RESUMO
The autophagy-related proteins ATG12 and ATG5 form a covalent complex essential for autophagy. Here, we demonstrate that ATG12 has distinct functions from ATG5 in pro-opiomelanocortin (POMC)-expressing neurons. Upon high-fat diet (HFD) consumption, mice lacking Atg12 in POMC-positive neurons exhibit accelerated weight gain, adiposity, and glucose intolerance, which is associated with increased food intake, reduced ambulation, and decreased LEP/leptin sensitivity. Importantly, although genetic deletion of either Atg12 or Atg5 renders POMC neurons autophagy-deficient, mice lacking Atg5 in POMC neurons do not exhibit these phenotypes. Hence, we propose nonautophagic functions for ATG12 in POMC neurons that counteract excessive weight gain in response to HFD consumption.
Assuntos
Dieta Hiperlipídica , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Pró-Opiomelanocortina/metabolismo , Proteínas/metabolismo , Adiposidade , Animais , Animais Recém-Nascidos , Proteína 12 Relacionada à Autofagia , Proteína 5 Relacionada à Autofagia , Peso Corporal , Metabolismo Energético , Comportamento Alimentar , Deleção de Genes , Marcação de Genes , Integrases/metabolismo , Leptina/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Estrogen-receptor alpha (ERα) neurons in the ventrolateral region of the ventromedial hypothalamus (VMHVL) control an array of sex-specific responses to maximize reproductive success. In females, these VMHVL neurons are believed to coordinate metabolism and reproduction. However, it remains unknown whether specific neuronal populations control distinct components of this physiological repertoire. Here, we identify a subset of ERα VMHVL neurons that promotes hormone-dependent female locomotion. Activating Nkx2-1-expressing VMHVL neurons via pharmacogenetics elicits a female-specific burst of spontaneous movement, which requires ERα and Tac1 signaling. Disrupting the development of Nkx2-1(+) VMHVL neurons results in female-specific obesity, inactivity, and loss of VMHVL neurons coexpressing ERα and Tac1. Unexpectedly, two responses controlled by ERα(+) neurons, fertility and brown adipose tissue thermogenesis, are unaffected. We conclude that a dedicated subset of VMHVL neurons marked by ERα, NKX2-1, and Tac1 regulates estrogen-dependent fluctuations in physical activity and constitutes one of several neuroendocrine modules that drive sex-specific responses.
Assuntos
Receptor alfa de Estrogênio/metabolismo , Locomoção/genética , Proteínas Nucleares/biossíntese , Obesidade/metabolismo , Taquicininas/genética , Fatores de Transcrição/biossíntese , Animais , Receptor alfa de Estrogênio/genética , Estrogênios/metabolismo , Feminino , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Proteínas Nucleares/genética , Obesidade/genética , Obesidade/fisiopatologia , Caracteres Sexuais , Taquicininas/metabolismo , Fator Nuclear 1 de Tireoide , Fatores de Transcrição/genética , Núcleo Hipotalâmico Ventromedial/metabolismo , Núcleo Hipotalâmico Ventromedial/patologiaRESUMO
Like obesity, prolonged food deprivation induces severe hepatic steatosis; however, the functional significance of this phenomenon is not well understood. In this study, we show that the fall in plasma leptin concentration during fasting is required for the development of hepatic steatosis in mice. Removal of leptin receptors from AGRP neurons diminishes fasting-induced hepatic steatosis. Furthermore, the suppressive effects of leptin on fasting-induced hepatic steatosis are absent in mice lacking the gene encoding agouti-related protein (Agrp), suggesting that this function of leptin is mediated by AGRP. Prolonged fasting leads to suppression of hepatic sympathetic activity, increased expression of acyl CoA:diacylglycerol acyltransferase-2 in the liver, and elevation of hepatic triglyceride content and all of these effects are blunted in the absence of AGRP. AGRP deficiency, despite having no effects on feeding or body adiposity in the free-fed state, impairs triglyceride and ketone body release from the liver during prolonged fasting. Furthermore, reducing CNS Agrp expression in wild-type mice by RNAi protected against the development of hepatic steatosis not only during starvation, but also in response to consumption of a high-fat diet. These findings identify the leptin-AGRP circuit as a critical modulator of hepatic triglyceride stores in starvation and suggest a vital role for this circuit in sustaining the supply of energy from the liver to extrahepatic tissues during periods of prolonged food deprivation.
