RESUMO
Hypothalamic AMPK plays a major role in the regulation of whole body metabolism and energy balance. Present evidence has demonstrated that this canonical mechanism is evolutionarily conserved. Thus, recent data demonstrated that inhibition of AMPKα2 in fish hypothalamus led to decreased food intake and liver capacity to use and synthesize glucose, lipids, and amino acids. We hypothesize that a signal of abundance of nutrients from the hypothalamus controls hepatic metabolism. The vagus nerve is the most important link between the brain and the liver. We therefore examined in the present study whether surgical transection of the vagus nerve in rainbow trout is sufficient to alter the effect in liver of central inhibition of AMPKα2. Thus, we vagotomized (VGX) or not (Sham) rainbow trout and then intracerebroventricularly administered adenoviral vectors tagged with green fluorescent protein alone or linked to a dominant negative isoform of AMPKα2. The inhibition of AMPKα2 led to reduced food intake in parallel with changes in the mRNA abundance of hypothalamic neuropeptides [neuropeptide Y (npy), agouti-related protein 1 (agrp1), and cocaine- and amphetamine-related transcript (cartpt)] involved in food intake regulation. Central inhibition of AMPKα2 resulted in the liver having decreased capacity to use and synthesize glucose, lipids, and amino acids. Notably, these effects mostly disappeared in VGX fish. These results support the idea that autonomic nervous system actions mediate the actions of hypothalamic AMPKα2 on liver metabolism. Importantly, this evidence indicates that the well-established role of hypothalamic AMPK in energy balance is a canonical evolutionarily preserved mechanism that is also present in the fish lineage.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Metabolismo Energético/fisiologia , Hipotálamo/enzimologia , Fígado/metabolismo , Oncorhynchus mykiss/fisiologia , Nervo Vago/fisiologia , Proteínas Quinases Ativadas por AMP/genética , Adenoviridae , Animais , Comportamento Alimentar/fisiologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Fígado/inervação , VagotomiaRESUMO
Silibinin, a flavonolignan derived from milk thistle (Silybum marianum), has been revealed to have a beneficial effect on improving diabetes-impaired glycemic control. However, the underlying mechanism is still unclear. In the present study, to evaluate whether the gut-brain-liver axis, an important neural pathway for the control of hepatic glucose production, is involved in silibinin-regulated glucose homeostasis, the expression of glucagon-like peptide-1 receptor (GLP1R) in the duodenum, activation of neurons in the nucleus of the solitary tract (NTS), as well as glycogen accumulation and expression of gluconeogenic enzymes in the livers of diabetic SHRSP·Z-Leprfa/IzmDmcr (SP·ZF) rats with 4-week oral administration of silibinin (100 and 300 mg kg-1 day-1) were evaluated. Common hepatic branch vagotomy was further conducted in high-fat diet/streptozotocin (HFD/STZ)-induced diabetic SD rats to confirm the role of the gut-brain-liver axis in silibinin-improved glycemic control. The results revealed a significant inhibition of fasting blood glucose after SP·ZF rats were administrated with silibinin for 4 weeks. The expression of GLP1R in the duodenum and the activation of neurons in the NTS increased, while hepatic glucose production decreased on silibinin administration. However, the hypoglycemic effect of silibinin was reversed by common hepatic branch vagotomy in diabetic SD rats. Our study suggested that silibinin may be useful as a potential functional food ingredient against diabetes by triggering the gut-brain-liver axis.
