Epinephrine and nor epinephrine are involved in the control of several important functions of the central nervous system (CNS), including sleep, arousal, mood, as well as appetite.  The effect of these catecholamines are mediated through adrenergic receptors which are members of the G-protein-coupled receptor superfamily of membrane proteins. At least five different adrenoceptor subtypes (_{1, 2}, ß₁, ß_2, and ß₃) have been described. J Pharmacol Exp Ther 298,403-410  Alpha adrenergic receptors (α1, α2) and β receptors  mediate the actions of the catecholamines in the brain. Adrenergic receptors in the CNS are hence being targeted for the treatment of depression, hypertension and obesity. β3 adrenergic receptors in brown adipose tissue mediate the thermogenic effects of that tissue.

ANS and Glucose metabolism

The liver is  innervated by the sympathetic and parasympathetic fibres via the splanchnic nerves. Parasympathetic stimulation in animals reduces glycogenolysis while enhancing glycogen synthesis, thus decreasing hepatic glucose output. Sympathetic stimulation on the other hand increases both glycogenolysis and gluconeogenesis in the liver. Catecholamines (epinephrine and nor epinephrine)  liberated through stimulation of the autonomic nervous system effects these metabolic changes which over time may have  effects on net body composition.  

Catecholamines stimulate glucose uptake in adipose tissue. Endocrinology. 1980 Mar;106(3):786-90.  Norepinephrine released from sympathetic nerves may increase glucose uptake in skeletal muscle and adipose tissues independent of insulin.  Diabetologia. 2000 May;43(5):533-49.    Chronic Norepinephrine infusion has been shown to  stimulate glucose uptake in white and brown adipose tissue independently of insulin. Am J Physiol. 1994 Mar;266(3 Pt 2):R914-20  On the other hand, Epinephrine increases hepatic glucose output while inhibiting insulin secretion,  J Clin Invest. 1967 Jan;46(1):86-94.;   Diabetes. 1982 Sep;31(9):802-7   and the glucose uptake by tissues induced by insulin. Stimulation of the sympathetic nerve fibres inhibits insulin secretion,  J Physiol. 1975 Dec;253(1):157-73.   while phentolamine an adrenergic antagonist reverses this effect. Am J Physiol. 1990 Jan;258(1 Pt 1):E220-7 .  Parasympathetic stimulation by parasympathomimetic agents stimulates insulin release, an effect that is blocked by the parasympatholytic, atropine.

Glucose entry into isolated human adipocytes has been shown to be under ß-adrenergic control, although ₁-adrenergic receptors are also increasingly recognised to mediate the glucose uptake in rats  J Pharmacol Exp Ther1998  286,607-610     and humans.  Obes Res 2002 10,555-558    Obes. Res 2004; 12(4): 612 - 620.     Stimulation of glucose transport into adipocytes occurs at low concentrations of glucose while inhibition of glucose transport is effected at high concentrations. 

   ANS and Obesity

Catecholamines increase thermogenesis and lipolysis, leading to increased energy expenditure, thus reducing  fat stores. These effects are thought to be mediated by β3 adrenergic receptors. Β3-adrenergic receptors are almost exclusively expressed in brown and white adipose tissues.  Cell Signal. 1995 Jan;7(1):9-15. Administration of β3 adrenoceptor agonist corrects obesity and hyperglycaemia  in diabetic rodents. An increase in the thermogenic activity of brown adipose tissue is thought to be responsible for this anti obesity action. Diabetes. 1997 Aug;46(8):1257-63  Human adipocytes express predominantly α adrenergic receptors which under catecholamine stimulation suppresses lipolysis, facilitating fat storage. Since β3 receptors are less florid in adult adipose tissue (due  to lower amounts of brown adipose tissue), the alpha adrenergic effect predominates with facilitation of obesity. In this context, the low amounts of brown adipose tissue in the adult human makes β3 agonists less likely to work as anti obesity agents. Yet, it has been shown that brown adipose tissue can be induced to increase in size with chronic β3 stimulation, as occurs in patients with phaeochromocytoma. Hence chronic β3 adrenergic stimulation may find a place in obesity treatment. Initial studies in humans with β3 adrenergic agonists have not shown encouraging results despite demonstration of a shift in respiratory quotient (increased lipid oxidation). Diabetes. 1998 Oct;47(10):1555-61.

A dysregulation of the autonomic system in obesity has been suggested by various observations.  Rats fed high fat diet show increased glucose induced insulin secretion but worsening glucose intolerance along with a decreased sympathetic tone, abnormalities which are corrected by treatment with alpha adrenergic agonists. Am J Physiol Endocrinol Metab. 2005 Jan;288(1):E148-54    Basal pancreatic norepinephrine levels were significantly higher in rats fed on high fat diet. Obesity resistant Lou/C rats show higher catecholaminergic activity in the white adipose tissue and interscapular brown adipose tissue and lower activity in the liver and adrenal gland  with low noradrenergic activity in the ventromedial nucleus of the hypothalamus. Auton Neurosci. 2003 Nov 28;109(1-2):1-9. 

