RESUMEN
Background High stress and depression during pregnancy are risk factors for worsened health trajectories for both mother and offspring. This is also true for pre-pregnancy obesity and excessive gestational weight gain. Reducing stress and depression may be one path to prevent excessive caloric intake and gestational weight gain. Study Purpose We tested the feasibility of two novel interventions aimed at reducing stress and overeating during pregnancy. Reflecting different theoretical underpinnings, the interventions target different mechanisms. Mindful Moms Training (MMT) uses mindfulness to improve awareness and acceptance of experiences and promote conscious rather than automatic behavior choices. Emotional Brain Training (EBT) uses active coping to change perceptions of negative experience and promote positive affective states. Methods Forty-six overweight/obese low-income women were assigned to either MMT (n = 24) or EBT (n = 22) for an 8-week feasibility study. Pre-post changes in perceived stress, eating and presumed mechanisms were assessed. Results Women reported high levels of stress at baseline. Both interventions were well attended and demonstrated clinically significant pre-post reductions in stress, depressive symptoms, and improved eating behaviors. MMT significantly decreased experiential avoidance, whereas EBT significantly increased positive reappraisal; these changes were marginally significantly different by group. Conclusions This feasibility study found that both interventions promoted meaningful reductions in stress and depressive symptoms and improved reported eating behaviors in a high-risk group of pregnant women. Each intervention has a potentially different pathway-acceptance for MMT and reappraisal for EBT. Larger studies are needed to test efficacy on longer term reductions in stress and overeating.
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Depresión/terapia , Conducta Alimentaria/psicología , Hiperfagia/terapia , Atención Plena/métodos , Complicaciones del Embarazo/terapia , Mujeres Embarazadas/psicología , Estrés Psicológico/terapia , Adolescente , Adulto , Depresión/psicología , Emociones , Estudios de Factibilidad , Femenino , Humanos , Hiperfagia/psicología , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/prevención & control , Sobrepeso/complicaciones , Sobrepeso/prevención & control , Embarazo , Complicaciones del Embarazo/psicología , Estrés Psicológico/psicología , Resultado del Tratamiento , Adulto JovenRESUMEN
Insulin and signalling through the vagus nerve act in concert to regulate metabolic homeostasis and ingestive behaviour. Our previous studies using streptozotocin (STZ)-diabetic rats have shown that hepatic branch vagotomy (HV), gastroduodenal branch vagotomy (GV) and capsaicin treatment of the common hepatic branch that selectively destroys afferent fibres (CapV), all promote lard, but not total, caloric intake to levels similar to those achieved with insulin treatment. Because hypothalamic and limbic mRNA expression of neuropeptides linked to energy balance is altered by STZ-diabetes and HV, we examined the role(s) of insulin and the common hepatic and gastroduodenal branches of the vagus nerve and hepatic afferent fibres in the regulation of these neuropeptides in rats with high, steady-state corticosterone levels. STZ-diabetic rats were prepared with osmotic minipumps containing either saline or insulin and were compared with nondiabetic counterparts: half of each group received a vagal manipulation, the other half were sham operated. Five days after surgery, rats were offered the choice of lard and chow to consume for another 5 days, when brains were collected and processed for in situ hybridisation. Paraventricular nucleus corticotrophin-releasing factor (CRF) mRNA was elevated by STZ treatment, an effect prevented by either insulin treatment or GV. By contrast, CRF mRNA expression in the central nucleus of the amygdala and bed nuclei of the stria terminalis was unaffected by STZ treatment, but HV and CapV manipulations elevated expression in the nondiabetic, but not STZ-diabetic groups. Arcuate nucleus neuropeptide Y, but not pro-opiomelanocortin, mRNA expression was elevated by STZ treatment and all vagal manipulations; however, exogenous insulin treatment failed to prevent this, in keeping with their previously documented elevated caloric intake. These results strongly suggest that the gastroduodenal branch and hepatic branch proper, which merge to form the common hepatic branch, differentially interact with prevailing insulin levels to regulate hypothalamic and limbic neuropeptide mRNA expression.