Assuntos
Proteína Relacionada com Agouti/genética , Metabolismo Energético/fisiologia , Hipotálamo/metabolismo , Leptina/metabolismo , Fígado/metabolismo , Receptores para Leptina/genética , Acil Coenzima A/genética , Acil Coenzima A/metabolismo , Proteína Relacionada com Agouti/metabolismo , Animais , Composição Corporal/efeitos dos fármacos , Composição Corporal/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Metabolismo Energético/efeitos dos fármacos , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Privação de Alimentos/fisiologia , Hipotálamo/efeitos dos fármacos , Leptina/farmacologia , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Norepinefrina/metabolismo , Obesidade/genética , Obesidade/metabolismo , Receptores para Leptina/metabolismoRESUMO
The central melanocortin system plays an essential role in the regulation of energy metabolism. Key to this regulation are the responses of neurons expressing proopiomelanocortin (POMC) and agouti-related protein (AgRP) to blood-borne metabolic signals. Recent evidence has demonstrated that POMC and AgRP neurons are not simply mirror opposites of each other in function and responsiveness to metabolic signals, nor are they exclusively first-order neurons. These neurons act as central transceivers, integrating both hormonal and neural signals, and then transmitting this information to peripheral tissues via the autonomic nervous system to coordinate whole-body energy metabolism. This review focuses on most recent developments obtained from rodent studies on the function, metabolic regulation, and circuitry of the central melanocortin system.
Assuntos
Melanocortinas/metabolismo , Proteína Relacionada com Agouti/metabolismo , Animais , Metabolismo Energético/fisiologia , Humanos , Leptina/metabolismo , Modelos Biológicos , Obesidade/metabolismo , Receptores de Melanocortina/metabolismoRESUMO
Hepatic steatosis is generally thought to develop via peripheral mechanisms associated with obesity. We show that chronic central infusion of leptin suppresses hepatic lipogenic gene expression and reduces triglyceride content via stimulation of hepatic sympathetic activity. This leptin function is independent of feeding and body weight but requires phosphatidylinositol 3-kinase (PI3K) signaling. Attenuation of leptin-induced PI3K signaling, brought about by transgenic expression of phosphatase and tensin homolog (PTEN) in leptin receptor neurons, leads to decreased hepatic sympathetic tone and increased triglyceride levels without affecting adiposity or hepatic insulin signaling. Central leptin's effects on hepatic norepinephrine levels and triglyceride content are blunted in these mutant mice. Simultaneous downregulation of PI3K and signal transducer and activator of transcription-3 (Stat3) in leptin receptor neurons does not exacerbate obesity but causes more severe hepatic steatosis. Together, our results indicate that central cellular leptin resistance in PI3K signaling manifests as hepatic steatosis without causing obesity.
RESUMO
The hypothalamic-pituitary-adrenal (HPA) axis self-regulates through a glucocorticoid negative feedback mechanism that is stereotypically slow and long lasting. Rapid (seconds to minutes) glucocorticoid feedback, however, inhibits stress-induced adrenocorticotropic hormone (ACTH) secretion too quickly to result from classic transcriptional effects of the occupied glucocorticoid receptor. Cannabinoids may act as rapid intermediary messengers between glucocorticoids and HPA activation via retroactive inhibition of afferent glutamate stimulation of the corticotropin-releasing factor neurons in the paraventricular nucleus. We demonstrated fast feedback effects of GR stimulation and blockade and observed the effect of cannabinoid receptor (CB1) antagonist AM251 on HPA axis reactivity in vivo. Rats were injected intraperitoneally with varying doses of the specific GR agonist RU28362, the GR antagonist RU486, or AM251 2 min before restraint. Blood was collected at predetermined times and corticosterone and ACTH concentrations were measured. RU28362 blunted stress-induced ACTH secretion while RU486 and AM251 significantly increased stress-induced ACTH release 15 min after restraint onset. Next, we injected AM251 58 min before RU28362, 2 min before restraint, to determine if inhibition of ACTH by RU28362 was contingent on CB1 activation. Unexpectedly, CB1 blockade failed to prevent glucocorticoid negative feedback and instead enhanced it. These studies not only establish an in vivo fast feedback model but show that rapid glucococorticoid negative feedback is similarly altered by GR and CB1 blockade. Although the hormonal consequences of acute AM251 treatment were strikingly similar to those of RU486 treatment, we are unable to draw conclusions about the serial nature of the interaction between GR activation and CB release from these results.
