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Summary Central insulin action activates hepatic IL-6/STAT3 signaling, which suppresses the gene expression of hepatic gluconeogenic enzymes. The vagus nerve plays an important role in this centrally mediated hepatic response; however, the precise mechanism underlying this brain-liver interaction is unclear. Here, we present our findings that the vagus nerve suppresses hepatic IL-6/STAT3 signaling via α7-nicotinic acetylcholine receptors (α7-nAchR) on Kupffer cells, and that central insulin action activates hepatic IL-6/STAT3 signaling by suppressing vagal activity. Indeed, central insulin-mediated hepatic IL-6/STAT3 activation and gluconeogenic gene suppression were impeded in mice with hepatic vagotomy, pharmacological cholinergic blockade, or α7-nAchR deficiency. In high-fat diet-induced obese and insulin-resistant mice, control of the vagus nerve by central insulin action was disturbed, inducing a persistent increase of inflammatory cytokines. These findings suggest that dysregulation of the α7-nAchR-mediated control of Kupffer cells by central insulin action may affect the pathogenesis of chronic hepatic inflammation in obesity. [ABSTRACT FROM AUTHOR]

BACKGROUND We aimed to assess the predictive value of circulating levels of des-acyl ghrelin, an abundant form of ghrelin in humans, for the risk of cardiovascular disease (CVD) in older hypertensive patients. We simultaneously evaluated other biomarkers, such as high-molecular-weight (HMW) adiponectin, high-sensitivity C-reactive protein (hs-CRP), and plasminogen activator inhibitor 1 (PAI-1), for their usefulness in risk prediction. METHODS We enrolled 590 older hypertensive patients (mean age = 72.9 years; 41.0% men). The incidences of CVD, including coronary artery disease, stroke, congestive heart failure, and sudden death, were prospectively ascertained. RESULTS During an average duration of 2.8 (SD = 0.7) years (1,653 person-years), there were 42 CVD events. Patients with CVD events had lower levels of des-acyl ghrelin at baseline than those without CVD events (median = 78.2 vs. 114.7fmol/ml; P < 0.001). No difference was found among other biomarkers between the patients with CVD events and those without such events. The Cox proportional hazards model adjusted by covariables revealed that the hazard ratio for CVD events in patients with a 1-SD decrease of log des-acyl ghrelin was 1.8 (95% confidence interval = 1.3−2.4). Incorporation of des-acyl ghrelin in the risk model (including age, current smoking, 24-hour systolic blood pressure, preexisting CVD, and carotid intima-media thickness) improved the C statistics (from 0.683 to 0.721; P = 0.22) and resulted in a net reclassification improvement of 20.5% (P = 0.02). In contrast, HMW adiponectin, hs-CRP, and PAI-1 provided no improvement in risk prediction. CONCLUSIONS Des-acyl ghrelin improved the prediction of CVD events in older hypertensive patients. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine whether elevation of muscle temperature per se might be a stimulatory factor to increase muscle glucose uptake. Heat stimulation to rat hindlimbs increased glucose uptake measured in vivo in the extensor digitorum longus (EDL) and soleus muscles with a significant increase in muscle temperature. This thermal effect was observed again when glucose uptake was measured in vitro in both isolated muscles immediately after the heat stimulation in vivo. When heat stimulation was imposed on isolated EDL muscles, glucose uptake was facilitated in proportion to the increase in muscle temperature. The heat stimulation led to a significant amplification in the phosphorylation of AMP-activated protein kinase (AMPK) and Akt, and treatment with compound C, wortmannin, or LY294002 partially blocked the thermal effect on muscle glucose uptake. We provide evidence that elevation of muscle temperature per se can directly stimulate muscle glucose uptake and that this thermal effect is compound C-, wortmannin-, and LY294002-inhibitable. [ABSTRACT FROM AUTHOR]