Assuntos
Encéfalo/fisiopatologia , Diabetes Mellitus Tipo 2/terapia , Suplementos Nutricionais , Trato Gastrointestinal/fisiopatologia , Hipoglicemiantes/uso terapêutico , Fígado/fisiopatologia , Silibina/uso terapêutico , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Duodeno/inervação , Duodeno/metabolismo , Duodeno/patologia , Duodeno/fisiopatologia , Trato Gastrointestinal/inervação , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/patologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Gluconeogênese , Hiperglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Fígado/inervação , Fígado/metabolismo , Fígado/patologia , Glicogênio Hepático/antagonistas & inibidores , Glicogênio Hepático/metabolismo , Masculino , Neurônios/metabolismo , Neurônios/patologia , Obesidade/complicações , Obesidade/etiologia , Ratos Sprague-Dawley , Ratos Zucker , Silibina/administração & dosagem , Núcleo Solitário/metabolismo , Núcleo Solitário/patologia , Núcleo Solitário/fisiopatologia , Organismos Livres de Patógenos Específicos , VagotomiaRESUMO
The tissue-specific response to rumen-protected conjugated linoleic acid supply (rpCLA) of liver, two muscles, and three adipose tissues of heavy lambs was studied. Twenty-four lambs, 8 months old, divided into 4 groups of 6, were fed at libitum on a ration supplemented without or with a mixture of rpCLA. Silica and hydrogenated soybean oil was the rpCLA coating matrix. The lambs were slaughtered at 11 months of age. Tissues were collected and analyzed for their FA profiles. The dietary rpCLA supplement had no influence on carcass fatness nor on the fat content of the liver and tissues and had little influence on the FA profiles of these tissues. In the adipose tissues, rpCLA increased the proportions of saturated FAs, 18:0 and 18:2t10c12, and decreased the proportions of monounsaturated FAs in the adipose tissues. In muscles, the effects were the opposite. The results suggest that Δ9 desaturase activity is inhibited by the rpCLA mixture in adipose tissues to a greater extent than in the other tissues.
Assuntos
Tecido Adiposo/metabolismo , Suplementos Nutricionais/análise , Ácidos Graxos/química , Ácidos Linoleicos Conjugados/metabolismo , Fígado/inervação , Carne/análise , Tecido Adiposo/química , Ração Animal/análise , Animais , Ácidos Graxos/metabolismo , Fígado/química , Músculo Esquelético/química , Músculo Esquelético/metabolismo , OvinosRESUMO
OBJECTIVES: Acute peripheral infection is associated with central and peripheral inflammation, increased oxidative stress, and adaptive sickness behaviors. Sulforaphane (SFN) activates the transcription factor nuclear factor E2-related factor 2 (Nrf2), which upregulates antioxidant genes and lowers inflammation. The objectives of this study were to examine the effects of SFN on proinflammatory markers and Nrf2 target genes in hippocampus and liver of mice challenged with lipopolysaccharide (LPS), and to evaluate sickness response following the LPS immune challenge. METHODS: Adult Balb/c mice received SFN (50â mg/kg, i.p.) for 3 days before being injected i.p. with LPS (1â µg) to mimic an acute peripheral infection. Sickness behaviors were measured at baseline and 6 hours after LPS. Expression of proinflammatory mediators and antioxidant genes were analyzed in hippocampus and liver 6 hours after LPS. RESULTS: SFN elevated Nrf2 target genes and reduced expression of proinflammatory mediators in hippocampus and liver, but did not improve LPS-induced sickness response. DISCUSSION: The nutritional bioactive SFN displays potent anti-inflammatory properties against LPS-induced inflammation in vitro, but has not been previously assessed in vivo during peripheral infection as a potential treatment for sickness behavior. These data indicate that SFN has anti-inflammatory effects in both brain and periphery, but that longer exposure to SFN may be necessary to reduce sickness behavior.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Mediadores da Inflamação/antagonistas & inibidores , Isotiocianatos/uso terapêutico , Inflamação Neurogênica/prevenção & controle , Neurônios/efeitos dos fármacos , Animais , Anticarcinógenos/uso terapêutico , Elementos de Resposta Antioxidante/efeitos dos fármacos , Antioxidantes/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Endotoxinas/toxicidade , Ingestão de Energia/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/imunologia , Hipocampo/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/imunologia , Hipotálamo/metabolismo , Mediadores da Inflamação/metabolismo , Injeções Intraperitoneais , Isotiocianatos/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/inervação , Fígado/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Inflamação Neurogênica/imunologia , Neurônios/imunologia , Neurônios/metabolismo , Especificidade de Órgãos , SulfóxidosRESUMO
A pandemic of diabetes and obesity has been developing worldwide in close association with excessive nutrient intake and a sedentary lifestyle. Variations in the protein content of the diet have a direct impact on glucose homeostasis because amino acids (AAs) are powerful modulators of insulin action. In this work we review our recent findings on how elevations in the concentration of the circulating AAs leucine and proline activate a metabolic mechanism located in the mediobasal hypothalamus of the brain that sends a signal to the liver via the vagus nerve, which curtails glucose output. This neurogenic signal is strictly dependent on the metabolism of leucine and proline to acetyl-coenzyme A (CoA) and the subsequent production of malonyl-CoA; the signal also requires functional neuronal ATP-sensitive potassium channels. The liver then responds by lowering the rate of gluconeogenesis and glycogenolysis, ultimately leading to a net decrease in glucose production and in concentrations of circulating glucose. Furthermore, we review here how our work with proline suggests a new role of astrocytes in the central regulation of glycemia. Last, we outline how factors such as the consumption of fat-rich diets can interfere with glucoregulatory mechanisms and, in the long term, may contribute to the development of hyperglycemia, a hallmark of type 2 diabetes.
