serum leptin levels were also measured because NUCB2 mRNA expression is positively regulated by leptin. In both the female and male rats, hypothalamic NUCB2 mRNA expression tended to fall throughout development. Similarly, higher serum leptin levels were detected on postnatal day 10 than on postnatal days 20 and 30 in both sexes. Hypothalamic NUCB2 mRNA expression was positively correlated with the serum leptin level in both the female and male rats; however, the relationship was not significant in males. The hypothalamic NUCB2 mRNA levels of the fed and 24h fasted groups did not differ at any time point in either sex. On the other hand, the serum leptin levels of the 24h fasted group were significantly lower than those of the fed group at all time points in both sexes. It can be speculated that the upregulation of hypothalamic leptin activity might induce a transient increase in hypothalamic NUCB2 mRNA expression during the early postnatal period (postnatal day 10) in both sexes. However, hypothalamic NUCB2 mRNA expression does not become sensitive to a negative energy balance during the neonatal to pre-pubertal period.