Toshinai K, Yamaguchi H, Kageyama H, Matsuo T, Koshinaka K, Sasaki K, Shioda S, Minamino N, Nakazato M. Neuroendocrine regulatory peptide-2 regulates feeding behavior via the orexin system in the hypothalamus. Am J Physiol Endocrinol Metab 299: E394-E401, 2010. First published June 15, 2010; doi: 10.1152/ajpendo.00768.2009.--Neuroendocrine regulatory peptide (NERP)-1 and NERP-2 are derived from distinct regions of VGF, a neurosecretory protein. Vgf-/- mice exhibit dwarfism and hypermetabolic rates, suggesting that VGF or VGF-derived peptides play important roles in energy metabolism. Here, we examined the role of NERPs in the central regulation of feeding and energy homeostasis. We attempted to identify NERPs expressing neurons in rats by immunohistochemistry. We studied the effects of intracerebroventricular (icv) administration of NERP-2 on feeding, body temperature, oxygen consumption, and locomotor activity in rats and mice. Intracerebroventricular administration of NERP-2, but not NERP-1 or a form of NERP-2 bearing a COOH-terminal glycine extension, increased food intake in rats. We investigated the downstream signal of NERP-2 on the basis of studies of NERP-2-induced feeding with neutralization of orexins, neuropeptide Y, or agouti-related protein. NERP-2 expression localized to the lateral hypothalamus (LH) and the dorsomedial perifornical hypothalamus in rats, colocalizing with orexins that activate feeding behavior and arousal. NERP-2 administration induced Fos protein, a marker of neuronal activation, in the orexin-immunoreactive neurons. Vgf mRNA levels were upregulated in the rat LH upon food deprivation. Intracerebroventricular administration of NERP-2 also increased body temperature, oxygen consumption, and locomotor activity in rats. Treatment with anti-NERP-2 IgG decreased food intake. NERP-2-induced bioactivities could be abrogated by administration of anti-orexins IgG or orexin receptor antagonists. NERP-2 did not induce food intake or locomotor activity in orexin-deficient mice. Our findings indicate that hypothalamic NERP-2 plays a role in the control of food intake and energy homeostasis via the orexin pathway. Thus, VGF serves as a precursor of multiple bioactive peptides exerting a diverse set of neuroendocrine functions. [ABSTRACT FROM AUTHOR]

Neuromedin U (NMU) is a hypothalamic peptide involved in energy homeostasis and stress responses. NMU, when administered intracerebroventricularly, decreases food intake and body weight while increasing body temperature and heat production. In addition, NMU, acting via the corticotropin-releasing hormone (CRH) system, induces gross locomotor activity and stress responses. We studied the effect of intracerebroventricularly administered NMU (0.5-4 nmol) in the regulation of gastric functions in conscious rats. Intracerebroventricular administration of NMU significantly decreased gastric acid output to 30-60% and gastric emptying to 35-70% in a dose-dependent manner. Vagotomy did not abolish the inhibitory effect of NMU on pentagastrin-induced gastric acid secretion. Pretreatment with indomethacin (10 mg/kg), an inhibitor of prostaglandin synthesis, also did not affect NMU-induced acid inhibition. Pretreatment with anti-CRH IgG (1 µg/rat), however, completely blocked NMU-induced acid inhibition (P < 0.01). Administration of yohimbine (4 mg/kg), an α[sub 2]adrenergic receptor antagonist, also abolished NMU-induced acid inhibition (P < 0.01). These findings suggest that NMU is critical in the central regulation of gastric acid secretion via CRH. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate whether high-intensity endurance training would alleviate exercise-induced oxidative stress. Nine untrained male subjects (aged 19–21 years) participated in a 12-week training programme, and performed an acute period of exhausting exercise on a cycle ergometer before and after training. The training programme consisted of running at 80% maximal exercise heart rate for 60 min · day-1, 5 days · week-1 for 12 weeks. Blood samples were collected at rest and immediately after exhausting exercise for measurements of indices of oxidative stress, and antioxidant enzyme activities [superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT)] in the erythrocytes. Maximal oxygen uptake (VO2max) increased significantly (P < 0.001) after training, indicating an improvement in aerobic capacity. A period of exhausting exercise caused an increase (P < 0.01) in the ability to produce neutrophil superoxide anion (O2•-) both before and after endurance training, but the magnitude of the increase was smaller after training (P < 0.05). There was a significant increase in lipid peroxidation in the erythrocyte membrane, but not in oxidative protein, after exhausting exercise, however training attenuated this effect. At rest, SOD and GPX activities were increased after training. However, there was no evidence that exhausting exercise enhanced the levels of any antioxidant enzyme activity. The CAT activity was unchanged either by training or by exhausting exercise. These results indicate that high-intensity endurance training can elevate antioxidant enzyme activities in erythrocytes, and decrease neutrophil O2•- production in response to exhausting exercise. Furthermore, this up-regulation in antioxidant defences was accompanied by a reduction in exercise-induced lipid peroxidation in erythrocyte membrane. [ABSTRACT FROM AUTHOR]

