Increased Activities of Glycogenolytic Enzymes in Liver after Splanchnic-Nerve Stimulation

Shimazu, Takashi; Fukuda, Aoi

doi:10.1126/science.150.3703.1607

Cited by 125 publications

(50 citation statements)

References 4 publications

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“…We demonstrated that HFD mice are able to increase quickly fasted glycemia (Fig. 7A, B) on apelin treatment; this corresponds to the activation of glycogenolysis but not gluconeogenesis (45)(46)(47)(48). In accordance to glycemia, hepatic glycogenolysis was activated by icv apelin and blocked when icv trolox was co-injected ( Fig.…”

Section: Central Apelin Stimulates Glycogenolysis But Not Gluconeogenmentioning

confidence: 68%

Hypothalamic Apelin/Reactive Oxygen Species Signaling Controls Hepatic Glucose Metabolism in the Onset of Diabetes

Drougard

Duparc

Brénachot

et al. 2014

Antioxidants & Redox Signaling

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Aims: We have previously demonstrated that central apelin is implicated in the control of peripheral glycemia, and its action depends on nutritional (fast versus fed) and physiological (normal versus diabetic) states. An intracerebroventricular (icv) injection of a high dose of apelin, similar to that observed in obese/diabetic mice, increase fasted glycemia, suggesting (i) that apelin contributes to the establishment of a diabetic state, and (ii) the existence of a hypothalamic to liver axis. Using pharmacological, genetic, and nutritional approaches, we aim at unraveling this system of regulation by identifying the hypothalamic molecular actors that trigger the apelin effect on liver glucose metabolism and glycemia. Results: We show that icv apelin injection stimulates liver glycogenolysis and gluconeogenesis via an over-activation of the sympathetic nervous system (SNS), leading to fasted hyperglycemia. The effect of central apelin on liver function is dependent of an increased production of hypothalamic reactive oxygen species (ROS). These data are strengthened by experiments using lentiviral vectormediated over-expression of apelin in hypothalamus of mice that present over-activation of SNS associated to an increase in hepatic glucose production. Finally, we report that mice fed a high-fat diet present major alterations of hypothalamic apelin/ROS signaling, leading to activation of glycogenolysis. Innovation/Conclusion: These data bring compelling evidence that hypothalamic apelin is one master switch that participates in the onset of diabetes by directly acting on liver function. Our data support the idea that hypothalamic apelin is a new potential therapeutic target to treat diabetes. Antioxid. Redox Signal. 20, 557-573.

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Section: Central Apelin Stimulates Glycogenolysis But Not Gluconeogenmentioning

confidence: 68%

Hypothalamic Apelin/Reactive Oxygen Species Signaling Controls Hepatic Glucose Metabolism in the Onset of Diabetes

Drougard

Duparc

Brénachot

et al. 2014

Antioxidants & Redox Signaling

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“…Thus, by cooling the vagus nerve, we created a situation that reproduced a feeding signal, which has been shown to decrease efferent sympathetic outflow (17). To the extent that basal sympathetic tone is important to glucose production by the liver, this would decrease glycogen phosphorylase activity, glycogenolysis, and eventually glucose production (20). The fact that acutely interrupting vagal transmission decreased hepatic glucose production is in contrast to other studies that have shown that hepatic vagotomy does not change basal hepatic glucose production (24).…”

Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated, for example, that electrical stimulation of the vagus nerves induces activation of the liver enzyme glycogen synthase, which in turn increases glycogen synthesis and reduces glucose output (19). Conversely, electrical stimulation of the splanchnic nerve induces activation of the liver enzyme glycogen phosphorylase, which in turn increases glycogenolysis and glucose output (20). Taken together, these data have been interpreted to suggest that activation of the parasympathetic nervous system promotes glucose uptake and hepatic glycogen deposition while activation of the sympathetic nervous system promotes glycogenolysis and glucose output.…”

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confidence: 99%

Involvement of the vagus nerves in the regulation of basal hepatic glucose production in conscious dogs