Assuntos
Canabinoides/metabolismo , Glucocorticoides/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipófise-Suprarrenal/fisiologia , Estresse Fisiológico/fisiologia , Hormônio Adrenocorticotrópico/metabolismo , Androstanóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Retroalimentação Fisiológica/efeitos dos fármacos , Retroalimentação Fisiológica/fisiologia , Antagonistas de Hormônios/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Mifepristona/farmacologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Piperidinas/farmacologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor CB2 de Canabinoide/metabolismo , Receptores de Glutamato/metabolismo , Restrição Física , Estresse Fisiológico/efeitos dos fármacosRESUMO
Corticosterone and insulin play complex roles in the amount and composition of calories ingested, and the utilization and deposition of this energy. Understanding the interplay of these two hormones is complicated because increasing concentrations of corticosterone dose-dependently increase circulating insulin levels. We addressed individual contributions of each hormone by controlling, at steady-state levels, corticosterone (by adrenalectomy and exogenous replacement) and insulin (by streptozotocin-induced destruction of pancreatic beta-cells and exogenous replacement) across a spectrum of concentrations in rats, creating 8 hormonal combinations. For 5 days after surgery, all rats received chow. At day 5, they were subdivided into those that continued to receive chow and those that had a choice between chow, lard, and 32% sucrose for a further 5 days. During the choice/chow period, total calories ingested were stimulated by corticosterone and choice diet, and subject to a corticosterone-insulin interaction. Sucrose, but not lard, intake was stimulated by insulin. Body weight was increased by insulin, decreased by high corticosterone, and unaffected by diet. White adipose tissue depot weights were stimulated by insulin, corticosterone, and diet. Plasma triglycerides, free fatty acids, total ketone bodies, glucose, and glycerol were all significantly increased by corticosterone and the choice diet but inhibited by insulin. In contrast, plasma leptin was only increased by insulin and diet, plasma glucagon and liver glycogen was only affected by insulin and liver triglycerides, and arcuate nucleus proopiomelanocortin mRNA was only influenced by diet. Collectively, these data show that corticosterone and insulin determine the intake, form, and compartmentalization of energy both independently and interactively.
Assuntos
Corticosterona/fisiologia , Ingestão de Energia/fisiologia , Metabolismo Energético/fisiologia , Insulina/fisiologia , Adrenalectomia , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Peso Corporal/fisiologia , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Glicogênio/metabolismo , Leptina/metabolismo , Fígado/metabolismo , Masculino , Neuropeptídeo Y/metabolismo , Pró-Opiomelanocortina/metabolismo , Ratos , Ratos Sprague-Dawley , Estreptozocina , Triglicerídeos/metabolismoRESUMO
OBJECTIVE: We sought to examine insulin-sensitive food intake behavior and neuroendocrine and metabolic variables of rats that had undergone a duodenal-jejunal bypass (DJB). SUMMARY OF BACKGROUND DATA: A DJB that circumvents the duodenum and proximal jejunum while leaving the stomach unperturbed rapidly improves insulin sensitivity in type 2 diabetic rats. This segment of proximal small intestine is innervated by the gastroduodenal branch of the vagus nerve, the transection of which influences food intake choices in streptozotocin-diabetic rats. METHODS: Rats were first placed on a choice of chow and lard for 7 days and additionally provided with an enriched liquid diet for another 7 days before surgery and were allowed only the liquid diet for 7 days after either a sham or DJB operation. RESULTS: After surgery, DJB-operated rats initially consumed less than the sham-operated counterparts. When the rats were subsequently provided with the choice of chow and lard for 7 days, there were no differences in intake between the DJB and sham-operated groups. Similarly, the majority of metabolic and neuroendocrine variables measured were unchanged. However, DJB-operated rats exhibited greater mesenteric white adipose tissue weight, fecal output, arcuate nucleus neuropeptide Y mRNA expression, plasma corticosterone, and glucagon levels together with reduced plasma leptin concentrations. CONCLUSIONS: DJB surgery does not produce significant differences in food intake choices after a period of recovery; however, there are enduring metabolic and neuroendocrine changes, which are collectively important to understanding the beneficial outcomes of the operation.