Asunto(s)
Regulación de la Expresión Génica , Hipotálamo/metabolismo , Insulina/farmacología , Sistema Límbico/metabolismo , Neuropéptidos/genética , Nervio Vago/fisiología , Animales , Corticosterona/sangre , Hormona Liberadora de Corticotropina/genética , Hormona Liberadora de Corticotropina/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Sistema Límbico/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/inervación , Masculino , Modelos Biológicos , Neuropéptido Y/genética , Neuropéptido Y/metabolismo , Neuropéptidos/metabolismo , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , EstreptozocinaRESUMEN
Two groups of rats, one bearing bilateral excitotoxic lesions of the medial prefrontal cortex (mPFC) and one sham-lesioned group, were run in a successive negative contrast paradigm. Both groups had telemeters implanted to monitor core temperature and activity. After ad libitum baseline and food restriction to 85% body weights, rats received a sucrose solution once daily for 5 min and 30 s at 10:30 h. They received their preshift 32% sucrose solution for 14 days followed by a sucrose concentration reduction (downshift) to 4% sucrose for 12 days. Rats were then upshifted to 32% for six additional days before being downshifted to 4% for the next 6 days. There were no differences in intake of the 32% sucrose during the preshift. All rats showed profound suppression of intake upon the shift to 4% sucrose. On the first day of the unexpected 4% sucrose, lesioned rats showed an enhanced psychogenic fever compared with Shams, whereas on the second day of 4% sucrose they showed an impaired ability to blunt that fever compared with Shams. In addition, lesioned rats showed greater rates of recovery and asymptotic drinking of the subsequent 4% sucrose solution than Shams, indicating impairments in the encoding or retrieval of the shift. In addition, lesioned rats showed enhanced entrainment to the 32% sucrose meals, normal damping of anticipation, and enhanced spontaneous recovery of anticipatory thermal responses to the calorically impoverished 4% solutions. These failures to inhibit responding point to a failure in interference learning in rats bearing lesions of the mPFC.
Asunto(s)
Fiebre/etiología , Corteza Prefrontal/lesiones , Corteza Prefrontal/fisiología , Recuperación de la Función/fisiología , Estrés Psicológico/fisiopatología , Sacarosa/administración & dosificación , Hormona Adrenocorticotrópica/sangre , Análisis de Varianza , Animales , Conducta Animal , Temperatura Corporal/fisiología , Peso Corporal , Condicionamiento Operante , Corticosterona/sangre , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/fisiología , Privación de Alimentos , Masculino , Actividad Motora/fisiología , Ratas , Ratas Wistar , Restricción Física/métodos , Estrés Psicológico/sangre , Estrés Psicológico/etiología , Factores de TiempoRESUMEN
In addition to the inhibitory role of central insulin on food intake, insulin also acts to promote lard intake. We investigated the neural pathways involved in this facet of insulin action. Insulin or saline was infused into either the superior mesenteric or right external jugular veins of streptozotocin-diabetic rodents with elevated steady-state circulating corticosterone concentrations. After postsurgical recovery, rats were offered the choice of chow or lard to eat. Irrespective of the site of venous infusion, insulin increased lard and decreased chow intake. After 4 days, lard was removed for 8 h. On return for 1 h, only insulin infused into the superior mesenteric vein resulted in lard intake. This facilitated distinction between the effects of circulating insulin concentrations (similar in the two insulin-infused groups) and lard ingestion on the patterns of c-Fos(+) cells in the brain, termed insulin- and lard-associated patterns, respectively. Insulin-associated changes in c-Fos(+) cell numbers were evident in the arcuate nucleus, bed nucleus of the stria terminalis and substantia nigra pars compacta, concomitant with elevated leptin levels and reduced chow intake. Lard-associated changes in c-Fos(+) cell numbers were observed in the nucleus of the tractus solitarius, lateral parabrachial nucleus, central nucleus of the amygdala, ventral tegmental area, nucleus accumbens shell and the prefrontal cortex, and were associated with lower levels of triglycerides and free fatty acids. The anterior paraventricular thalamic nucleus exhibited both patterns. These data collectively fit into a framework for food intake and reward and provide targets for pharmacological manipulation to influence the choice of food intake.
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Regulación del Apetito/fisiología , Mapeo Encefálico , Hipotálamo/metabolismo , Insulina/fisiología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Encéfalo/metabolismo , Conducta de Elección , Corticosterona/sangre , Diabetes Mellitus Experimental/metabolismo , Grasas de la Dieta/metabolismo , Conducta Alimentaria/fisiología , Preferencias Alimentarias/fisiología , Inmunohistoquímica , Inyecciones Intraventriculares , Insulina/administración & dosificación , Masculino , Vías Nerviosas/metabolismo , Corteza Prefrontal/metabolismo , Ratas , Ratas Sprague-Dawley , Sustancia Negra/metabolismoRESUMEN
The brain takes a primary position in the organism. We present the novel view that the brain gives priority to controlling its own adenosine triphosphate (ATP) concentration. It fulfils this tenet by orchestrating metabolism in the organism. The brain activates an energy-on-request system that directly couples cerebral supply with cerebral need. The request system is hierarchically organized among the cerebral hemispheres, the hypothalamus, and peripheral somatomotor, autonomic-visceromotor, and the neuroendocrine-secretomotor neurons. The system initiates allocative behavior (i.e. allocation of energy from body to brain), ingestive behavior (intake of energy from the immediate environment), or exploratory behavior (foraging in the distant environment). Cerebral projections coordinate all three behavioral strategies in such a way that the brain's energy supply is guaranteed continuously. In an ongoing learning process, the brain's request system adapts to various environmental conditions and stressful challenges. Disruption of a cerebral energy-request pathway is critical to the development of obesity: if the brain fails to receive sufficient energy from the peripheral body, it compensates for the undersupply by increasing energy intake from the immediate environment, leaving the body with a surplus. Obesity develops in the long term.