Cardin

Walmsley

Neal

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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. Involvement of the vagus nerves in the regulation of basal hepatic glucose production in conscious dogs. Am J Physiol Endocrinol Metab 283: E958-E964, 2002; 10.1152/ajpendo.00566. 2001.-We determined if blocking transmission in the fibers of the vagus nerves would affect basal hepatic glucose metabolism in the 18-h-fasted conscious dog. A pancreatic clamp (somatostatin, basal portal insulin, and glucagon) was employed. A 40-min control period was followed by a 90-min test period. In one group, stainless steel cooling coils (Sham, n ϭ 5) were perfused with a 37°C solution, while in the other (Cool, n ϭ 6), the coils were perfused with Ϫ20°C solution. Vagal blockade was verified by heart rate change (80 Ϯ 9 to 84 Ϯ 14 beats/min in Sham; 98 Ϯ 12 to 193 Ϯ 22 beats/min in Cool). The arterial glucose level was kept euglycemic by glucose infusion. No change in tracer-determined glucose production occurred in Sham, whereas in Cool it dropped significantly (2.4 Ϯ 0.4 to 1.9 Ϯ 0.4 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Net hepatic glucose output did not change in Sham but decreased from 1.9 Ϯ 0.3 to 1.3 Ϯ 0.3 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 in the Cool group. Hepatic gluconeogenesis did not change in either group. These data suggest that vagal blockade acutely modulates hepatic glucose production by inhibiting glycogenolysis. vagal cooling; liver nerves; parasympathetic blockade; gluconeogenesis; glycogenolysis THE AUTONOMIC NERVOUS SYSTEM is involved in the regulation of hepatic glucose metabolism. It has been demonstrated, for example, that electrical stimulation of the vagus nerves induces activation of the liver enzyme glycogen synthase, which in turn increases glycogen synthesis and reduces glucose output (19). Conversely, electrical stimulation of the splanchnic nerve induces activation of the liver enzyme glycogen phosphorylase, which in turn increases glycogenolysis and glucose output (20). Taken together, these data have been interpreted to suggest that activation of the parasympathetic nervous system promotes glucose uptake and hepatic glycogen deposition while activation of the sympathetic nervous system promotes glycogenolysis and glucose output.It is also known that glucosensors within the hepatoportal region have the ability to sense glucose and inform the brain of its concentration via afferent fibers traveling, at least in part, along the hepatic vagus nerves (16). It has been hypothesized that the brain uses this information to minimize fluctuations in the plasma glucose level after feeding (18). The efferent responses of this feedback loop involve the pancreas, adrenal glands, adipocytes, skeletal muscles, and the liver (2). Although it is known that the autonomic nervous system is vital to the regulation of glucose metabolism in times of stress, evidence is accumulating to support a role for it in the postprandial state. Nevertheless, its role in regulating hepatic glucose metabolism after an overnight fast is not clear.Our aim, therefore, was to cool the vagus nerves, in the presence of a pancreatic clamp, to study the involve...

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“…Electrical stimulation of the peripheral end of the splanchnic nerve innervating the' liver causes prompt activation ofglycogen phosphorylase and promotes glycogenolysis in the liver (Shimazu & Fukuda, 1965;Shimazu & Amakawa, 1968 a), which in turn rapidly supplies the blood with glucose (Edwards & Silver, 1970; Edwards, 1972 a, b). This effect of splanchnic nerve stimulation on phosphorylase activation and glucose output from the liver is not mediated by adrenomedullary catecholamines or pancreatic glucagon, but depends on the integrity of the hepatic sympathetic innervation.…”

Section: Introductionmentioning

confidence: 99%

Further studies on the mechanism of phosphorylase activation in rabbit liver in response to splanchnic nerve stimulation

Shimazu

Usami

1982

The Journal of Physiology

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SUMMARY1. The mechanism of activation of liver phosphorylase after splanchnic nerve stimulation has been investigated in rabbits and compared with the effects of intraportal injections of noradrenaline.2. The increase in the activity of liver phosphorylase-a, the active form of this key glycogenolytic enzyme, in response to injections of noradrenaline was blocked by ,f-adrenergic antagonists, but not by a-adrenergic antagonists, suggesting that the effect of noradrenaline is mediated mainly through f-adrenoceptors in vivo. In contrast, the increase in phosphorylase activity in response to stimulation of the peripheral end of the splanchnic nerve was resistant to both a-and f-adrenoceptor blockade.3. When diltiazem and verapamil, selective Ca2+ antagonists that restrict calcium influx across the cell membrane, were infused intraportally, the phosphorylase response to splanchnic nerve stimulation was virtually abolished, while the response to noradrenaline was unaltered.4. Infusion of the prostaglandin-synthesis inhibitor indomethacin at a dose of 3-4 ,sg/min was found to block the activation of liver phosphorylase in response to stimulation of the splanchnic innervation. 5. These results suggest that the mechanism whereby stimulation ofthe sympathetic innervation to the liver leads to activation of phosphorylase is not mediated by either a-or 8f-adrenoceptors, but appears to depend upon prostaglandin formation and influx of Ca2+ ions into the hepatocytes.

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Increased Activities of Glycogenolytic Enzymes in Liver after Splanchnic-Nerve Stimulation

Cited by 125 publications

References 4 publications

Hypothalamic Apelin/Reactive Oxygen Species Signaling Controls Hepatic Glucose Metabolism in the Onset of Diabetes

Hypothalamic Apelin/Reactive Oxygen Species Signaling Controls Hepatic Glucose Metabolism in the Onset of Diabetes

Involvement of the vagus nerves in the regulation of basal hepatic glucose production in conscious dogs

Further studies on the mechanism of phosphorylase activation in rabbit liver in response to splanchnic nerve stimulation

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