Assuntos
Aminoácidos/sangue , Glucose/metabolismo , Hipotálamo/fisiologia , Fígado/metabolismo , Animais , Astrócitos/fisiologia , Glicemia/análise , Gorduras na Dieta/administração & dosagem , Gluconeogênese/fisiologia , Glicogenólise/fisiologia , Homeostase/fisiologia , Humanos , Leucina , Fígado/inervação , Neurônios/fisiologia , Prolina/sangue , Nervo Vago/fisiologiaRESUMO
Nesfatin-1 acts on the hypothalamus and regulates the autonomic nervous system. However, the hypothalamic mechanisms of nesfatin-1 on the autonomic nervous system are not well understood. In this study, we found that intracerebroventricular (ICV) administration of nesfatin-1 increased the extracellular signal-regulated kinase (ERK) activity in rats. Furthermore, the activity of sympathetic nerves, in the kidneys, liver, and white adipose tissue (WAT), and blood pressure was stimulated by the ICV injection of nesfatin-1, and these effects were abolished owing to pharmacological inhibition of ERK. Renal sympathoexcitatory and hypertensive effects were also observed with nesfatin-1 microinjection into the paraventricular hypothalamic nucleus (PVN). Moreover, nesfatin-1 increased the number of phospho (p)-ERK1/2-positive neurons in the PVN and coexpression of the protein in neurons expressing corticotropin-releasing hormone (CRH). Pharmacological blockade of CRH signaling inhibited renal sympathetic and hypertensive responses to nesfatin-1. Finally, sympathetic stimulation of WAT and increased p-ERK1/2 levels in response to nesfatin-1 were preserved in obese animals such as rats that were fed a high-fat diet and leptin receptor-deficient Zucker fatty rats. These findings indicate that nesfatin-1 regulates the autonomic nervous system through ERK signaling in PVN-CRH neurons to maintain cardiovascular function and that the antiobesity effect of nesfatin-1 is mediated by hypothalamic ERK-dependent sympathoexcitation in obese animals.
Assuntos
Proteínas de Ligação ao Cálcio/farmacologia , Proteínas de Ligação a DNA/farmacologia , Hipotálamo/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas do Tecido Nervoso/farmacologia , Neurônios/metabolismo , Sistema Nervoso Simpático/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/inervação , Animais , Pressão Sanguínea/efeitos dos fármacos , Dieta Hiperlipídica , Hipotálamo/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/inervação , Fígado/efeitos dos fármacos , Fígado/inervação , Masculino , Neurônios/efeitos dos fármacos , Nucleobindinas , Fosforilação , Ratos , Ratos Zucker , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
Human and animal studies increasingly point toward a neural pathogenesis of the metabolic syndrome, involving hypothalamic and autonomic nervous system dysfunction. We hypothesized that increased very-low-density lipoprotein-triglyceride (VLDL-TG) secretion by the liver in a rat model for dyslipidemia, that is, the obese Zucker (fa/fa) rat, is due to relative hyperactivity of sympathetic, and/or hypoactivity of parasympathetic hepatic innervation. To test the involvement of the autonomic nervous system, we surgically denervated the sympathetic or parasympathetic hepatic nerve in obese Zucker rats. Our results show that cutting the sympathetic hepatic nerve lowers VLDL-TG secretion in obese rats, finally resulting in lower plasma TG concentrations after 6 weeks. In contrast, a parasympathetic denervation results in increased plasma total cholesterol concentrations. The effect of a sympathetic or parasympathetic denervation of the liver was independent of changes in humoral factors or changes in body weight or food intake. In conclusion, a sympathetic denervation improves the lipid profile in obese Zucker rats, whereas a parasympathetic denervation increases total cholesterol levels. We believe this is a novel treatment target, which should be further investigated.
