Hepatic Sympathetic Denervation Research Articles

Safety of surgical denervation of the common hepatic artery in insulin-resistant dogs.

The objective of this study was to assess the safety of surgical common hepatic artery denervation (CHADN). This procedure has previously been shown to improve glucose tolerance in dogs fed a high‐fat high‐fructose (HFHF) diet. We assessed the hypoglycemic response of dogs by infusing insulin at a constant rate (1.5 mU/kg/min) for 3 h and monitoring glucose and the counterregulatory hormones (glucagon, catecholamine, and cortisol). After an initial hypoglycemic study, the dogs were randomly assigned to a SHAM surgery (n = 4) or hepatic sympathetic denervation (CHADN, n = 5) and three follow‐up studies were performed every month up to 3 months after the surgery. The level of norepinephrine (NE) in the liver and the pancreas was significantly reduced in the CHADN dogs, showing a decrease in sympathetic tone to the splanchnic organs. There was no evidence of any defect of the response to hypoglycemia after the CHADN surgery. Indeed, the extent of hypoglycemia was similar in the SHAM and CHADN groups (~45 mg/dl) for the same amount of circulating insulin (~50 µU/ml) regardless of time or surgery. Moreover the responses of the counterregulatory hormones were similar in extent and pattern during the 3 h of hypoglycemic challenge. Circulating lactate, glycerol, free fatty acids, and beta‐hydroxybutyrate were also unaffected by CHADN during fasting conditions or during the hypoglycemia. There were no other notable surgery‐induced changes over time in nutrients, minerals, and hormones clinically measured in the dogs nor in the blood pressure and heart rate of the animals. The data suggest that the ablation of the sympathetic nerve connected to the splanchnic bed is not required for a normal counterregulatory response to insulin‐induced hypoglycemia and that CHADN could be a safe new therapeutic intervention to improve glycemic control in individuals with metabolic syndrome or type 2 diabetes.

Hepatic Sympathetic Denervation Reduces Non‐alcoholic Fatty Liver Disease in Diet‐Induced Obese Mice

Hepatic Sympathetic Denervation Reduces Non‐alcoholic Fatty Liver Disease in Diet‐Induced Obese Mice

Effect of hepatic sympathetic denervation on hepatocyte proliferation in rats after partial hepatectomy

Effect of hepatic sympathetic denervation on hepatocyte proliferation in rats after partial hepatectomy

Glucocorticoid Signaling in the Arcuate Nucleus Modulates Hepatic Insulin Sensitivity

Glucocorticoid receptors are highly expressed in the hypothalamic paraventricular nucleus (PVN) and arcuate nucleus (ARC). As glucocorticoids have pronounced effects on neuropeptide Y (NPY) expression and as NPY neurons projecting from the ARC to the PVN are pivotal for balancing feeding behavior and glucose metabolism, we investigated the effect of glucocorticoid signaling in these areas on endogenous glucose production (EGP) and insulin sensitivity by local retrodialysis of the glucocorticoid receptor agonist dexamethasone into the ARC or the PVN, in combination with isotope dilution and hyperinsulinemic–euglycemic clamp techniques. Retrodialysis of dexamethasone for 90 min into the ARC or the PVN did not have significant effects on basal plasma glucose concentration. During the hyperinsulinemic–euglycemic clamp, retrodialysis of dexamethasone into the ARC largely prevented the suppressive effect of hyperinsulinemia on EGP. Antagonizing the NPY1 receptors by intracerebroventricular infusion of its antagonist largely blocked the hepatic insulin resistance induced by dexamethasone in the ARC. The dexamethasone-ARC–induced inhibition of hepatic insulin sensitivity was also prevented by hepatic sympathetic denervation. These data suggest that glucocorticoid signaling specifically in the ARC neurons modulates hepatic insulin responsiveness via NPY and the sympathetic system, which may add to our understanding of the metabolic impact of clinical conditions associated with hypercortisolism.

A Major Role for Perifornical Orexin Neurons in the Control of Glucose Metabolism in Rats

OBJECTIVEThe 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 METHODSWe 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.RESULTSHypothalamic disinhibition of neuronal activity by the γ-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.CONCLUSIONSHypothalamic 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.

Thyroid hormone modulates glucose production via a sympathetic pathway from the hypothalamic paraventricular nucleus to the liver