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Regulación del Apetito/fisiología , Encéfalo/fisiología , Metabolismo Energético , Modelos Biológicos , Obesidad/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Retroalimentación Fisiológica/fisiología , Hipotálamo , Potenciación a Largo Plazo/fisiología , Redes y Vías Metabólicas , Vías Nerviosas/metabolismoRESUMEN
Acutely, glucocorticoids act to inhibit stress-induced corticotrophin-releasing factor (CRF) and adrenocorticotrophic hormone (ACTH) secretion through their actions in brain and anterior pituitary (canonical feedback). With chronic stress, glucocorticoid feedback inhibition of ACTH secretion changes markedly. Chronically stressed rats characteristically exhibit facilitated ACTH responses to acute, novel stressors. Moreover, in adrenalectomized rats in which corticosterone was replaced, steroid concentrations in the higher range are required for facilitation of ACTH responses to occur after chronic stress or diabetes. Infusion of corticosterone intracerebroventricularly into adrenalectomized rats increases basal ACTH, tends to increase CRF, and allows facilitation of ACTH responses to repeated restraint. Therefore, with chronic stressors, corticosterone seems to act in brain in an excitatory rather than an inhibitory fashion. We believe, under conditions of chronic stress, that there is an indirect glucocorticoid feedback that is mediated through the effects of the steroid +/- insulin on metabolism. Increased energy stores feedback on brain to inhibit hypothalamic CRF and decrease the expression of dopamine-beta-hydroxylase in the locus coeruleus. These changes would be expected to decrease the level of discomfort and anxiety induced by chronic stress. Moreover, central neural actions of glucocorticoids abet the peripheral effects of the steroids by increasing the salience and ingestion of pleasurable foods.
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Encéfalo/fisiopatología , Corticosterona/fisiología , Estrés Fisiológico/fisiopatología , Animales , Enfermedad Crónica , Diabetes Mellitus Tipo 1/fisiopatología , HumanosRESUMEN
In adrenalectomized (ADX) rats, either corticosterone replacement or increased sucrose intake will restore body weight gain, uncoupling protein-1, fat depot mass, food intake and corticotropin-releasing factor mRNA expression to normal. Here, we tested the potential interactions between sucrose intake and circulating corticosterone on behavioural, metabolic, autonomic and neuroendocrine responses to the stress of cold. Rats were left intact, sham-ADX, or ADX and replaced with pellets that provided normal, basal (30%B) or high stress (100%B) constant circulating concentrations of corticosterone +/- sucrose. More calories were consumed in cold than at room temperature (RT), provided that corticosterone concentrations were elevated above mean daily basal values in cold. Neither increased sucrose nor increased chow ingestion occurred in cold if the rats were ADX and replaced with 30%B. However, sucrose drinking in this group markedly ameliorated other responses to cold. By contrast, ADX30%B rats not drinking sucrose fared poorly, and none of the metabolic or endocrine variables were similar to those in sham-ADX controls. ADX100%B group in cold, resembled intact rats without sucrose; however, this group was metabolically abnormal at RT. We conclude that drinking sucrose lowers stress-induced corticosterone secretion while reducing many responses to cold; elevated corticosterone concentrations in the stress-response range are essential for the normal integrated cold-induced responses to occur.
