Hepatic Denervation Research Articles

Dopamine in the nucleus accumbens shell controls systemic glucose metabolism via the lateral hypothalamus and hepatic vagal innervation in rodents

BackgroundGrowing evidence demonstrates the role of the striatal dopamine system in the regulation of glucose metabolism. Treatment with dopamine antagonists is associated with insulin resistance and hyperglycemia, while dopamine agonists are used in treatment of type 2 diabetes. The mechanism underlying striatal dopamine effects in glucose metabolism, however is not fully understood. Here, we provide mechanistic insights into the role of nucleus accumbens shell (sNAc) dopaminergic signaling in systemic glucose metabolism. MethodsEndogenous glucose production (EGP), blood glucose and mRNA expression in the lateral hypothalamic area (LHA) in male Wistar rats were measured following infusion of vanoxerine (VNX, dopamine reuptake inhibitor) in the sNAc. Thereafter, we analyzed projections from sNAc Drd1-expressing neurons to LHA using D1-Cre male Long-Evans rats, Cre-dependent viral tracers and fluorescence immunohistochemistry. Brain slice electrophysiology in adult mice was used to study spontaneous excitatory postsynaptic currents of sNAc Drd1-expressing neurons following VNX application. Finally, we assessed whether GABAergic LHA activity and hepatic vagal innervation were required for the effect of sNAc-VNX on glucose metabolism by combining infusion of sNAc-VNX with LHA-bicuculline, performing vagal recordings and combining infusion of sNAc-VNX with hepatic vagal denervation. ResultsVNX infusion in the sNAc strongly decreased endogenous glucose production, prevented glucose increases over time, reduced Slc17A6 and Hcrt mRNA in LHA, and increased vagal activity. Furthermore, sNAc Drd1-expressing neurons increased spontaneous firing following VNX application, and viral tracing of sNAc Drd1-expressing neurons revealed direct projections to LHA with on average 67 % of orexin cells directly targeted by sNAc Drd1-expressing neurons. Importantly, the sNAc-VNX-induced effect on glucose metabolism was dependent on GABAergic signaling in the LHA and on intact hepatic vagal innervation. ConclusionsWe show that sNAc dopaminergic signaling modulates hepatic glucose metabolism through GABAergic inputs to glutamatergic LHA cells and hepatic vagal innervation. This demonstrates that striatal control of glucose metabolism involves a dopaminergic sNAc-LHA-liver axis and provides a potential explanation for the effects of dopamine agonists and antagonists on glucose metabolism.

Hepatic phosphate uptake and subsequent nerve-mediated phosphaturia are crucial for phosphate homeostasis following portal vein passage of phosphate in rats

Fibroblast growth factor 23, parathyroid hormone, and 1,25-dihydroxyvitamin D are critical in phosphate homeostasis. Despite these factors’ importance, regulators of phosphaturia in the acute postprandial phase remain largely unknown. This study investigated the mechanism of acute phosphate regulation in the postprandial phase in rats. Duodenal administration of radiolabeled phosphate (32P) showed that 32P levels in the inferior vena cava (IVC) blood were lower than those in the portal vein (PV) blood. Serum phosphate concentration transiently increased 5 min after phosphate solution administration through IVC, while it was maintained after the administration through PV. Phosphate administration through both IVC and PV resulted in increased fractional excretion of phosphate (FEPi) at 10 min without elevation of the known circulating factors, but urinary phosphate excretion during the period was 8% of the dose. Experiments using 32P or partial hepatectomy showed that the liver was one of the phosphate reservoirs. The elevation of FEPi and suppression of sodium-phosphate cotransporter 2a in the kidney at 10 min was attenuated in rats with SCH23390, hepatic denervation, or renal denervation, thus indicating that the liver communicated with the kidney via the nervous system to promote phosphaturia. These results revealed previously unknown mechanisms for serum phosphate maintenance.

Leptin increases hepatic triglyceride export via a vagal mechanism in humans

Recombinant human leptin (metreleptin) reduces hepatic lipid content in patients with lipodystrophy and overweight patients with non-alcoholic fatty liver disease and relative hypoleptinemia independent of its anorexic action. In rodents, leptin signaling in the brain increases very-low-density lipoprotein triglyceride (VLDL-TG) secretion and reduces hepatic lipid content via the vagus nerve. In this randomized, placebo-controlled crossover trial (EudraCT Nr. 2017-003014-22), we tested whether a comparable mechanism regulates hepatic lipid metabolism in humans. A single metreleptin injection stimulated hepatic VLDL-TG secretion (primary outcome) and reduced hepatic lipid content in fasted, lean men (n= 13, age range 20-38 years) but failed to do so in metabolically healthy liver transplant recipients (n= 9, age range 26-62 years) who represent a model for hepatic denervation. In an independent cohort of lean men (n= 10, age range 23-31 years), vagal stimulation by modified sham feeding replicated the effects of metreleptin on VLDL-TG secretion. Therefore, we propose that leptin has anti-steatotic properties that are independent of food intake by stimulating hepatic VLDL-TG export via a brain-vagus-liver axis.