Thyrotoxicosis increases endogenous glucose production (EGP) and induces hepatic insulin resistance. We have recently shown that these alterations can be modulated by selective hepatic sympathetic and parasympathetic denervation, pointing to neurally mediated effects of thyroid hormone on glucose metabolism. Here, we investigated the effects of central triiodothyronine (T(3)) administration on EGP. We used stable isotope dilution to measure EGP before and after i.c.v. bolus infusion of T(3) or vehicle in euthyroid rats. To study the role of hypothalamic preautonomic neurons, bilateral T(3) microdialysis in the paraventricular nucleus (PVN) was performed for 2 h. Finally, we combined T(3) microdialysis in the PVN with selective hepatic sympathetic denervation to delineate the involvement of the sympathetic nervous system in the observed metabolic alterations. T(3) microdialysis in the PVN increased EGP by 11 +/- 4% (P = 0.020), while EGP decreased by 5 +/- 8% (ns) in vehicle-treated rats (T(3) vs. Veh, P = 0.030). Plasma glucose increased by 29 +/- 5% (P = 0.0001) after T(3) microdialysis versus 8 +/- 3% in vehicle-treated rats (T(3) vs. Veh, P = 0.003). Similar effects were observed after i.c.v. T(3) administration. Effects of PVN T(3) microdialysis were independent of plasma T(3), insulin, glucagon, and corticosterone. However, selective hepatic sympathectomy completely prevented the effect of T(3) microdialysis on EGP. We conclude that stimulation of T(3)-sensitive neurons in the PVN of euthyroid rats increases EGP via sympathetic projections to the liver, independently of circulating glucoregulatory hormones. This represents a unique central pathway for modulation of hepatic glucose metabolism by thyroid hormone.

In-Chern-Hau-Tang and Genipin Reduces Acute Urinary Bladder Distension Evoked Sympathetic Activation-Induced Hepatic Dysfunction in Rats

Increased norepinephrine production by acute urine retention (AUR) induced sympathetic activation may contribute to acute liver injury (ALI) via the action of hepatic vasoconstriction and increased reactive oxygen species (ROS) production. We evaluated whether In-Chern-Hau-Tang, a hepatoprotective herb medicine, and its major ingredient genipin, may ameliorate norepinephrine-induced liver injury in the rat. We determined the effects of In-Chern-Hau-Tang and genipin on norepinephrine-induced oxidative stress in the Kupffer and endothelial cells and AUR-induced ALI in the rat via a chemiluminescence analyzer, physiologic and biochemical determination and western blot. The results of in vitro study showed that genipin with efficient H(2)O(2) and HOCl scavenging activities decreased norepinephrine-enhanced ROS production in the Kupffer cell and endothelial cell cultures. AUR activated hepatic sympathetic nervous activity lead to a hepatic hypoxia/hypoperfusion, and a reduction in bile flow. AUR increased intercellular adhesion molecular 1 (ICAM-1) protein expression, and hepatic ROS production from the activated leukocyte NADPH oxidase activity subsequently leading to plasma aspartate aminotransferase (AST) elevation. Hepatic sympathetic denervation, or oral pretreatment of In-Chern-Hau-Tang or genipin for 1 week ameliorated the level in AUR-induced hepatic hypoxia/hypoperfusion, and bile stasis. Hepatic denervation, In-Chern-Hau-Yang and genipin inhibited AUR-enhanced hepatic ICAM-1 expression, hepatic ROS production, leukocyte NADPH oxidase activity and plasma AST activity. In conclusion, In-Chern-Hau-Tang along with its active component, genipin, can ameliorate AUR-induced ALI via the alleviation of oxidative stress possibly by the inhibition of sympathetic induced hypoxia/hypoperfusion and leukocyte NADPH oxidase activity.

Colorectal distension enforce acute urinary bladder distension-induced hepatic vasoconstriction in the rat

Acute urinary bladder distension (AUBD) and colorectal distension (CRD) activated mechanical afferents from the urinary bladder and colon and the activated afferent signaling affected visceral organ behavior. AUBD and CRD have been reported to affect the arterial blood pressure (ABP) response in the rat. We hypothesized that AUBD and CRD may influence the cardiovascular response in the liver by neurokinin receptor-mediated afferent transmission and sympathetic nerve-mediated vesicovascular reflex. We simultaneously evaluated the bladder and colorectal pressure, hepatic microcirculation and arterial blood pressure (ABP) in response to AUBD (0-60mmHg) and/or CRD stimulation (0-80mmHg) in the urethane anesthetized rat. Hepatic sympathetic denervation and intravenous CP96,345 (neurokinin 1 receptor antagonist) and SR48968 (neurokinin 2 receptor antagonist) were adopted to determine the possible neural pathways in response to AUBD and/or CRD stimulation. Our results showed that AUBD or CRD evoked a pressor response in ABP and a hepatic vasoconstriction in a pressure-dependent manner. The pressor response was demonstrated in an order AUBD>AUBD+CRD>CRD. The hepatic vasoconstrictor response was displayed in an order AUBD+CRD>AUBD>CRD. Hepatic sympathetic denervation and CP96,345 (neurokinin 1 receptor antagonist), not SR48968 (neurokinin 2 receptor antagonist), significantly inhibited AUBD, CRD and AUBD+CRD induced hepatic vasoconstriction. CRD significantly inhibited AUBD evoked spontaneous bladder contractions and ABP elevation. In conclusion, our results indicated that AUBD and CRD via neurokinin 1 receptors activate hepatic sympathetic nerve-mediated vesicovascular reflex and consequently lead to hepatic vasoconstriction. CRD exerts different cross-talk effects to influence AUBD-evoked bladder contractions and vesicovascular reflex.