Assuntos
Dislipidemias/metabolismo , Hipotálamo/metabolismo , Lipoproteínas VLDL/metabolismo , Fígado/inervação , Obesidade/patologia , Sistema Nervoso Simpático/patologia , Triglicerídeos/metabolismo , Animais , Denervação , Modelos Animais de Doenças , Fígado/metabolismo , Ratos , Ratos ZuckerRESUMO
Glucose produced by the liver is a major energy source for the brain. Considering its critical dependence on glucose, it seems only natural that the brain is capable of monitoring and controlling glucose homeostasis. In addition to neuroendocrine pathways, the brain uses the autonomic nervous system to communicate with peripheral organs. Within the brain, the hypothalamus is the key region to integrate signals on energy status, including signals from lipid, glucose, and hormone sensing cells, with afferent neural signals from the internal and external milieu. In turn, the hypothalamus regulates metabolism in peripheral organs, including the liver, not only via the anterior pituitary gland but also via multiple neuropeptidergic pathways in the hypothalamus that have been identified as regulators of hepatic glucose metabolism. These pathways comprise preautonomic neurons projecting to nuclei in the brain stem and spinal cord, which relay signals from the hypothalamus to the liver via the autonomic nervous system. The neuroendocrine and neuronal outputs of the hypothalamus are not separate entities. They appear to act as a single integrated regulatory system, far more subtle, and complex than when each is viewed in isolation. Consequently, hypothalamic regulation should be viewed as a summation of both neuroendocrine and neural influences. As a result, our endocrine-based understanding of diseases such as diabetes and obesity should be expanded by integration of neural inputs into our concept of the pathophysiological process.
Assuntos
Sistema Nervoso Autônomo/fisiologia , Glucose/biossíntese , Fígado/inervação , Fígado/metabolismo , Ingestão de Alimentos/fisiologia , Homeostase/fisiologia , Humanos , Hipotálamo/fisiologia , Neuropeptídeos/fisiologiaRESUMO
Leptin action in the brain has emerged as an important regulator of liver function independently from its effects on food intake and body weight. The autonomic nervous system plays a key role in the regulation of physiological processes by leptin. Here, we used direct recording of nerve activity from sympathetic or vagal nerves subserving the liver to investigate how brain action of leptin controls hepatic autonomic nerve activity. Intracerebroventricular (ICV) administration of leptin activated hepatic sympathetic traffic in rats and mice in dose- and receptor-dependent manners. The hepatic sympatho-excitatory effects of leptin were also observed when leptin was microinjected directly into the arcuate nucleus (ARC), but not into the ventromedial hypothalamus (VMH). Moreover, using pharmacological and genetic approaches, we show that leptin-induced increase in hepatic sympathetic outflow depends on PI3K but not AMP-activated protein kinase (AMPK), STAT3, or ERK1/2. Interestingly, ICV leptin also increased hepatic vagal nerve activity in rats. We show that this response is reproduced by intra-ARC, but not intra-VMH, leptin administration and requires PI3K and AMPK. We conclude that central leptin signaling conveys the information to the liver through the sympathetic and parasympathetic branches of the autonomic nervous system. Our data also provide important insight into the molecular events underlying leptin's control of hepatic autonomic nerve activity by implicating PI3K and AMPK pathways.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Hipotálamo/metabolismo , Fígado/inervação , Fosfatidilinositol 3-Quinases/metabolismo , Receptores para Leptina/metabolismo , Nervo Vago/fisiologia , Animais , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiologia , Leptina/farmacologia , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Ratos , Ratos Wistar , Fator de Transcrição STAT3/metabolismoRESUMO
The brain emerges as a regulator of hepatic triglyceride-rich very-low-density lipoproteins (VLDL-TG). The neurocircuitry involved as well as the ability of fatty acids to trigger a neuronal network to regulate VLDL-TG remain unknown. Here we demonstrate that infusion of oleic acid into the mediobasal hypothalamus (MBH) activates a MBH PKC-δâKATP-channel signalling axis to suppress VLDL-TG secretion in rats. Both NMDA receptor-mediated transmissions in the dorsal vagal complex (DVC) and hepatic innervation are required for lowering VLDL-TG, illustrating a MBH-DVC-hepatic vagal neurocircuitry that mediates MBH fatty acid sensing. High-fat diet (HFD)-feeding elevates plasma TG and VLDL-TG secretion and abolishes MBH oleic acid sensing to lower VLDL-TG. Importantly, HFD-induced dysregulation is restored with direct activation of either MBH PKC-δ or KATP-channels via the hepatic vagus. Thus, targeting a fatty acid sensing-dependent hypothalamic-DVC neurocircuitry may have therapeutic potential to lower hepatic VLDL-TG and restore lipid homeostasis in obesity and diabetes.