Device-Based Sympathetic Nerve Regulation for Cardiovascular Diseases.

Sympathetic overactivation plays an important role in promoting a variety of pathophysiological processes in cardiovascular diseases (CVDs), including ventricular remodeling, vascular endothelial injury and atherosclerotic plaque progression. Device-based sympathetic nerve (SN) regulation offers a new therapeutic option for some CVDs. Renal denervation (RDN) is the most well-documented method of device-based SN regulation in clinical studies, and several large-scale randomized controlled trials have confirmed its value in patients with resistant hypertension, and some studies have also found RDN to be effective in the control of heart failure and arrhythmias. Pulmonary artery denervation (PADN) has been clinically shown to be effective in controlling pulmonary hypertension. Hepatic artery denervation (HADN) and splenic artery denervation (SADN) are relatively novel approaches that hold promise for a role in cardiovascular metabolic and inflammatory-immune related diseases, and their first-in-man studies are ongoing. In addition, baroreflex activation, spinal cord stimulation and other device-based therapies also show favorable outcomes. This review summarizes the pathophysiological rationale and the latest clinical evidence for device-based therapies for some CVDs.

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.

Combined renal and common hepatic artery denervation as a novel approach to reduce cardiometabolic risk: technical approach, feasibility and safety in a pre-clinical model

BackgroundCardiovascular and metabolic regulation is governed by neurohumoral signalling in relevant organs such as kidney, liver, pancreas, duodenum, adipose tissue, and skeletal muscle. Combined targeting of relevant neural outflows may provide a unique therapeutic opportunity for cardiometabolic disease.ObjectivesWe aimed to investigate the feasibility, safety, and performance of a novel device-based approach for multi-organ denervation in a swine model over 30 and 90 days of follow-up.MethodsFive Yorkshire cross pigs underwent combined percutaneous denervation in the renal arteries and the common hepatic artery (CHA) with the iRF Denervation System. Control animals (n = 3) were also studied. Specific energy doses were administered in the renal arteries and CHA. Blood was collected at 30 and 90 days. All animals had a pre-terminal procedure angiography. Tissue samples were collected for norepinephrine (NEPI) bioanalysis. Histopathological evaluation of collateral structures and tissues near the treatment sites was performed to assess treatment safety.ResultsAll animals entered and exited the study in good health. No stenosis or vessel abnormalities were present. No significant changes in serum chemistry occurred. NEPI concentrations were significantly reduced in the liver (− 88%, p = 0.005), kidneys (− 78%, p < 0.001), pancreas (− 78%, p = 0.018) and duodenum (− 95%, p = 0.028) following multi-organ denervation treatment compared to control animals. Histologic findings were consistent with favourable tissue responses at 90 days follow-up.ConclusionsSignificant and sustained denervation of the treated organs was achieved at 90 days without major safety events. Our findings demonstrate the feasibility of multi-organ denervation using a novel iRF Denervation System in a single procedure.

Light at Night Exposure Effects on Differentiation and Cell Cycle in the Rat Liver With Autonomic Nervous System Denervation.