Assuntos
Derivação Jejunoileal , Obesidade Mórbida/metabolismo , Obesidade Mórbida/cirurgia , Animais , Modelos Animais de Doenças , Ingestão de Alimentos , Resistência à Insulina/fisiologia , Intestino Delgado/metabolismo , Intestino Delgado/fisiopatologia , Masculino , Sistemas Neurossecretores/fisiopatologia , Período Pós-Operatório , Ratos , Ratos Sprague-DawleyRESUMO
Activity of the hypothalamo-pituitary-adrenal (HPA) axis is regulated by a negative feedback loop that dampens central drive of the axis via the actions of the secreted glucocorticoids. Conversely, under conditions of chronic stress, glucocorticoids delivered centrally increase hypothalamic paraventricular nucleus (PVN) corticotrophin-releasing factor (CRF) expression and the response to restraint. However, HPA axis activity and PVN CRF mRNA expression under chronic stress conditions are often reduced, implying other indirect peripheral or extra-hypothalamic glucocorticoid actions. Glucocorticoids chronically increase palatable food intake, which increases abdominal fat depots and circulating insulin levels, both of which negatively correlate with PVN CRF mRNA expression and may in turn dampen the response to stress. Such an effect is dependent on food choices, rather than total calories ingested. Considering stress is omnipresent in the workplace, palatable food ingestion may represent a means to combat the feeling of stress which is ultimately maladaptive when unresolved.
Assuntos
Preferências Alimentares , Glucocorticoides/metabolismo , Insulina/metabolismo , Obesidade/metabolismo , Estresse Fisiológico , Animais , Hormônio Liberador da Corticotropina/metabolismo , Ingestão de Alimentos , Retroalimentação Fisiológica , Humanos , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipófise-Suprarrenal/fisiologiaRESUMO
Previous studies have shown reduced hypothalamo-pituitary-adrenal responses to both acute and chronic restraint stressors in rats allowed to ingest highly palatable foods (32% sucrose +/- lard) prior to restraint. In this study we tested the effects of prior access (7 d) to chow-only, sucrose/chow, lard/chow, or sucrose/lard/chow diets on central corticotropin-releasing factor (CRF) expression in rats studied in two experiments, 15 and 240 min after onset of restraint. Fat depot, particularly intraabdominal fat, weights were increased by prior access to palatable food, and circulating leptin concentrations were elevated in all groups. Metabolite concentrations were appropriate for values obtained after stressors. For unknown reasons, the 15-min experiment did not replicate previous results. In the 240-min experiment, ACTH and corticosterone responses were inhibited, as previously, and CRF mRNA in the hypothalamus and oval nucleus of the bed nuclei of the stria terminalis were reduced by palatable foods, suggesting strongly that both neuroendocrine and autonomic outflows are decreased by increased caloric deposition and palatable food. In the central nucleus of the amygdala, CRF was increased in the sucrose-drinking group and decreased in the sucrose/lard group, suggesting that the consequence of ingestion of sucrose uses different neural networks from the ingestion of lard. The results suggest strongly that ingestion of highly palatable foods reduces activity in the central stress response network, perhaps reducing the feeling of stressors.