Assuntos
Ácidos Graxos/química , Hipotálamo/metabolismo , Lipoproteínas/metabolismo , Fígado/metabolismo , Triglicerídeos/metabolismo , Adenoviridae/metabolismo , Animais , Apolipoproteínas B/metabolismo , Encéfalo/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Homeostase , Lipoproteínas VLDL , Fígado/inervação , Masculino , Neurônios/fisiologia , Ácido Oleico/química , Canais de Potássio/metabolismo , Proteína Quinase C/metabolismo , Ratos , Ratos Sprague-Dawley , Nervo Vago/fisiologiaRESUMO
Orexin-A (a neuropeptide in the hypothalamus) plays an important role in many physiological functions, including the regulation of glucose metabolism. We have previously found that the development of post-ischemic glucose intolerance is one of the triggers of ischemic neuronal damage, which is suppressed by hypothalamic orexin-A. Other reports have shown that the communication system between brain and peripheral tissues through the autonomic nervous system (sympathetic, parasympathetic and vagus nerve) is important for maintaining glucose and energy metabolism. The aim of this study was to determine the involvement of the hepatic vagus nerve on hypothalamic orexin-A-mediated suppression of post-ischemic glucose intolerance development and ischemic neuronal damage. Male ddY mice were subjected to middle cerebral artery occlusion (MCAO) for 2 h. Intrahypothalamic orexin-A (5 pmol/mouse) administration significantly suppressed the development of post-ischemic glucose intolerance and neuronal damage on day 1 and 3, respectively after MCAO. MCAO-induced decrease of hepatic insulin receptors and increase of hepatic gluconeogenic enzymes on day 1 after was reversed to control levels by orexin-A. This effect was reversed by intramedullary administration of the orexin-1 receptor antagonist, SB334867, or hepatic vagotomy. In the medulla oblongata, orexin-A induced the co-localization of cholin acetyltransferase (cholinergic neuronal marker used for the vagus nerve) with orexin-1 receptor and c-Fos (activated neural cells marker). These results suggest that the hepatic branch vagus nerve projecting from the medulla oblongata plays an important role in the recovery of post-ischemic glucose intolerance and mediates a neuroprotective effect by hypothalamic orexin-A.
Assuntos
Intolerância à Glucose/metabolismo , Hipotálamo/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Fígado/inervação , Neuropeptídeos/farmacologia , Fármacos Neuroprotetores/farmacologia , Nervo Vago/fisiologia , Animais , Benzoxazóis/farmacologia , Colina O-Acetiltransferase/metabolismo , Hipotálamo/efeitos dos fármacos , Masculino , Camundongos , Naftiridinas , Receptores de Orexina/metabolismo , Orexinas , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ureia/análogos & derivados , Ureia/farmacologia , Nervo Vago/efeitos dos fármacosRESUMO
BACKGROUND: In human beings or animals, ischemia/reperfusion (I/R) injury of the liver may occur in many clinical conditions, such as circulating shock, liver transplantation and surgery and several other pathological conditions. I/R injury has a complex pathophysiology resulting from a number of contributing factors. Therefore, it is difficult to achieve effective treatment or protection by individually targeting the mediators. This study aimed at studying the effects of local somatothermal stimulation preconditioning on the right Qimen (LR14) on hepatic I/R injury in rats. METHODS: Eighteen male Sprague-Dawley rats were randomly divided into three groups. The rats were preconditioned with thermal tolerance study, which included one dose of local somatothermal stimulation (LSTS) on right Qimen (LR14) at an interval of 12 h, followed by hepatic ischemia for 60 min and then reperfusion for 60 min. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) have been used to assess the liver functions, and liver tissues were taken for the measurements such as malondialdehyde (MDA), glutathione (GSH), catalase (CAT), superoxidase dismutase (SOD), and myeloperoxidase (MPO). RESULTS: The results show that the plasma ALT and AST activities were higher in the I/R group than in the control group. In addition, the plasma ALT and AST activities decreased in the groups that received LSTS. The hepatic SOD levels reduced significantly by I/R injury. Moreover, the hepatic MPO activity significantly increased by I/R injury while it decreased in the groups given LSTS. CONCLUSIONS: Our findings show that LSTS provides a protective effects on the liver from the I/R injury. Therefore, LSTS might offer an easy and inexpensive intervention for patients who have suffered from I/R of the liver especially in the process of hepatotomy and hepatic transplantation.