Effects of thyrotoxicosis and selective hepatic autonomic denervation on hepatic glucose metabolism in rats

Thyrotoxicosis is known to induce a broad range of changes in carbohydrate metabolism. Recent studies have identified the sympathetic and parasympathetic nervous system as major regulators of hepatic glucose metabolism. The present study aimed to investigate the pathogenesis of altered endogenous glucose production (EGP) in rats with mild thyrotoxicosis. Rats were treated with methimazole in drinking water and l-thyroxine (T(4)) from osmotic minipumps to either reinstate euthyroidism or induce thyrotoxicosis. Euthyroid and thyrotoxic rats underwent either a sham operation, a selective hepatic sympathetic denervation (Sx), or a parasympathetic denervation (Px). After 10 days of T(4) administration, all animals were submitted to a hyperinsulinemic euglycemic clamp combined with stable isotope dilution to measure EGP. Plasma triiodothyronine (T(3)) showed a fourfold increase in thyrotoxic compared with euthyroid animals. EGP was increased by 45% in thyrotoxic compared with euthyroid rats and correlated significantly with plasma T(3). In thyrotoxic rats, hepatic PEPCK mRNA expression was increased 3.5-fold. Relative suppression of EGP during hyperinsulinemia was 34% less in thyrotoxic than in euthyroid rats, indicating hepatic insulin resistance. During thyrotoxicosis, Sx attenuated the increase in EGP, whereas Px resulted in increased plasma insulin with unaltered EGP compared with intact animals, compatible with a further decrease in hepatic insulin sensitivity. We conclude that chronic, mild thyrotoxicosis in rats increases EGP, whereas it decreases hepatic insulin sensitivity. Sympathetic hepatic innervation contributes only to a limited extent to increased EGP during thyrotoxicosis, whereas parasympathetic hepatic innervation may function to restrain EGP in this condition.

Galanin is localized in sympathetic neurons of the dog liver

Stimulation of canine hepatic nerves releases the neuropeptide galanin from the liver; therefore, galanin may be a sympathetic neurotransmitter in the dog liver. To test this hypothesis, we used immunocytochemistry to determine if galanin is localized in hepatic sympathetic nerves and we used hepatic sympathetic denervation to verify such localization. Liver sections from dogs were immunostained for both galanin and the sympathetic enzyme marker tyrosine hydroxylase (TH). Galanin-like immunoreactivity (GALIR) was colocalized with TH in many axons of nerve trunks as well as individual nerve fibers located both in the stroma of hepatic blood vessels and in the liver parenchyma. Neither galanin- nor TH-positive cell bodies were observed. Intraportal 6-hydroxydopamine (6-OHDA) infusion, a treatment that selectively destroys hepatic adrenergic nerve terminals, abolished the GALIR staining in parenchymal neurons but only moderately diminished the GALIR staining in the nerve fibers around blood vessels. To confirm that 6-OHDA pretreatment proportionally depleted galanin and norepinephrine in the liver, we measured both the liver content and the hepatic nerve-stimulated spillover of galanin and norepinephrine from the liver. Pretreatment with 6-OHDA reduced the content and spillover of both galanin and norepinephrine by > 90%. Together, these results indicate that galanin in dog liver is primarily colocalized with norepinephrine in sympathetic nerves and may therefore function as a hepatic sympathetic neurotransmitter.

Liver phosphorylase activation during early phase of feeding behavior: A neurohumoral regulation

The mechanisms of liver glycogen depletion during the early phase of spontaneous feeding were examined in adult rats. A 40% increase in the activity of phosphorylase a, the active form of a key glycogenolytic enzyme, was detected 5 min after the onset of feeding, with a concomitant decrease of glycogen in the liver after 5 and 15 min. Within 60 min after the onset of feeding, the enzyme activity returned to the basal level and the glycogen content was restored. These metabolic responses were impaired by hepatic sympathetic denervation or by bilateral adrenodemedullation. It was concluded that the onset of meals may evoke an arousal of the sympatho-adrenal system including the hepatic innervation, and that activation of this system is important in stimulating liver phosphorylase activity and glycogenolysis during the early phase of spontaneous feeding.

Hepatic sympathetic denervation potentiates glucagon-stimulated glycogenolysis and hyperinsulinaemia in the rat

The influence of hepatic nerves on glucagon-stimulated hyperglycaemia and hyperinsulinaemia was studied in rats. Using microsurgical techniques, hepatic sympathectomy (resulting in approximately 80% reduction of liver noradrenaline content) or hepatic vagotomy was performed. Glucagon (10 μg/kg b.wt.) was injected i.v. one week after the operative procedure. Plasma levels of glucose and insulin rose more rapidly and to a higher level in rats subjected to hepatic sympathectomy than in sham-operated or non-operated control animals. In contrast, hepatic vagotomy did not influence the plasma glucose or insulin response to glucagon. In conclusion, our findings suggest a role for the hepatic sympathetic nerves in glucagon-stimulated glycogenolysis and insulin secretion in the rat.