Introduction: N Exposure to artificial light at night (LAN) affects human health and causes several functional modifications in the body. Obesity, diabetes, and hormonal changes are reported after exposure to LAN in humans. This study aims to highlight the critical features of biological terms that are affected in the liver of rats which received autonomic nervous system denervation. Methods: The liver gene expression profiles of 8 male Wistar rats that received sympathetic plus parasympathetic hepatic denervation and were exposed to LAN from Gene Expression Omnibus (GEO) for 1 hour were compared with 5 controls. The significant differentially-expressed genes (DEGs) were screened by the protein-protein interaction (PPI) network analysis STRING database (an application of Cytoscape software). Also, CuleGO and CleuDedia, the 2 applications of Cytoscape software, were used for more analysis. Results: Among 250 DEGs, 173 characterized genes with fold change more than 2 plus 100 added relevant genes were included in the PPI network. The analysis of the main connected component (MCC) led to introducing 15 hubs and 15 bottlenecks. CCT2, COPS7A, KAT2A, and ERCC1 were determined as hub-bottlenecks. Among hubs and bottlenecks, DHX15, KAT2A, CCT2, HSP90AB1, CCNE1, DHX16, LSM2, WEE1, CWC27, BAZ1B, RAB22A, DNM2, and DHX30 were linked to each other by various kinds of actions. CCT2 and KAT2A, the 2 hub-bottlenecks, were included in the interacted genes in the action map. Four classes of biological terms including negative regulation of non-motile cilium assembly, negative regulation of transforming growth factor beta activation, alpha-tubulin acetylation, and histamine-induced gastric acid secretion were identified as the critical biochemical pathways and biological processes. Conclusion: Several essential functions such as differentiation, cell cycle, ribosome assembly, and splicing are affected by LAN in rat livers with autonomic nervous system denervation.

Liver sympathetic denervation reverses obesity-induced hepatic steatosis.

Non-alcoholic fatty liver disease, characterized in part by elevated liver triglycerides (i.e. hepatic steatosis), is a growing health problem. In this study, we found that hepatic steatosis is associated with robust hepatic sympathetic overactivity. Removal of hepatic sympathetic nerves reduced obesity-induced hepatic steatosis. Liver sympathetic innervation modulated hepatic lipid acquisition pathways during obesity. Non-alcoholic fatty liver disease (NAFLD) affects 1 in 3 Americans and is a significant risk factor for typeII diabetes mellitus, insulin resistance and hepatic carcinoma. Characterized in part by excessive hepatic triglyceride accumulation (i.e. hepatic steatosis), the incidence of NAFLD is increasing - in line with the growing obesity epidemic. The role of the autonomic nervous system in NAFLD remains unclear. Here, we show that chronic hepatic sympathetic overactivity mediates hepatic steatosis. Direct multiunit recordings of hepatic sympathetic nerve activity were obtained in high fat diet and normal chow fed male C57BL/6J mice. To reduce hepatic sympathetic nerve activity we utilized two approaches including pharmacological ablation of the sympathetic nerves and phenol-based hepatic sympathetic nerve denervation. Diet-induced NAFLD was associated with a nearly doubled firing rate of the hepatic sympathetic nerves, which was largely due to an increase in efferent nerve traffic. Furthermore, established high fat diet-induced hepatic steatosis was effectively reduced with pharmacological or phenol-based removal of the hepatic sympathetic nerves, independent of changes in body weight, caloric intake or adiposity. Ablation of liver sympathetic nerves was also associated with improvements in liver triglyceride accumulation pathways including free fatty acid uptake and de novo lipogenesis. These findings highlight an unrecognized pathogenic link between liver sympathetic outflow and hepatic steatosis and suggest that manipulation of the liver sympathetic nerves may represent a novel therapeutic strategy for NAFLD.

Effects of Light-at-Night on the Rat Liver – A Role for the Autonomic Nervous System

Exposure to light at night (LAN) has been associated with serious pathologies, including obesity, diabetes and cancer. Recently we showed that 2 h of LAN impaired glucose tolerance in rats. Several studies have suggested that the autonomic nervous system (ANS) plays an important role in communicating these acute effects of LAN to the periphery. Here, we investigated the acute effects of LAN on the liver transcriptome of male Wistar rats. Expression levels of individual genes were not markedly affected by LAN, nevertheless pathway analysis revealed clustered changes in a number of endocrine pathways. Subsequently, we used selective hepatic denervations [sympathetic (Sx), parasympathetic (Px), total (Tx, i.e., Sx plus Px), sham] to investigate the involvement of the ANS in the effects observed. Surgical removal of the sympathetic or parasympathetic hepatic branches of the ANS resulted in many, but small changes in the liver transcriptome, including a pathway involved with circadian clock regulation, but it clearly separated the four denervation groups. On the other hand, analysis of the liver metabolome was not able to separate the denervation groups, and only 6 out of 78 metabolites were significantly up- or downregulated after denervations. Finally, removal of the sympathetic and parasympathetic hepatic nerves combined with LAN exposure clearly modulated the effects of LAN on the liver transcriptome, but left most endocrine pathways unaffected.Conclusion: One-hour light-at-night acutely affects the liver transcriptome. Part of this effect is mediated via the nervous innervation, as a hepatectomy modulated and reduced the effect of LAN on liver transcripts.