Assuntos
Pontos de Acupuntura , Hipertermia Induzida , Isquemia/prevenção & controle , Precondicionamento Isquêmico/métodos , Hepatopatias/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Temperatura , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Catalase/metabolismo , Glutationa/análise , Isquemia/enzimologia , Isquemia/metabolismo , Isquemia/terapia , Fígado/enzimologia , Fígado/inervação , Fígado/metabolismo , Fígado/patologia , Hepatopatias/enzimologia , Hepatopatias/metabolismo , Hepatopatias/terapia , Masculino , Malondialdeído/análise , Peroxidase/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/terapia , Superóxido Dismutase/metabolismoRESUMO
Long-term reduced hypothalamic estrogen signaling leads to increased food intake and decreased locomotor activity and energy expenditure, and ultimately results in obesity and insulin resistance. In the current study, we aimed to determine the acute obesity-independent effects of hypothalamic estrogen signaling on glucose metabolism. We studied endogenous glucose production (EGP) and insulin sensitivity during selective modulation of systemic or intrahypothalamic estradiol (E2) signaling in rats 1 week after ovariectomy (OVX). OVX caused a 17% decrease in plasma glucose, which was completely restored by systemic E2. Likewise, the administration of E2 by microdialysis, either in the hypothalamic paraventricular nucleus (PVN) or in the ventromedial nucleus (VMH), restored plasma glucose. The infusion of an E2 antagonist via reverse microdialysis into the PVN or VMH attenuated the effect of systemic E2 on plasma glucose. Furthermore, E2 administration in the VMH, but not in the PVN, increased EGP and induced hepatic insulin resistance. E2 administration in both the PVN and the VMH resulted in peripheral insulin resistance. Finally, sympathetic, but not parasympathetic, hepatic denervation blunted the effect of E2 in the VMH on both EGP and hepatic insulin sensitivity. In conclusion, intrahypothalamic estrogen regulates peripheral and hepatic insulin sensitivity via sympathetic signaling to the liver.
Assuntos
Estradiol/metabolismo , Glucose/metabolismo , Hipotálamo/metabolismo , Sistema Nervoso Simpático/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Estradiol/sangue , Estradiol/farmacologia , Antagonistas de Estrogênios/farmacologia , Feminino , Gluconeogênese/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Insulina/sangue , Insulina/farmacologia , Resistência à Insulina/fisiologia , Fígado/efeitos dos fármacos , Fígado/inervação , Fígado/metabolismo , Parassimpatectomia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Simpatectomia , Sistema Nervoso Simpático/efeitos dos fármacos , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacosRESUMO
Excessive secretion of triglyceride-rich very low-density lipoproteins (VLDL-TG) contributes to diabetic dyslipidemia. Earlier studies have indicated a possible role for the hypothalamus and autonomic nervous system in the regulation of VLDL-TG. In the current study, we investigated whether the autonomic nervous system and hypothalamic neuropeptide Y (NPY) release during fasting regulates hepatic VLDL-TG secretion. We report that, in fasted rats, an intact hypothalamic arcuate nucleus and hepatic sympathetic innervation are necessary to maintain VLDL-TG secretion. Furthermore, the hepatic sympathetic innervation is necessary to mediate the stimulatory effect of intracerebroventricular administration of NPY on VLDL-TG secretion. Since the intracerebroventricular administration of NPY increases VLDL-TG secretion by the liver without affecting lipolysis, its effect on lipid metabolism appears to be selective to the liver. Together, our findings indicate that the increased release of NPY during fasting stimulates the sympathetic nervous system to maintain VLDL-TG secretion at a postprandial level.