Assuntos
Hormônio Adrenocorticotrópico/sangue , Corticosterona/sangue , Hormônio Liberador da Corticotropina/sangue , Metabolismo Energético/fisiologia , Alimentos , Estresse Fisiológico/fisiologia , Paladar/fisiologia , Tecido Adiposo/crescimento & desenvolvimento , Animais , Peso Corporal/fisiologia , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo , Ingestão de Energia/fisiologia , Hipotálamo/metabolismo , Insulina/sangue , Leptina/sangue , Masculino , Palato/fisiologia , Ratos , Ratos Sprague-Dawley , Restrição Física/fisiologia , Restrição Física/psicologiaRESUMO
The common hepatic branch of the vagus nerve negatively regulates lard intake in rats with streptozotocin (STZ)-induced, insulin-dependent diabetes. However, this branch consists of two subbranches: the hepatic branch proper, which serves the liver, and the gastroduodenal branch, which serves the distal stomach, pancreas, and duodenum. The aim of this study was to determine whether the gastroduodenal branch specifically regulates voluntary lard intake. We performed a gastroduodenal branch vagotomy (GV) on nondiabetic, STZ-diabetic, and STZ-diabetic insulin-treated groups of rats and compared them with sham-operated counterparts. All rats had high steady-state corticosterone levels to maximize lard intake. Five days after surgery, all rats were provided with the choice of chow or lard to eat for another 5 days. STZ-diabetes resulted in a reduction in lard intake that was partially rescued by either GV or insulin treatment. Patterns of white adipose tissue (WAT) deposition differed after GV- and insulin-induced lard intake, with subcutaneous WAT increasing exclusively after the former and mesenteric WAT increasing exclusively in the latter. GV also prevented the insulin-induced reduction in the STZ-elevated plasma glucagon, triglycerides, free fatty acids, and total ketone bodies but did not alter the effect of insulin-induced reduction of plasma glucose levels. These data suggest that the gastroduodenal branch of the vagus inhibits lard intake and regulates WAT deposition and plasma metabolite levels in STZ-diabetic rats.
Assuntos
Distribuição da Gordura Corporal , Diabetes Mellitus Experimental/metabolismo , Fígado/inervação , Fígado/metabolismo , Nervo Vago/fisiologia , Animais , Glicemia/metabolismo , Corticosterona/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Gorduras na Dieta/farmacologia , Ingestão de Alimentos/fisiologia , Ácidos Graxos/sangue , Polipeptídeo Inibidor Gástrico/sangue , Glucagon/sangue , Glicogênio/metabolismo , Hipoglicemiantes/sangue , Hipoglicemiantes/farmacologia , Insulina/sangue , Insulina/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Vagotomia , Nervo Vago/anatomia & histologia , Redução de Peso/fisiologiaRESUMO
The common hepatic branch of the vagus nerve is a two-way highway of communication between the brain and the liver, duodenum, stomach and pancreas that regulates many aspects of food intake and metabolism. In this study, we utilized the afferent-specific neurotoxin capsaicin to examine if common hepatic vagal sensory afferents regulate lard intake. Rats implanted with a corticosterone pellet were made diabetic using streptozotocin (STZ) and a subset received steady-state exogenous insulin replacement into the superior mesenteric vein. These were compared with non-diabetic counterparts. Each group was then subdivided into those whose common hepatic branch of the vagus was treated with vehicle or capsaicin. Five days after surgery, the rats were offered the choice of chow and lard to consume for a further 5 days. The STZ-diabetic rats ate significantly less lard than the non-diabetic rats. Capsaicin treatment restored lard intake to that of the insulin-replaced, STZ-diabetic rats, but modified neither chow nor total caloric intake. This increased lard intake led to selective fat deposition into the mesenteric white adipose tissue depot, as opposed to an increase in all visceral fat pad depots evident after insulin replacement-induced lard intake. Capsaicin treatment also increased the levels of circulating glucose and triglycerides and negated the actions of insulin on these and free fatty acids and ketone bodies. Collectively, these data suggest that afferent signalling through the common hepatic branch of the vagus inhibits lard, but not chow, intake, directs fat deposition and regulates plasma metabolite levels.