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Sistema Nervioso Autónomo/fisiología , Frío , Corticosterona/farmacología , Sacarosa en la Dieta/farmacología , Ingestión de Alimentos/fisiología , Sistemas Neurosecretores/fisiología , Tejido Adiposo/fisiología , Adrenalectomía , Animales , Regulación de la Temperatura Corporal/efectos de los fármacos , Regulación de la Temperatura Corporal/fisiología , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Enfermedad Crónica , Corticosterona/sangre , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Lípidos/sangre , Masculino , Ratas , Ratas Sprague-Dawley , Estrés Fisiológico/fisiopatología , Testosterona/sangreRESUMEN
Increased hypothalamo-pituitary-adrenal axis drive has been reported in obese subjects but with paradoxically low or normal levels of plasma cortisol. Our current study was designed to investigate whether glucocorticoid feedback was altered in obesity, both under basal and stressed conditions. Plasma ACTH and cortisol concentrations in male control or obese subjects (age range 20-50 yr) were measured at frequent intervals over 24 h during infusion of saline or hydrocortisone at two physiological doses (7.5 and 15 mg/d) designed to occupy predominantly mineralocorticoid rather than glucocorticoid receptors. The same subjects then underwent insulin-induced hypoglycemia either in the morning or the evening. Obese subjects had significantly higher basal ACTH and lower cortisol concentrations throughout the 24 h infusion period, compared with controls (P < 0.05, two-way ANOVA followed by Newman-Keuls posthoc analysis). Basal plasma ACTH was decreased in obese groups given low- or high-dose hydrocortisone during the day (P < 0.05) but not during the night, unlike controls who responded to hydrocortisone both during the day and at night (P < 0.05). Obese subjects also showed resistance to steroid-induced inhibition of the ACTH response to hypoglycemia, compared with controls (P < 0.05). These data clearly show that obesity is associated with a relative insensitivity to glucocorticoid feedback, which is most marked during the night, and suggest that this condition is characterized by a decreased mineralocorticoid receptor response to circulating corticosteroids.
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Glucocorticoides/fisiología , Obesidad/fisiopatología , Hormona Adrenocorticotrópica/sangre , Adulto , Retroalimentación/fisiología , Humanos , Hidrocortisona/administración & dosificación , Hidrocortisona/sangre , Hidrocortisona/farmacología , Hipoglucemiantes/farmacología , Infusiones Intravenosas , Insulina/farmacología , Masculino , Persona de Mediana Edad , RadioinmunoensayoRESUMEN
Chronic stress stimulates corticosterone secretion and recruits brain pathways that regulate energy balance (caloric acquisition and deposition) and facilitate hypothalamic-pituitary-adrenal responsiveness to new stressors. We implanted corticosterone or cholesterol bilaterally either near the central nucleus of the amygdala (CeA) or in the prefrontal cortex to determine whether high concentrations of the steroid act at either site, with or without chronic stress. Rats were adrenalectomized and treated systemically with low doses of corticosterone. Half were maintained at room temperature and the other half were exposed to 5 degrees C cold for 5 days before all rats were restrained. There was limited diffusion of corticosterone from brain implants. Corticosterone in prefrontal cortex, but not CeA, decreased plasma insulin and adrenocorticotropic hormone (ACTH) responses to acute restraint in both control and chronically cold stressed rats. Corticosterone implants near CeA decreased the weight of fat depots only in cold; corticosterone implants in prefrontal cortex were ineffective. We conclude that (i) corticosterone inhibits insulin and ACTH secretion by an action in prefrontal cortex but not CeA; (ii) high concentrations of corticosterone secreted during chronic stress alter metabolism through (autonomic) outputs of the CeA and prefrontal cortex in site- and variable-specific fashion; and (iii) the amygdala is a component of a stress-recruited, state-dependent pathway.
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Tejido Adiposo/anatomía & histología , Hormona Adrenocorticotrópica/metabolismo , Amígdala del Cerebelo/fisiología , Corticosterona/farmacología , Insulina/metabolismo , Corteza Prefrontal/fisiología , Tejido Adiposo/efectos de los fármacos , Adrenalectomía , Amígdala del Cerebelo/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Enfermedad Crónica , Frío , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Hormonas/sangre , Masculino , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Restricción Física , Estrés Fisiológico/fisiopatologíaRESUMEN
Both CRF and norepinephrine (NE) inhibit food intake and stimulate ACTH secretion and sympathetic outflow. CRF also increases anxiety; NE increases attention and cortical arousal. Adrenalectomy (ADX) changes CRF and NE activity in brain, increases ACTH secretion and sympathetic outflow and reduces food intake and weight gain; all of these effects are corrected by administration of adrenal steroids. Unexpectedly, we recently found that ADX rats drinking sucrose, but not saccharin, also have normal caloric intake, metabolism, and ACTH. Here, we show that ADX (but not sham-ADX) rats prefer to consume significantly more sucrose than saccharin. Voluntary ingestion of sucrose restores CRF and dopamine-beta-hydroxylase messenger RNA expression in brain, food intake, and caloric efficiency and fat deposition, circulating triglyceride, leptin, and insulin to normal. Our results suggest that the brains of ADX rats, cued by sucrose energy (but not by nonnutritive saccharin) maintain normal activity in systems that regulate neuroendocrine (hypothalamic-pituitary-adrenal), behavioral (feeding), and metabolic functions (fat deposition). We conclude that because sucrose ingestion, like glucocorticoid replacement, normalizes energetic and neuromodulatory effects of ADX, many of the actions of the steroids on the central nervous system under basal conditions may be indirect and mediated by signals that result from the metabolic effects of adrenal steroids.