Assuntos
Hipotálamo/metabolismo , Lipoproteínas VLDL/metabolismo , Fígado/metabolismo , Neuropeptídeo Y/metabolismo , Sistema Nervoso Simpático/fisiologia , Triglicerídeos/metabolismo , Animais , Glicemia , Privação de Alimentos , Glucose/metabolismo , Insulina/sangue , Insulina/metabolismo , Fígado/inervação , Masculino , Ratos , Ratos WistarRESUMO
The central nervous system plays an important role in the regulation of energy balance and glucose homeostasis mainly via controlling the autonomic output to the visceral organs. The autonomic output is regulated by hormones and nutrients to maintain adequate energy and glucose homeostasis. Insulin action is mediated via insulin receptors (IR) resulting in phosphorylation of insulin receptor substrates (IRS) inducing activation of downstream pathways. Furthermore, insulin enhances transient receptor potential vanilloid type 1 (TRPV1) mediated currents. Activation of the TRPV1 receptor increases excitatory neurotransmitter release in autonomic centers of the brain, thereby impacting energy and glucose homeostasis. The aim of this study is to determine co-expression of IRS2 and TRPV1 receptors in the paraventricular nucleus of the hypothalamus (PVN) and dorsal motor nucleus of the vagus (DMV) in the mouse brain as well as expression of IRS2 and TRPV1 receptors at liver-related preautonomic neurons pre-labeled with a trans-neural, viral tracer (PRV-152). The data indicate that IRS2 and TRPV1 receptors are present and co-express in the PVN and the DMV. A large portion (over 50%) of the liver-related preautonomic DMV and PVN neurons expresses IRS2. Moreover, the majority of liver-related DMV and PVN neurons also express TRPV1 receptors, suggesting that insulin and TRPV1 actions may affect liver-related preautonomic neurons.
Assuntos
Tronco Encefálico/metabolismo , Hipotálamo/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Fígado/inervação , Neurônios/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Tronco Encefálico/citologia , Hipotálamo/citologia , Imuno-Histoquímica , Proteínas Substratos do Receptor de Insulina/biossíntese , Fígado/citologia , Fígado/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos , Neurônios/citologia , Canais de Cátion TRPV/biossínteseRESUMO
MKR mice, lacking insulin-like growth factor 1 receptor (IGF-1R) signaling in skeletal muscle, are lean yet hyperlipidemic, hyperinsulinemic, and hyperglycemic, with severe insulin resistance and elevated hepatic and skeletal muscle levels of triglycerides. We have previously shown that chronic peripheral administration of the adipokine leptin improves hepatic insulin sensitivity in these mice independently of its effects on food intake. As central leptin signaling has been implicated in the control of peripheral glucose homeostasis, here we examined the ability of central intracerebroventricular leptin administration to affect energy balance and peripheral glucose homeostasis in non-obese diabetic male MKR mice. Central leptin significantly reduced food intake, body weight gain and adiposity, as well as serum glucose, insulin, leptin, free fatty acid and triglyceride levels relative to ACSF treated controls. These reductions were accompanied by increased fat oxidation as measured by indirect calorimetry, as well as increased oxygen consumption. Central leptin also improved glucose tolerance and hepatic insulin sensitivity determined using the euglycemic-hyperinsulinemic clamps relative to pair fed vehicle treated controls, as well as increasing the rate of glucose disappearance. Hepatic vagotomy only partially reversed the ability of central leptin to improve glucose tolerance. These results demonstrate that central leptin dramatically improves insulin sensitivity independently of its effects on food intake, in a lean mouse model of type 2 diabetes. The findings also suggest that: 1) both hepatic vagal and non-vagal pathways contribute to this improvement, and 2) central leptin alters glucose disposal in skeletal muscle in this model.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Leptina/administração & dosagem , Fígado/inervação , Nervo Vago/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Avaliação Pré-Clínica de Medicamentos , Infusões Intraventriculares , Leptina/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Magreza/metabolismo , Magreza/patologia , Nervo Vago/metabolismo , Nervo Vago/fisiologiaRESUMO
