Central nervous system regulation of liver and adipose tissue metabolism

Abstract

Hypothalamic and autonomic nervous regulation of carbohydrate and amino acid metabolism in the liver and of lipid metabolism in adipose tissues is described. The direct neural mechanism underlying this regulation has been evaluated. Electrical stimulation of the ventromedial hypothalamic nucleus (VMH)-splanchnic nerve system causes glycogenolysis in the liver by rapid activation of glycogen phosphorylase, whereas electrical stimulation of the lateral hypothalamic nucleus (LH)-vagus nerve system promotes glycogenesis in the liver by activation of glycogen synthetase, through direct neural and neural-hormonal mechanisms. Studies on chemical coding of the hypothalamic neurones have revealed that norepinephrine-sensitive neurones in the VMH and acetylcholine-sensitive neurones in the LH are specifically involved in the regulation of liver phosphorylase and glycogen synthetase, respectively. Acetylcholine-sensitive neurones of the LH were also found to be concerned in regulation of hepatic tyrosine and aminotransferase activity, through intermediation of the cholinergic system in the LH-vagal pathway. Finally, it has been shown that the VMH acts as a regulatory centre for lipolysis in adipose tissues by modulating activation of the sympathetic nervous system. In addition, stimulation of the VMH enhanced lipogenesis in brown adipose tissue preferentially, probably through a mechanism mediated by sympathetic innervation of this tissue. The latter finding suggests that both the breakdown and resynthesis of triglycerides in brown adipose tissue, but not in white adipose tissue, are accelerated by stimulation of the VMH.

Increased responsiveness to the hyperglycemic, hyperglucagonemic and hyperinsulinemic effects of circulating norepinephrine in ob/ob mice

“…This observation together with the present ®ndings suggest that hyperglucagonemia of obaob mice may be a function more of a-cell secretory regulation (in part by the SNS) than a-cell morphology or glucagon content. The resultant increase in NE stimulated glucagon secretion of obaob mice may support increased hepatic glucose output as previously described 18,19 and evidenced by the yohimbine and BCaSKF glucose responses demonstrated herein. Once again, this indirect effect of glucagon via increased HGO and blood glucose level may contribute to the hyperinsulinemic response to NE infusion in obaob mice.…”

“…30,31 In all, the results of this study implicate a role for peripheral noradrenergic activities in the hyperglycemic, hyperglucagonemic and hyperinsulinemic state of obaob mice. It should be noted that, although hypothalamic NE activities increase peripheral SNS functions, including a rise in circulating NE levels, 18,19,27 the exogenous NE infusion in this study may be expected to exert its effects primarily on peripheral tissues inasmuch as monoamines poorly traverse the blood ± brain barrier. 41 Increases in circulating norepinephrine increase HGO directly by stimulating liver glycogenolysis and gluconeogenesis and indirectly by stimulating Hypersensitivity to circulating norepinephrine in obaob mice Y Liang and AH Cincotta glucagon secretion (primarily via a 2 receptors) from pancreatic islet a cells.…”

“…10,11 However, NE stimulation of the VMH also stimulates increases in plasma glucose, insulin and glucagon via activation of the peripheral SNS. 18,19,27 Secondly, the hypersensitivity to intravenous NE observed in obaob mice may be the result of classic counter-regulatory over-compensation to low circulating endogenous NE levels (ie, increased target tissue noradrenergic receptor number andaor af®nity). However, available evidence does not indicate reduced peripheral norepinephrine turnover in obaob vs lean mice.…”

“…A large body of available evidence indicates that this hypersensitivity to NE in obaob mice is not due to counter-regulatory compensation of low endogenous NE levels but rather to alterations in hypothalamic systems resulting in potentiation of noradrenergic functions in liver and islet a-cells. 8,9,13,18,19,27,28 The consequent hyperglucagonemia coupled with increased b-cell insulin secretory responsiveness to glucagon in these animals in turn facilitates increased islet b-cell secretion of insulin and hyperinsulinemia. The systemic NE-induced increases in blood glucose may also contribute to its hyperinsulinemic effect in these obaob mice.…”

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

“…The mechanism by which splanchnic nerve stimulation causes rapid activation of hepatic phosphorylase was shown not to involve fl-receptor-mediated increase in cyclic AMP and subsequent activation of protein kinase and phosphorylase kinase, but Ca2+-mediated stimulation of phosphorylase kinase and presumably also inhibition of phosphorylase phosphatase that counteracts the activation of phosphorylase by phosphorylase kinase (Shimazu & Amakawa, 1968b. Thus, these phenomena seem to be typical examples of metabolic responses subject to direct neural control (Shimazu, 1979(Shimazu, , 1981.…”