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Adrenalectomía , Encéfalo/metabolismo , Hormona Liberadora de Corticotropina/genética , Metabolismo Energético/efectos de los fármacos , ARN Mensajero/metabolismo , Sacarosa/farmacología , Administración Oral , Amígdala del Cerebelo/metabolismo , Animales , Conducta de Elección , Dopamina beta-Hidroxilasa/metabolismo , Glucocorticoides/metabolismo , Locus Coeruleus/metabolismo , Masculino , Núcleo Hipotalámico Paraventricular/metabolismo , Ratas , Ratas Sprague-Dawley , Valores de ReferenciaRESUMEN
To reveal direct effects of androgens, independent of glucocorticoids, we studied the effects of gonadectomy (GDX) in adrenalectomized (ADX) rats with or without androgen replacement on corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) mRNA expression within various forebrain sites known to regulate the hypothalamic-pituitary-adrenal axis. These included the medial parvocellular portion of the paraventricular nucleus of the hypothalamus (mp PVN), the central and medial nuclei of the amygdala and bed nuclei of the stria terminalis (BNST). In the mp PVN, ADX stimulated both CRH and AVP mRNA expression. Combined ADX + GDX inhibited only AVP, and testosterone and dihydrotestosterone (DHT) restored AVP mRNA. In the central nucleus of the amygdala, ADX decreased CRH mRNA expression, and this response was unaffected by GDX +/- testosterone or DHT replacement. In the medial amygdala, AVP mRNA expression was decreased by ADX, abolished by ADX + GDX, and restored by androgen replacement. ADX had no effect on CRH and AVP mRNA expression in the BNST. GDX + ADX, however, reduced CRH mRNA expression only within the fusiform nuclei of the BNST and reduced the number of AVP-expressing neurones in the posterior BNST. Androgen replacement reversed both responses. In summary, in ADX rats, AVP, but not CRH mRNA expression in the amygdala and mp PVN, is sensitive to GDX +/- androgen replacement. Both CRH- and AVP-expressing neurones in the BNST respond to GDX and androgen replacement, but not to ADX alone. Because androgen receptors are not expressed by hypophysiotropic PVN neurones, we conclude that glucocorticoid-independent, androgenic influences on medial parvocellular AVP mRNA expression are mediated upstream from the PVN, and may involve AVP-related pathways in the medial amygdala, relayed to and through CRH- and AVP-expressing neurones of the BNST.
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Arginina Vasopresina/genética , Hormona Liberadora de Corticotropina/genética , Hormonas Esteroides Gonadales/farmacología , Sistema Hipotálamo-Hipofisario/fisiología , Sistema Hipófiso-Suprarrenal/fisiología , Testosterona/farmacología , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/fisiología , Animales , Peso Corporal/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Masculino , Orquiectomía , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/fisiología , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Núcleos Septales/efectos de los fármacos , Núcleos Septales/fisiologíaRESUMEN
Previous studies suggested that adults respond differently than pubertal male rats to cold stress. To test the role of androgens in this difference, we adrenalectomized and replaced with corticosterone either 60- or 40-day-old male rats, then sham gonadectomized (Intact), gonadectomized (GDX), or GDX and replaced with testosterone (T; GDX+T) or dihydrotestosterone (DHT). One-half remained at room temperature (RT), and one-half lived in cold for 5 days. Cold reduced T in adult but not in pubertal Intacts. In 60-day-old rats, GDX with or without T replacement had minor effects on body weight (BW) and food intake (FI) at RT and cold. In 40-day-old rats at RT, androgens had slight effects; however, androgens affected almost all variables in cold. Separation of 40-day-old T-treated rats into two groups (moderate T levels, 1.4 ng/ml; high T levels, 1.9 ng/ml) revealed major differences between the groups. Moderate T (and DHT) prevented cold-induced loss of BW and increased FI. No T and high T induced decreased BW and FI in cold. We conclude that at 40 days of age, partial resistance to stress-induced reduction of T and high sensitivity to small changes in T have markedly positive effects on threatened energy balance.