1801-P: Common Hepatic Artery Denervation Does Not Alter the Counterregulatory Response to Hypoglycemia in an Insulin Resistant Canine Model

With the recent interest in sympathetic modulation as a way to improve insulin sensitivity and insulin secretion, it is important to assess the safety of the procedure. Five dogs were fed a high fat high fructose diet for 5-week before undergoing a hyperinsulinemic hypoglycemic clamp (insulin infused IV at a rate of 1.5 mU/kg/min). Then the dogs underwent a common hepatic artery surgical denervation (CHAD n=5) and were studied 1, 2 and 3 months post-surgery with the same hypoglycemic challenge. At the end of the protocol, the norepinephrine content in the liver (7±3 ng/g) and pancreas (91±34 ng/g) were significantly lower than levels in the livers and pancreas of 4 sham denervated animals (460±100 and 590±93 ng/g respectively), indicating successful denervation. There were no significant differences in fasting insulin, glucose or glucagon concentrations over the 3 months (see Table). The insulin and glucose concentrations during the last 90 min of the hypoglycemic challenge prior to and post-CHAD were also not different. The peak in plasma glucagon and epinephrine levels occurred at 30 and 120 min respectively and were similar in magnitude pre- and post-CHAD. Four sham denervated animals had the same response to the insulin induced hypoglycemic challenge as CHAD dogs. In conclusion, the response to hypoglycemia was not affected by sympathetic denervation of the common hepatic artery. Disclosure G. Kraft: Consultant; Self; Metavention. L. Moore: None. B. Farmer: None. M.F. Scott: None. D.S. Edgerton: Speaker's Bureau; Self; Novo Nordisk A/S. P.E. Williams: None. B. Azamian: Employee; Self; Metavention. A.D. Cherrington: Board Member; Self; Biocon, Fractyl Laboratories, Inc., Metavention, Sensulin, LLC., vTv Therapeutics, Zafgen, Inc. Consultant; Self; Abvance, Boston Scientific Corporation, California Institute for Biomedical Research, Galvani Bioelectronics Limited, MedImmune, Novo Nordisk Inc., Thetis Pharmaceuticals LLC. Research Support; Self; Abvance, Diasome Pharmaceuticals, Inc., Novo Nordisk Inc. Stock/Shareholder; Self; Abvance, Biocon, Fractyl Laboratories, Inc., Metavention, Novo Nordisk Inc., Sensulin, LLC., Thetis Pharmaceuticals LLC, Zafgen, Inc. Funding Metavention, Inc.

A Subfornical Organ→Paraventricular Nucleus Neuronal Network Contributes to Non‐Alcoholic Fatty Liver Disease via Hepatic Sympathetic Outflow

Non‐alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, affects 1 in 3 adults and leads to an increased risk for metabolic and cardiovascular diseases. Our recent work indicates that obesity‐induced NAFLD is mediated by elevations in hepatic sympathetic nerve activity. However, the neural pathways that contribute to hepatic sympathetic overactivity and subsequent NAFLD development remain unknown. The subfornical organ (SFO) ‐ a forebrain circumventricular region that lies outside the blood brain barrier ‐ senses, integrates and responds to circulating stimuli. Anatomical and electrophysiological data support dense, excitatory projections from the SFO to the paraventricular nucleus of the hypothalamus (SFO→PVN), an integrative nucleus with direct hepatic spinal projections. Taken together, we hypothesized that an SFO→PVN excitatory neuronal network causes hepatic steatosis via elevations in liver sympathetic outflow. An intersectional viral strategy was used in which a retrograde transported canine adenovirus was targeted to the PVN to express Cre‐recombinase in SFO→PVN neurons (CAV2‐Cre‐GFP). This was combined with SFO‐targeted delivery of a Cre‐inducible designer receptors engineered against designer drugs (DREADDs) excitatory construct (AAV2‐DIO‐hM3Gq‐mCherry). With this approach, the pharmacological ligand clozapine‐N‐oxide (CNO; 3 mg/kg i.p.) was administered once daily over 6 days to activate SFO→PVN neurons (n=4). Short‐term activation of SFO→PVN neurons resulted in hepatic steatosis (2.6±0.02 vs 2.9±0.02 density*107, saline vs CNO, p&lt;0.05) that was paralleled by an elevation in liver tyrosine hydroxylase protein (1.8±0.4 CNO fold saline, p&lt;0.05), the rate‐limiting enzyme for catecholamine synthesis within postganglionic nerve terminals. Based on this, we combined the above viral strategy with selective hepatic denervation (phenol application) or sham surgery (n=5–6). Oil Red O staining (Figure 1) demonstrated that hepatic denervation prevented liver lipid accumulation in response to 6‐day activation of SFO→PVN neurons (1.9±0.01 vs 1.7±0.01 density*107, CNO sham vs CNO denervation, p&lt;0.05). Importantly, this occurred independent of changes in body weight and food intake. Hepatic denervation was confirmed by a reduction in liver tyrosine hydroxlase protein expression (0.3±0.1 vs 1.8±0.3 vs 0.4±0.1 fold saline sham, CNO sham vs saline denervation vs CNO denervation, all p&lt;0.05). Lastly, male C57Bl/6 mice that were fed a high fat diet (10 wks) underwent intersectional viral targeting for expression of an inhibitory DREADDs construct (AAV2‐DIO‐hM4Gi‐mCherry) in SFO→PVN neurons. Remarkably, acute inhibition of SFO→PVN neurons in obese mice resulted in an approximate 45% reduction in hepatic steatosis (Figure 2, n=4/group). Collectively, these findings indicate that activation of SFO→PVN neurons causes liver triglyceride deposition via elevations in hepatic sympathetic outflow. Furthermore, in the context of obesity, inhibition of this forebrain‐hypothalamic‐autonomic circuit results in a marked reduction in NAFLD.Support or Funding InformationR01DK117007This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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