Assuntos
Biomarcadores/sangue , Diabetes Mellitus Experimental/fisiopatologia , Gorduras na Dieta/metabolismo , Comportamento Alimentar , Fígado/inervação , Nervo Vago/fisiopatologia , Tecido Adiposo Branco/patologia , Glândulas Suprarrenais/patologia , Vias Aferentes/fisiopatologia , Animais , Glicemia/metabolismo , Peso Corporal , Capsaicina/farmacologia , Corticosterona/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Gorduras na Dieta/administração & dosagem , Comportamento Alimentar/efeitos dos fármacos , Preferências Alimentares , Glucagon/sangue , Glicogênio/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Insulina/farmacologia , Insulina/uso terapêutico , Leptina/sangue , Lipídeos/sangue , Fígado/metabolismo , Masculino , Tamanho do Órgão , Ratos , Ratos Sprague-Dawley , Baço/patologia , Timo/patologia , Fatores de Tempo , Nervo Vago/efeitos dos fármacosRESUMO
Glucocorticoids act primarily in a feed-forward fashion on brain to activate CNS pathways that implement wanting appropriate to physiological needs. Thus, depending on the available conditions, elevated glucocorticoids may augment the behavioural want to run, fight or feed. Although glucocorticoids stimulate intake of chow, fat and sucrose, insulin appears to sculpt calorie-associated desires toward foods high in fat, acting through hepatic branch afferents of the vagus nerve. Both conditions of reduced food allowance and chronic stress excite glucocorticoid-augmented central neural networks that may lead toward ultimate abdominal obesity.
Assuntos
Encéfalo/metabolismo , Ingestão de Energia , Comportamento Alimentar , Glucocorticoides/metabolismo , Insulina/metabolismo , Obesidade/metabolismo , Adrenalectomia , Animais , Encéfalo/fisiopatologia , Gorduras na Dieta/metabolismo , Sacarose Alimentar/metabolismo , Retroalimentação Fisiológica , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Fígado/inervação , Fígado/metabolismo , Obesidade/fisiopatologia , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Nervo Vago/fisiopatologiaRESUMO
Although high insulin concentrations reduce food intake, low insulin concentrations promote lard intake over chow, possibly via an insulin-derived, liver-mediated signal. To investigate the role of the hepatic vagus in voluntary lard intake, streptozotocin-diabetic rats with insulin or vehicle replaced into either the superior mesenteric or jugular veins received a hepatic branch vagotomy (HV) or a sham operation. All rats received a pellet of corticosterone that clamped the circulating steroid at moderately high concentrations to enhance lard intake. After 5 d of recovery, rats were offered the choice of lard and chow for 5 d. In streptozotocin-diabetic rats, HV, like insulin replacement, restored lard intake to nondiabetic levels. Consequently, this reduced chow intake without affecting total caloric intake, and insulin site-specifically increased white adipose tissue weight. HV also ablated the effects of insulin on reducing circulating glucose levels and attenuated the streptozotocin-induced weight loss in most groups. Collectively, these data suggest that the hepatic vagus normally inhibits lard intake and can influence glucose homeostasis and the pattern of white adipose tissue deposition. These actions may be modulated by insulin acting both centrally and peripherally.
Assuntos
Tecido Adiposo Branco/metabolismo , Diabetes Mellitus Experimental/terapia , Gorduras na Dieta/metabolismo , Insulina/farmacologia , Vagotomia/métodos , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Corticosterona/administração & dosagem , Corticosterona/farmacologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/fisiopatologia , Gorduras na Dieta/administração & dosagem , Ingestão de Energia/efeitos dos fármacos , Ácidos Graxos não Esterificados/sangue , Glicogênio/metabolismo , Hipoglicemiantes/farmacologia , Insulina/sangue , Corpos Cetônicos/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Estreptozocina , Fatores de Tempo , Triglicerídeos/sangue , Nervo Vago/fisiopatologiaRESUMO
In mammals, glucocorticoid actions appear to have evolved to maintain and enhance energy stores to be used for life-saving gluconeogenesis. They act on the brain to stimulate search behaviors, palatable feeding and emotionally relevant memories, and they act on the body to mobilize stored peripheral energy and direct it to central depots that serve the substrate needs of the liver. Our work in rats shows that searching and intake of palatable foods (sucrose, saccharin and lard) are stimulated by corticosterone in a dose-related fashion. Adrenalectomized rats gain weight poorly, have low fat content, increased sympathetic neural and hypothalamo-pituitary-adrenal outflow, and altered behaviors. Replacement with corticosterone reverses these effects. Surprisingly, when such rats are provided with 30% sucrose to drink, in addition to saline, all of the usual effects of adrenalectomy are corrected without corticosterone. We hypothesize that there is a metabolic feedback system that decreases stress-responsiveness. Although we have not yet identified the signal associated with sucrose drinking, the weight of mesenteric fat correlates inversely with hypothalamic corticotropin-releasing factor (CRF). When rats eat lard and sucrose ad libitum, fat stores increase and CRF, ACTH and corticosterone responses are reduced. During stress, chow intake decreases but intake of lard and sucrose does not. Our current working model suggests that palatability signals and neural signals from fat stores act on brain to reduce activity in the central stress response system. Correlative results from a clinical study support the powerful role of small changes in glucocorticoids in type 2 diabetes.