Asunto(s)
Frío , Metabolismo Energético/fisiología , Hormonas Esteroides Gonadales/farmacología , Maduración Sexual/fisiología , Estrés Fisiológico/metabolismo , Testosterona/farmacología , Tejido Adiposo/anatomía & histología , Tejido Adiposo/metabolismo , Adrenalectomía , Factores de Edad , Análisis de Varianza , Animales , Dihidrotestosterona/sangre , Dihidrotestosterona/farmacología , Metabolismo Energético/efectos de los fármacos , Hormonas Esteroides Gonadales/sangre , Insulina/sangre , Leptina/sangre , Masculino , Orquiectomía , Tamaño de los Órganos/fisiología , Fotoperiodo , Ratas , Ratas Sprague-Dawley , Testosterona/sangre , Timo/anatomía & histología , Timo/metabolismoRESUMEN
Adrenal steroids are essential for homeostasis and survival during severe physiological stress. Analysis of a patient heterozygous for the steroidogenic factor-1 (SF-1) gene suggested that reduced expression of this nuclear receptor leads to adrenal failure. We therefore examined SF-1 heterozygous (+/-) mice as a potential model for delineating mechanisms underlying this disease. Here we show that SF-1 +/- mice exhibit adrenal insufficiency resulting from profound defects in adrenal development and organization. However, compensatory mechanisms, such as cellular hypertrophy and increased expression of the rate-limiting steroidogenic protein StAR, help to maintain adrenal function at near normal capacity under basal conditions. In contrast, adrenal deficits in SF-1 heterozygotes are revealed under stressful conditions, demonstrating that normal gene dosage of SF-1 is required for mounting an adequate stress response. Our findings predict that natural variations leading to reduced SF-1 function may underlie some forms of subclinical adrenal insufficiency, which become life threatening during traumatic stress.
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Glándulas Suprarrenales/crecimiento & desarrollo , Proteínas de Unión al ADN/fisiología , Estrés Fisiológico , Factores de Transcripción/fisiología , Glándulas Suprarrenales/patología , Médula Suprarrenal/patología , Alelos , Animales , Proteínas de Unión al ADN/genética , Femenino , Factores de Transcripción Fushi Tarazu , Regulación de la Expresión Génica , Proteínas de Homeodominio , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Receptor de Melanocortina Tipo 2 , Receptores de Corticotropina/genética , Receptores Citoplasmáticos y Nucleares , Factor Esteroidogénico 1 , Factores de Transcripción/genéticaRESUMEN
Mild chronic stressors characteristically increase circadian trough corticosteroid concentrations in rats and man. The elevation in trough concentrations is often accompanied by a reduction in peak concentrations and no change in the daily mean values. Here we point out that elevation of trough glucocorticoids, probably through daily increases of glucocorticoid receptor occupancy, has major metabolic effects that bias organisms toward storage of calories as fat. Thus, chronic mild stress, by overriding the normal mineralocorticoid receptor-mediated corticosteroid feedback regulation of trough CRF and ACTH secretion, facilitates development of the metabolic syndrome.
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Ritmo Circadiano , Glucocorticoides/sangre , Corticoesteroides/sangre , Hormona Adrenocorticotrópica/metabolismo , Animales , Retroalimentación , Humanos , Ratas , Estrés Fisiológico/sangreRESUMEN
The mediobasal hypothalamus regulates functions necessary for survival, including body energy balance and adaptation to stress. The purpose of this experiment was to determine the contribution of the arcuate nucleus (ARC) in controlling these two functions by the paraventricular nucleus (PVN). Circular, horizontal cuts (1.0 mm radius) were placed immediately above the anterior ARC to sever afferents to the PVN. In shams the knife was lowered to the same coordinates but was not rotated. Food intake and body weight were monitored twice daily, at the beginning and end of the light cycle, for 1 week. On the final day the animals were restrained for 30 min. Lesioned animals had increased food intake in light and dark periods, higher weight gain per day, and more body fat as compared with shams. There was no difference in caloric efficiency. Unlike shams, lesioned rats had no predictable relationship between plasma insulin and leptin. Plasma ACTH was increased at 0 min in lesioned rats but was decreased 15 and 30 min after restraint as compared with shams. There was no difference in plasma corticosterone. Immunostaining revealed that alpha-melanocortin (alphaMSH) and neuropeptide Y (NPY) accumulated below the cuts, and both were decreased in PVN. Food intake and body weight were correlated negatively to alphaMSH, but not NPY in PVN. There was no difference in proopiomelanocortin (POMC) mRNA, but NPY mRNA was reduced in the ARC of lesioned animals. We conclude that ARC controls body energy balance in unstressed rats, possibly by alphaMSH input to PVN, and that ARC also is necessary for PVN regulation of ACTH.