OBJECTIVE: The hypothalamic neuropeptide orexin influences (feeding) behavior as well as energy metabolism. Administration of exogenous orexin-A into the brain has been shown to increase both food intake and blood glucose levels. In the present study, we investigated the role of endogenous hypothalamic orexin release in glucose homeostasis in rats. RESEARCH DESIGN AND METHODS: We investigated the effects of the hypothalamic orexin system on basal endogenous glucose production (EGP) as well as on hepatic and peripheral insulin sensitivity by changing orexinergic activity in the hypothalamus combined with hepatic sympathetic or parasympathetic denervation, two-step hyperinsulinemic-euglycemic clamps, immunohistochemistry, and RT-PCR studies. RESULTS: Hypothalamic disinhibition of neuronal activity by the gamma-aminobutyric acid receptor antagonist bicuculline (BIC) increased basal EGP, especially when BIC was administered in the perifornical area where orexin-containing neurons but not melanocortin-concentrating hormone-containing neurons were activated. The increased BIC-induced EGP was largely prevented by intracerebroventricular pretreatment with the orexin-1 receptor antagonist. Intracerebroventricular administration of orexin-A itself caused an increase in plasma glucose and prevented the daytime decrease of EGP. The stimulatory effect of intracerebroventricular orexin-A on EGP was prevented by hepatic sympathetic denervation. Plasma insulin clamped at two or six times the basal levels did not counteract the stimulatory effect of perifornical BIC on EGP, indicating hepatic insulin resistance. RT-PCR showed that stimulation of orexin neurons increased the expression of hepatic glucoregulatory enzymes. CONCLUSIONS: Hypothalamic orexin plays an important role in EGP, most likely by changing the hypothalamic output to the autonomic nervous system. Disturbance of this pathway may result in unbalanced glucose homeostasis.
Assuntos
Ácido Glucárico/metabolismo , Hipotálamo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neurônios/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Animais , Bicuculina/farmacologia , Antagonistas GABAérgicos/farmacologia , Técnica Clamp de Glucose , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Hiperinsulinismo/metabolismo , Hipotálamo/citologia , Injeções Intraventriculares , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Fígado/inervação , Fígado/metabolismo , Masculino , Inibição Neural/fisiologia , Neuropeptídeos/farmacologia , Receptores de Orexina , Orexinas , Parassimpatectomia , Sistema Nervoso Parassimpático/fisiologia , Ratos , Ratos Wistar , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Simpatectomia , Sistema Nervoso Simpático/fisiologia , Ácido gama-Aminobutírico/metabolismoRESUMO
There are no reports that hypothalamus can directly affect the expression of neuron-related genes and immune-related genes in liver. We identified genes of which expression profiles showed significant modulation in rat liver after ventromedial hypothalamic (VMH) lesions. Total RNA was extracted, and differences in the gene expression profiles between rats at day 3 after VMH lesioning and sham-VMH lesioned rats were investigated using DNA microarray analysis. The result revealed that VMH lesions regulated the genes that were involved in functions related to neuronal development and immunofunction in the liver. Real-time PCR also confirmed that gene expression of SULT4A1 was upregulated, but expression of ACSL1 and CISH were downregulated at day 3 after VMH lesions. VMH lesions may change the expression of neuron-related genes and immune-related genes in rat liver.
Assuntos
Regulação da Expressão Gênica , Hipotálamo/fisiologia , Fígado/imunologia , Fígado/metabolismo , Neuroimunomodulação , Neurônios/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Feminino , Perfilação da Expressão Gênica , Hipotálamo/citologia , Fígado/inervação , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Ratos , Ratos Sprague-Dawley , Sulfotransferases/biossíntese , Sulfotransferases/genética , Proteínas Supressoras da Sinalização de Citocina/biossíntese , Proteínas Supressoras da Sinalização de Citocina/genéticaRESUMO
The liver plays a pivotal role in the regulation of glucose metabolism because it is the key organ that maintains glucose levels during fasting. An emerging body of literature has demonstrated the important role of the hypothalamus in controlling hepatic glucose production (HGP). The hypothalamus senses circulating nutrients and hormones, conveying the energy status to the central nervous system, which, in turn, controls HGP in part by way of the autonomic nervous system. Overfeeding results in the failure of the hypothalamus to sense circulating nutrients and hormones, and in a loss of the central control of HGP.
Assuntos
Glucose/metabolismo , Hipotálamo/fisiologia , Resistência à Insulina/fisiologia , Fígado/metabolismo , Animais , Ingestão de Alimentos/fisiologia , Alimentos , Humanos , Hipotálamo/metabolismo , Insulina/fisiologia , Leptina/metabolismo , Leptina/fisiologia , Fígado/inervação , Fígado/fisiologia , Modelos BiológicosRESUMO
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.