Assuntos
Glucocorticoides/metabolismo , Doenças Metabólicas/etiologia , Obesidade/etiologia , Animais , Humanos , Insulina/metabolismo , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Modelos Biológicos , Obesidade/metabolismo , Obesidade/patologia , Fatores de RiscoRESUMO
The hypothalamo-pituitary-adrenal (HPA) axis is the critical mediator of the vertebrate stress response system, responding to environmental stressors by maintaining internal homeostasis and coupling the needs of the body to the wants of the mind. The HPA axis has numerous complex drivers and highly flexible operating characterisitics. Major drivers include two circadian drivers, two extra-hypothalamic networks controlling top-down (psychogenic) and bottom-up (systemic) threats, and two intra-hypothalamic networks coordinating behavioral, autonomic, and neuroendocrine outflows. These various networks jointly and flexibly control HPA axis output of periodic (oscillatory) functions and a range of adventitious systemic or psychological threats, including predictable daily cycles of energy flow, actual metabolic deficits over many time scales, predicted metabolic deficits, and the state-dependent management of post-prandial responses to feeding. Evidence is provided that reparation of metabolic derangement by either food or glucocorticoids results in a metabolic signal that inhibits HPA activity. In short, the HPA axis is intimately involved in managing and remodeling peripheral energy fluxes, which appear to provide an unidentified metabolic inhibitory feedback signal to the HPA axis via glucocorticoids. In a complementary and perhaps a less appreciated role, adrenocortical hormones also act on brain to provide not only feedback, but feedforward control over the HPA axis itself and its various drivers, as well as coordinating behavioral and autonomic outflows, and mounting central incentive and memorial networks that are adaptive in both appetitive and aversive motivational modes. By centrally remodeling the phenotype, the HPA axis provides ballistic and predictive control over motor outflows relevant to the type of stressor. Evidence is examined concerning the global hypothesis that the HPA axis comprehensively induces integrative phenotypic plasticity, thus remodeling the body and its governor, the brain, to yoke the needs of the body to the wants of the mind. Adverse side effects of this yoking under conditions of glucocorticoid excess are discussed.
Assuntos
Sistema Hipotálamo-Hipofisário/fisiologia , Motivação , Fenótipo , Sistema Hipófise-Suprarrenal/fisiologia , Animais , Glucocorticoides/fisiologia , Humanos , Sistema Hipotálamo-Hipofisário/anatomia & histologia , Modelos Biológicos , Rede Nervosa/fisiologia , Vias Neurais/fisiologia , Sistema Hipófise-Suprarrenal/anatomia & histologia , Estresse FisiológicoRESUMO
Based on observed phenotypic differences in growth and ACTH responses to stress in Sprague Dawley rats obtained from different vendors, we ran head-to-head comparisons on rats obtained from three different vendors, Harlan, Charles River, and Simonsen, with respect to baseline phenotypic differences and a metabolic feedback hypothesis of hypothalamo-pituitary-adrenal (HPA) regulation. Charles River and Harlan rats gained weight faster than Simonsen rats, but chow intake standardized for body weight was not increased, consistent with their greater caloric efficiency. Weight gain was inversely related with mean daily temperatures, without differences in activity levels. Half of the animals given lard and 32% sucrose solutions in addition to chow increased caloric intake and core temperature, decreased caloric efficiency, and increased fat depots, leptin, and in Simonsen rats, insulin. A 5-day regimen of once-daily 2-h restraint decreased feeding and caloric efficiency. Rats from two vendors with the availability of sucrose and lard, Charles River and Simonsen, showed blunted HPA responses to restraint compared to chow controls, whereas the Harlans exhibited no adrenocorticotropin (ACTH) response and an amplified adrenocortical response on the high-energy diet compared to chow controls. Substantial phenotypic differences exist between Sprague Dawley rats from different vendors with respect to metabolism and HPA function. The metabolic feedback hypothesis was supported in two of the three vendors' rats.