Asunto(s)
Núcleo Arqueado del Hipotálamo/fisiología , Relojes Biológicos/fisiología , Metabolismo Energético/fisiología , Núcleo Hipotalámico Paraventricular/fisiología , Estrés Psicológico/fisiopatología , Hormona Adrenocorticotrópica/sangre , Vías Aferentes/fisiología , Animales , Núcleo Arqueado del Hipotálamo/fisiopatología , Peso Corporal , Ritmo Circadiano/fisiología , Corticosterona/sangre , Ingestión de Energía , Insulina/sangre , Leptina/sangre , Masculino , Vías Nerviosas/fisiología , Vías Nerviosas/fisiopatología , Neuropéptido Y/genética , Neuropéptido Y/metabolismo , Núcleo Hipotalámico Paraventricular/fisiopatología , Proopiomelanocortina/genética , Ratas , Ratas Sprague-Dawley , Restricción Física , Transcripción Genética , Aumento de Peso , alfa-MSH/metabolismoRESUMEN
Chronic stress alters hypothalamic-pituitary-adrenal (HPA) responses to acute, novel stress. After acute restraint, the posterior division of the paraventricular thalamic nucleus (pPVTh) exhibits increased numbers of Fos-expressing neurons in chronically cold-stressed rats compared with stress-naive controls. Furthermore, lesions of the PVTh augment HPA activity in response to novel restraint only in previously stressed rats, suggesting that the PVTh is inhibitory to HPA activity but that inhibition occurs only in chronically stressed rats. In this study, we further examined pPVTh functions in chronically stressed rats. We identified afferent projections to the pPVTh using injection of the retrograde tracer fluorogold. Of the sites containing fluorogold-labeled cells, neurons in the lateral parabrachial, periaqueductal gray, and dorsal raphe containing fluorogold also expressed cholecystokinin (CCK) mRNA. We then examined whether these CCKergic inputs to the pPVTh were involved in HPA responses to acute, novel restraint after chronic stress. We injected the CCK-B receptor antagonist PD 135,158 into the PVTh before restraint in control and chronically cold-stressed rats. ACTH responses to restraint stress were augmented by PD 135,158 only in chronically stressed rats but not in controls. In addition, CCK-B receptor mRNA expression in the pPVTh was not altered by chronic cold stress. We conclude that previous chronic stress specifically facilitates the release of CCK into the pPVTh in response to acute, novel stress. The CCK is probably secreted from neurons in the lateral parabrachial, the periaqueductal gray, and/or the dorsal raphe nuclei. Acting via CCK-B receptors in pPVTh, CCK then constrains facilitated ACTH responses to novel stress in chronically stressed but not naive rats. These results demonstrate clearly that chronic stress recruits a new set of pathways that modulate HPA responsiveness to a novel stress.
Asunto(s)
Colecistoquinina/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Núcleos Talámicos de la Línea Media/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Estilbamidinas , Estrés Fisiológico/metabolismo , Hormona Adrenocorticotrópica/sangre , Vías Aferentes/metabolismo , Animales , Transporte Axonal , Tronco Encefálico/metabolismo , Colecistoquinina/genética , Colorantes Fluorescentes , Hipotálamo/metabolismo , Sistema Límbico/metabolismo , Masculino , Núcleos Talámicos de la Línea Media/anatomía & histología , Vías Nerviosas/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Colecistoquinina B , Receptores de Colecistoquinina/agonistas , Receptores de Colecistoquinina/antagonistas & inhibidores , Receptores de Colecistoquinina/genética , Receptores de Colecistoquinina/metabolismo , TiempoRESUMEN
Hypothalamic melanocortins are among several neuropeptides strongly implicated in the control of food intake. Agonists for melanocortin 4 (MC-4) receptors such as alpha-melanocyte-stimulating hormone (alpha-MSH), a product of proopiomelanocortin (POMC), reduce food intake, whereas hypothalamic agouti-related protein (AgRP) is a MC-4 receptor antagonist that increases food intake. To investigate whether reduced melanocortin signaling contributes to hyperphagia induced by uncontrolled diabetes, male Sprague-Dawley rats were studied 7 days after administration of streptozotocin (STZ) or vehicle. In addition, we wished to determine the effect of diabetes on muscle uncoupling protein 3 (UCP-3), a potential regulator of muscle energy metabolism. STZ diabetic rats were markedly hyperglycemic (31.3 +/- 1.0 mmol/l; P < 0.005) compared with nondiabetic controls (9.3 +/- 0.2 mmol/l). Insulin treatment partially corrected the hyperglycemia (18.8 +/- 2.5 mol/l; P < 0.005). Plasma leptin was markedly reduced in STZ diabetic rats (0.4 +/- 0.1 ng/ml; P < 0.005) compared with controls (3.0 +/- 0.4 ng/ml), an effect that was also partially reversed by insulin treatment (1.8 +/- 0.3 ng/ml). Untreated diabetic rats were hyperphagic, consuming 40% more food (48 +/- 1 g/day; P < 0.005) than controls (34 +/- 1 g/day). Hyperphagia was prevented by insulin treatment (32 +/- 2 g/day). In untreated diabetic rats, hypothalamic POMC mRNA expression (measured by in situ hybridization) was reduced by 80% (P < 0.005), whereas AgRP mRNA levels were increased by 60% (P < 0.01), suggesting a marked decrease of hypothalamic melanocortin signaling. The change in POMC, but not in AgRP, mRNA levels was partially reversed by insulin treatment. By comparison, the effects of diabetes to increase hypothalamic neuropeptide Y (NPY) expression and to decrease corticotropin-releasing hormone (CRH) expression were normalized by insulin treatment, whereas the expression of mRNA encoding the long form of the leptin receptor in the arcuate nucleus was unaltered by diabetes or insulin treatment. UCP-3 mRNA expression in gastrocnemius muscle from diabetic rats was increased fourfold (P < 0.005), and the increase was prevented by insulin treatment. The effect of uncontrolled diabetes to decrease POMC, while increasing AgRP gene expression, suggests that reduced hypothalamic melanocortin signaling, along with increased NPY and decreased CRH signaling, could contribute to diabetic hyperphagia. These responses, in concert with increased muscle UCP-3 expression, may also contribute to the catabolic effects of uncontrolled diabetes on fuel metabolism in peripheral tissues.