 Obese women seem to have higher sympathetic nervous system activity than lean controls.  Metabolism. 2003 Nov;52(11):1426-32.   Visceral adipose tissue has been shown to positively correlate with sympathetic/parasympathetic ratio. Obes Res. 2005 Apr;13(4):717-28   Alterations in sympathetic outflow to the pancreas, liver, adrenal medulla and adipose tissue could potentially modulate glucose and fat metabolism. Leptin has been shown to  influence the central nervous system to increase sympathetic outflow independent of its effect on feeding, and could  effect changes in glucose and fat metabolism at least partly via the autonomic nervous system.

11 β HSD 1 (11 β-hydroxysteroid dehydrogenase) facilitates the regeneration of active cortisol and corticosterone (11 hydroxy glucocorticoids) from their  inactive 11-keto forms namely cortisone and 11 dehydrocorticosterone  Endocrinology. 2001 Apr;142(4):1371-6.  by its oxidoreductase (11 β reductase) action.    While down-regulation of 11 β-HSD1 activity induces lipolysis, up-regulation of 11β-HSD-1 expression and activity enhances lipolysis. Regulation of Β HSD1 activity in the hypothalamus by the sympathetic system could well be involved in obesity induction. In patients with hypothalamic obesity, increased Β HSD1 activity has been demonstrated by increased urinary 11-OH/11-oxo ratios, which correlated with visceral  to subcutaneous adipose tissue ratio.  Horm Metab Res. 2004 Jun;36(6):365-9.  Β adrenergic stimulation by sympathetic activity may be responsible for this up-regulation of 11 β HSD activity, and might provide yet another target  to be modulated in obesity therapy.

Catecholamines can decrease insulin sensitivity through interference with insulin signalling and insulin receptor substrates, Biol Chem. 1999 Dec 3;274(49):34795-802,   a mechanism exemplified in patients with phaeochromocytomas, J Clin Endocrinol Metab. 2003 Aug;88(8):3632-6.   resulting in hyperinsulinaemia. Hyperinsulinaemia is thought to contribute to production and perpetuation of the metabolic syndrome which encompasses obesity. Increased insulin levels (possibly evoked by autonomic nervous stimulation) could produce further activation of the sympathetic system. Clin Exp Hypertens. 1995 Jan-Feb;17(1-2):39-50.   Hyperinsulinaemic euglycaemic clamps have demonstrated an activation of the sympathetic system, Metabolism. 2005 Mar;54(3):391-6.   with concomitant increased catecholamine levels  Exp Clin Endocrinol Diabetes. 2000;108(8):498-505   and hence a chronic hyperinsulinaemia can be postulated to produce sympathetic system-mediated effects on obesity.

Dysregulation of the autonomic system in the obese could contribute to the "essential" hypertension in obesity, partly through an effect on volume expansion due to sympathetic nervous system stimulation,  Curr Pharm Des. 2004;10(29):3621-37.    and partly through an increase in arterial wall rigidity. Arch Mal Coeur Vaiss. 2004 Jul-Aug;97(7-8):749-52    Angiotensin II, a potential adipokine,  can alter the blood flow to the adipose tissue through its action on sympathetic nervous system and by direct effects on the stromal vascular cells in the adipose tissue, thus regulating adipose tissue function to a degree. Angiotensin II has an effect both on the central nervous system enhancing sympathetic outflow, and on the peripheral sympathetic nerves.  Curr Hypertens Rep. 2001 Sep;3 Suppl 1:S3-9.   Stimulation of the alpha 2 adrenergic system by Angiotensin II may contribute to it's anti-lipolytic (and hence pro-lipogenic) action. J Neural Transm. 1999;106(7-8):631-44.  

Exercise increases parasympathetic tone. While obesity is thought to facilitate sympathetic predominance over parasympathetic activity with resultant unfavourable cardiovascular responses, weight loss has been shown to reverse this profile. J Endocrinol Invest. 2003 Feb;26(2):138-42.

Overfeeding of rats results in increase in both sympathetic and parasympathetic tone, with decreased norepinephrine responses to exercise. Cardiovasc Drugs Ther. 1996 Jun;10 Suppl 1:263-73.

 Significantly increased norepinephrine levels have been found in the subcutaneous abdominal adipose tissue levels in patients with anorexia nervosa compared to control subjects reflecting  increased sympathetic nervous system activity locally. Physiol Res. 2004;53(4):409-13  Carbohydrate meals tend to produce greater thermogenesis compared to fat rich meals in both the obese and lean although this was not associated with changes in heart rate variability, suggesting that sympathetic system activation may not influence the thermic effect of the food in either lean or obese. Metabolism. 2003 Nov;52(11):1426-32. 

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