Impaired hepatic counterregulatory response to insulin-induced hypoglycemia in hepatic denervated pigs

ObjectiveThe liver reacts to hypoglycemia by increasing its glucose output. This response is assumed to depend both on glucose sensing at the liver and the brain, as well as efferent impulses from the brain to the liver. We tested the importance of this signaling pathway by studying the hepatic response to insulin-induced hypoglycemia in hepatic complete denervated pigs. Materials/methodsTwo weeks prior to the metabolic study, 36-kg pigs underwent either total hepatic denervation (DN; n = 12) or sham operation (sham; n = 12). On the metabolic study day, measurements were performed at baseline conditions and during a hypoglycemic hyperinsulinemic (5 mU/kg/min) clamp. Endogenous insulin and glucagon secretions were inhibited by somatostatin, and glucagon was replaced at baseline levels. Endogenous glucose production (EGP) and glucose utilization (Rd) were determined by [3-3H] glucose infusion. ResultsBaseline plasma concentrations of glucose, insulin, EGP and Rd did not differ significantly between the two groups of animals. During insulin infusion, the plasma glucose concentration was clamped at ~3 mmol/L in both groups of animals resulting in an increase in plasma concentrations of epinephrine and norepinephrine in sham pigs (both P < 0.05), while this effect was abolished in DN pigs. While insulin action (P = 0.09) and glucose utilization (P = 0.44) were similar, EGP was markedly decreased in the DN pigs (P < 0.05). ConclusionThe findings indicate a blunted hepatic counterregulatory response to hypoglycemia following complete hepatic denervation. This implies that intact neural impulses to and from the liver are necessary to maintain the increase in EGP that protects the organism against hypoglycemia.

Postprandial insulin action relies on meal composition and hepatic parasympathetics: dependency on glucose and amino acids: Meal, parasympathetics & insulin action

Insulin sensitivity (IS) increases following a meal. Meal composition affects postprandial glucose disposal but still remains unclear which nutrients and mechanisms are involved. We hypothesized that gut-absorbed glucose and amino acids stimulate hepatic parasympathetic nerves, potentiating insulin action.Male Sprague–Dawley rats were 24 h fasted and anesthetized. Two series of experiments were performed. (A) IS was assessed before and after liquid test meal administration (10 ml.kg−1, intraenteric): glucose + amino acids + lipids (GAL, n=6); glucose (n=5); amino acids (n=5); lipids (n=3); glucose + amino acids (GA, n=9); amino acids + lipids (n=3); and glucose + lipids (n=4). (B) Separately, fasted animals were submitted to hepatic parasympathetic denervation (DEN); IS was assessed before and after GAL (n=4) or GA administration (n=4).(A) Both GAL and GA induced significant insulin sensitization. GAL increased IS from 97.9±6.2 mg glucose/kg bw (fasting) to 225.4±18.3 mg glucose/kg bw (P<0.001; 143.6±26.0% potentiation of IS); GA increased IS from 109.0±6.6 to 240.4±18.0 mg glucose/kg bw (P<0.001; 123.1±13.4% potentiation). None of the other meals potentiated IS. (B) GAL and GA did not induce a significant insulin sensitization in DEN animal.To achieve maximal insulin sensitization following a meal, it is required that gut-absorbed glucose and amino acids trigger a vagal reflex that involves hepatic parasympathetic nerves.