Assuntos
Metabolismo Basal/fisiologia , Composição Corporal/fisiologia , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipófise-Suprarrenal/fisiologia , Ratos Sprague-Dawley/fisiologia , Estresse Psicológico/metabolismo , Hormônio Adrenocorticotrópico/sangue , Animais , Temperatura Corporal/fisiologia , Peso Corporal/fisiologia , Corticosterona/sangue , Ingestão de Energia/fisiologia , Comportamento Alimentar/fisiologia , Insulina/sangue , Leptina/sangue , Masculino , Fenótipo , Ratos , Especificidade da EspécieRESUMO
Glucocorticoids either inhibit or sensitize stress-induced activity in the hypothalamo-pituitary-adrenal (HPA) axis, depending on time after their administration, the concentration of the steroids, and whether there is a concurrent stressor input. When there are high glucocorticoids together with a chronic stressor, the steroids act in brain in a feed-forward fashion to recruit a stress-response network that biases ongoing autonomic, neuroendocrine, and behavioral outflow as well as responses to novel stressors. We review evidence for the role of glucocorticoids in activating the central stress-response network, and for mediation of this network by corticotropin-releasing factor (CRF). We briefly review the effects of CRF and its receptor antagonists on motor outflows in rodents, and examine the effects of glucocorticoids and CRF on monoaminergic neurons in brain. Corticosteroids stimulate behaviors that are mediated by dopaminergic mesolimbic "reward" pathways, and increase palatable feeding in rats. Moreover, in the absence of corticosteroids, the typical deficits in adrenalectomized rats are normalized by providing sucrose solutions to drink, suggesting that there is, in addition to the feed-forward action of glucocorticoids on brain, also a feedback action that is based on metabolic well being. Finally, we briefly discuss the problems with this network that normally serves to aid in responses to chronic stress, in our current overindulged, and underexercised society.
Assuntos
Glucocorticoides/metabolismo , Obesidade/metabolismo , Estresse Fisiológico/metabolismo , Animais , Doença Crônica , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismoRESUMO
In this study, epididymal adipose tissue from male annexin 1 (ANXA1)-null and wild-type control mice were used to explore the potential role of ANXA1 in adipocyte biology. ANXA1 was detected by Western blot analysis in wild-type tissue and localized predominantly to the stromal-vascular compartment. Epididymal fat pad mass was reduced by ANXA1 gene deletion, but adipocyte size was unchanged, suggesting that ANXA1 is required for the maintenance of adipocyte and/or preadipocyte cell number. Epididymal tissue from wild-type mice responded in vitro to noradrenaline and isoprenaline with increased glycerol release, reduced IL-6 release, and increased cAMP accumulation. Qualitatively similar but significantly attenuated responses to the catecholamines were observed in tissue from ANXA1-null mice, an effect that was not associated with changes in beta-adrenoceptor mRNA expression. Lipopolysaccharide (LPS) also stimulated lipolysis in vitro, but its effects were muted by ANXA1 gene deletion. By contrast, LPS failed to influence IL-6 release from wild-type tissue but stimulated the release of the cytokine from tissue from ANXA1-null mice. ANXA1 gene deletion did not affect glucocorticoid receptor expression or the ability of dexamethasone to suppress catecholamine-induced lipolysis. It did, however, augment IL-6 expression and modify the inhibitory effects of glucocorticoids on IL-6 release. Collectively, these studies suggest that ANXA1 supports aspects of adipose tissue mass and alters the sensitivity of epididymal adipose tissue to catecholamines, glucocorticoids, and LPS, thereby modulating lipolysis and IL-6 release.