Asunto(s)
Proteínas Portadoras/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Hipotálamo/metabolismo , Insulina/uso terapéutico , Proopiomelanocortina/metabolismo , Receptores de Superficie Celular , Animales , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/fisiopatología , Ingestión de Alimentos/efectos de los fármacos , Hormonas/sangre , Canales Iónicos , Masculino , Proteínas Mitocondriales , Proteínas Musculares/metabolismo , Neuropéptido Y/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Leptina , Proteína Desacopladora 3RESUMEN
Unlike normal rats, adrenalectomized rats do not voluntarily drink sweet saccharin solutions. To test whether this is a function of corticosterone in the circulation, and if corticosterone also increases the impetus for drinking saccharin after a period of withdrawal, we performed the following experiments. Young male rats were sham adrenalectomized (sham) or adrenalectomized (ADX); the ADX rats were provided with subcutaneous pellets containing (percent replacement of corticosterone, %B) 0%B, 15%B, 30%B or 100%B. Sham and ADX rats were immediately provided with saline (0.5%) and saccharin (2 mM) bottles in their home cages. Saccharin was allowed for 4 days on, 3 days off, 4 days on, 3 days off and a final day on, over the 15 days experiment. The dose of corticosterone determined both how much saccharin was voluntarily drunk by the ADX rats and the degree of overshoot after days off. Corticosterone also determined energy balance of the groups of ADX rats. The 30%B pellets restored food intake, body weight gain, insulin and caloric efficiency to the normal levels observed in sham rats. White fat depot weights and uncoupling protein concentration in brown adipose tissue were restored to sham levels by 100%B, suggesting that these variables which depend on activity in the sympathetic nervous system require considerable glucocorticoid receptor occupancy. We conclude that corticosterone increases the willingness to ingest sweetened water in a unimodal, dose-related manner, while moderate doses of corticosterone restore energy balance.
Asunto(s)
Adrenalectomía , Corticosterona/farmacología , Sacarina/administración & dosificación , Hormona Adrenocorticotrópica/sangre , Animales , Corticosterona/administración & dosificación , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Autoadministración , SolucionesRESUMEN
We tested whether corticosterone replacement causes increased sucrose drinking in adrenalectomized (ADX) rats compared to sham-ADX (sham) rats. ADX rats given high doses of corticosterone drank as much sucrose as sham rats, whereas at three lower doses of corticosterone, drinking was similar between groups and was only approximately 40% of that ingested by shams. Compared to sham rats, ADX rats drinking saline, or saline and saccharin, gain weight more slowly, contain less white adipose tissue, and have higher sympathetic outflow as assessed by uncoupling protein content in brown adipose tissue. Allowing sucrose as well as saline to drink restored all of these variables to normal in ADX rats with no- or low-corticosterone. All endpoints from sucrose-drinking ADX rats with no-or low-corticosterone were indistinguishable from those in water-drinking shams. By contrast, sucrose-drinking ADX rats that were given high doses of corticosterone exhibited the usual catabolic effects of corticosterone on body weight gain and, unlike sucrose-drinking shams, were obese. We conclude that (i) high corticosterone stimulates the potability of sucrose and inhibits sympathetic stimulation of uncoupling protein; (ii) sucrose, without corticosterone, normalizes metabolic deficits in ADX rats probably through actions mediated both peripherally and by the central nervous system; and (iii) ADX rats have a distinct sucrose appetite.