The aim of the current study was to elucidate the synergism of dietary calcium restriction and exhaustive exercise in the antioxidant enzyme system of rat soleus muscle, and to investigate the involvement of neutrophils in exercise-induced muscle damage. Forty-eight male Wistar rats were assigned to the following groups: control (C) or calcium-restricted [1 month (1 M) or 3 months (3 M)]. Each group was subdivided into acutely exercised or non-exercised groups. Soleus muscle from each rat was analysed to determine the levels of antioxidant enzymes [Mn-superoxide dismutase (SOD), Cu,Zn-SOD, glutathione peroxidase (GPX), and catalase (CAT)]. Dietary calcium restriction resulted in calcium deficiency and upregulated the antioxidant enzymes examined except GPX. Conversely, exhaustive exercise significantly decreased GPX and CAT, but not SODs activities in the calcium-restricted (1 M and/or 3 M) rats. Contents of immunoreactive Mn-SOD and Cu,Zn-SOD were only increased in the 3 M rats. During calcium restriction, the mRNA expression of both forms of SOD showed initial upregulation, followed by downregulation. Exhaustive exercise significantly increased the mRNA expressions only in the 3 M rats. Moreover, exhaustive exercise markedly increased myeloperoxidase activity in soleus muscles from the 1 M and 3 M rats compared with the C rats, and significantly enhanced the ability of neutrophils to generate superoxide in the 3 M rats. The results demonstrate that dietary calcium restriction upregulates certain antioxidant enzyme activities in rat soleus muscle, indicating an enhanced resistance to potential increases in intracellular reactive oxygen species. The results also suggest that exhaustive exercise may cause oxidative damage in soleus muscle of calcium-deficient rats through the activation of neutrophils. [ABSTRACT FROM AUTHOR]

The gastrointestinal tract transmits feeding-regulatory signals to the brain via neuronal and hormonal pathways. Here we studied the interaction between the orexigenic gastric peptide, ghrelin, and the anorectic intestinal peptide, glucagon-like peptide 1 (GLP-1), in terms of feeding regulation via the vagal afferents. GLP-1 preadministration 30 min before ghrelin administration to rats and mice abolished ghrelin-induced food intake, while ghrelin preadministration abolished the anorectic effect of GLP-1. Ghrelin preadministration suppressed GLP-1-induced Fos expression in the nodose ganglia (NG). Electrophysiological assessment confirmed that the initially administered peptide abolished the vagal afferent electrical alteration induced by the subsequently administered peptide. Both the growth hormone secretagogue receptor (GHSR) and the GLP-1 receptor (GLP-1R) are co-localised in a major proportion of NG neurons that innervate the stomach. In these Ghsr+Glp1r+ neurons, ghrelin preadministration abolished the GLP-1-induced calcium response. Ghrelin generated a hyperpolarising current and GLP-1 generated a depolarising current in isolated NG neurons in a patch-clamp experiment. Ghrelin and GLP-1 potently influenced each other in terms of vagally mediated feeding regulation. This peptidergic interaction allows for fine control of the electrophysiological properties of NG neurons. [ABSTRACT FROM AUTHOR]