The autonomic nervous system regulates postprandial hepatic lipid metabolism

The liver is a key organ in controlling glucose and lipid metabolism during feeding and fasting. In addition to hormones and nutrients, inputs from the autonomic nervous system are also involved in fine-tuning hepatic metabolic regulation. Previously, we have shown in rats that during fasting an intact sympathetic innervation of the liver is essential to maintain the secretion of triglycerides by the liver. In the current study, we hypothesized that in the postprandial condition the parasympathetic input to the liver inhibits hepatic VLDL-TG secretion. To test our hypothesis, we determined the effect of selective surgical hepatic denervations on triglyceride metabolism after a meal in male Wistar rats. We report that postprandial plasma triglyceride concentrations were significantly elevated in parasympathetically denervated rats compared with control rats (P = 0.008), and VLDL-TG production tended to be increased (P = 0.066). Sympathetically denervated rats also showed a small rise in postprandial triglyceride concentrations (P = 0.045). On the other hand, in rats fed on a six-meals-a-day schedule for several weeks, a parasympathetic denervation resulted in >70% higher plasma triglycerides during the day (P = 0.001), whereas a sympathetic denervation had no effect. Our results show that abolishing the parasympathetic input to the liver results in increased plasma triglyceride levels during postprandial conditions.

Intrahypothalamic Estradiol Regulates Glucose Metabolism via the Sympathetic Nervous System in Female Rats

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.

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

The Impact of Hepatic Denervation on the Accumulation of Hepatic Progenitor Cells during Liver Regeneration in Rats

All autonomic hepatic nerves are transected following liver transplantation. Recent studies have shown the relationship between an inhibition of autonomic nerves and the accumulation of hepatic progenitor cells (HPC). This study aims to elucidate the influence of hepatic denervation on the accumulation of HPC in the process of liver regeneration. Male Sprague-Dawley rats underwent hepatic denervation. Immediately after either denervation (DN group, n=30) or a sham operation (control group, n=30), a two-thirds hepatectomy was performed, and these were sacrificed chronologically. An immunohistochemical analysis of HPC was performed with a mouse monoclonal OV6 type antibody. The liver per body weight ratio gradually increased in both groups. On postoperative day (POD) 7, the DN group showed a significantly higher ratio. The HPC expression gradually increased in both groups. The maximal HPC number was observed on POD 7 in the DN group and on POD 3 in the control group. Although there was no significant difference in the HPC numbers between the DN and control group until POD 3, the number of HPC were significantly higher in livers of the denervated rats than in those of the sham operated rats between POD 5 and 14. The hepatic autonomic nerves were thus suggested to play an important role in the accumulation of HPC during liver regeneration in rats.

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.

Impaired hepatic function and central dopaminergic denervation in a rodent model of Parkinson's disease: A self-perpetuating crosstalk?

In Parkinson's disease (PD), aside from the central lesion, involvement of visceral organs has been proposed as part of the complex clinical picture of the disease. The issue is still poorly understood and relatively unexplored. In this study we used a classic rodent model of nigrostriatal degeneration, induced by the intrastriatal injection of 6-hydroxydopamine (6-OHDA), to investigate whether and how a PD-like central dopaminergic denervation may influence hepatic functions. Rats received an intrastriatal injection of 6-OHDA or saline (sham), and blood, cerebrospinal fluid, liver and brain samples were obtained for up to 8 weeks after surgery. Specimens were analyzed for changes in cytokine and thyroid hormone levels, as well as liver mitochondrial alterations. Hepatic mitochondria isolated from animals bearing extended nigrostriatal lesion displayed increased ROS production, while membrane potential (ΔΨ) and ATP production were significantly decreased. Reduced ATP production correlated with nigral neuronal loss. Thyroid hormone levels were significantly increased in serum of PD rats compared to sham animals while steady expression of selected cytokines was detected in all groups. Hepatic enzyme functions were comparable in all animals. Our study indicates for the first time that in a rodent model of PD, hepatic mitochondria dysfunctions arise as a consequence of nigrostriatal degeneration, and that thyroid hormone represents a key interface in this CNS-liver interaction. Liver plays a fundamental detoxifying function and a better understanding of PD-related hepatic mitochondrial alterations, which might further promote neurodegeneration, may represent an important step for the development of novel therapeutic strategies.