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2002; Volume 12(5) from Clinical Autonomic Research                                           
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Obesity: An Autonomic Dysfunction?
    Obesity, a disorder reaching epidemic proportions, is the result of dietary intake that exceeds energy expenditure. There is a complex relationship between the sympathetic nervous system and obesity, with interactions in the central nervous system and peripheral tissues (for review see Esler et al, Am J Hyperten 2001;14:304S-309S).  The following are recent publications that highlight the complexities of this interaction.
    Increase in dietary intake triggers compensatory mechanisms that signal the brain to reduce appetite and peripheral organs to increase energy expenditure (“diet-induced thermogenesis”), presumably by activation of $-adrenoreceptors.  Of particular interest has been the role of $3-adrenoreceptors may play in obesity. However, gene knock-out mice lacking $3-adrenoreceptors do not develop significant obesity.  Because other receptor subtypes may compensate when the function of one is eliminated, Bachman et al. cross-breed mice to lack all three $-adrenoreceptor subtypes (“$-less mice”).  On a regular diet, $-less mice had a reduced metabolic rate and were slightly obese.  On a high-fat diet, $-less mice developed massive obesity that was entirely due to absence of diet-induced thermogenesis.  These findings indicate that the sympathetic nervous system, acting through $-adrenoreceptors, is essential for diet-induced thermogenesis, and that this pathway plays a critical role in the body’s defense against obesity induced by excess intake. 
    Catecholamines act on fat cells to promote lipolysis, resulting in the release of free-fatty acids (nonesterified fatty acids, NEFA) and glycerol.  The in vivo importance of this effect in humans is not completely understood.  Patel et al., hypothesized that sympathetic activity to fat tissue is increased during fasting, and may explain the increase in lipolysis seen in that state.  They infused tritiated norepinephrine systemically, while sampling venous effluent draining abdominal subcutaneous tissue, before and after a 72 hour fast.  Fasting did not alter total body or forearm norepinephrine spillover, but increased abdominal subcutaneous spillover.  Thus, the body may adapt to starvation in part by selectively increasing sympathetic activity to adipose tissue, which results in mobilization of energy from adipose stores.  It would be of interest to determine if this mechanism differs between lean and obese individuals.
    Leptin has received much attention as a peptide regulating appetite.  Corticotropin-releasing hormone (CRH) is another peptide that acts in the hypothalamus to reduce appetite and, by inducing sympathetic activation, increase energy expenditure.  Urocortin (UCN), a neuropeptide closely related to CRH (45% sequence identity) which acts on CRH receptors, also acts in the hypothalamus to decrease appetite.  De Fanti and Martinez examined if central UCN also increases energy expenditure.  Intracerebroventrical injection of UCN in male Wistar rats significantly increased whole body oxygen consumption.  It also increased core temperature, an effect that was prevented once autonomic function was eliminated by the ganglionic blocker chlorisondamine.  These studies suggest that UCN acts centrally to activate sympathetic tone, resulting in an increase in energy expenditure.  It should be noted that different investigators found opposite results in mice, suggesting possible species differences.  Which animal model replicates human physiology remains to be determined.
            Bachman ES, Dhillon H, Zhang C-Y, et al (2002) $AR signaling required for diet-induced thermogenesis and obesity resistance.  Science 297:843-845.
            Patel JN, Coppack SW, Goldstein DS, Miles JM, Eisenhofer G (2002) Norepinephrine spillover from human adipose tissue before and after a 72-hour fast. J Clin Endocrinol Metab 87:3373-3377.
            De Fanti BA, Martinez JA (2002) Central urocortin activation of sympathetic-regulated energy metabolism in Wistar rats. Brain Res 930:37-41.

Parasympathetic deficiency and fatal arrhythmias in mice lacking the development gene Nhlh1
    The basic helix-loop-helix family of transcription factors is involved in the regulation of multiple developmental processes.  One of these factors, Nhlh1, is expressed during embryonic development in neural tissue.  Cogliati et al. generated Nhlh1-deficient mice to explore the function of this gene on neural development.  Mice were viable and developed normally to maturity, but had a reduced life expectancy because of “sudden death”.  Mice had a decrease in total power of heart rate variability (HRV) and an increase in the ratio between low and high frequency HRV.  This was interpreted as indicative of parasympathetic deficiency (high frequency HRV values were not reported).  Baroreflex-mediated changes in heart rate and the normal diving-reflex bradycardia were impaired, consistent with parasympathetic impairment.  Nhlh1-null mice also seemed to develop ventricular arrhythmias during swimming stress.  Expression of Nhlh1 was found in developing brain stem and in the vagal nucleus.  The transcription factor Nhlh1, therefore, appears to be important for normal autonomic development.
            Cogliati T, Good DJ, Haigney M, et al (2002) Predisposition to arrhythmia and autonomic dysfunction in Nhlh1-deficient mice. Mol Cel Biol 22:4977-4983.

Phophorylation of "-synuclein in synucleinopathy lesions
            "-synuclein is one of the major components of Lewy bodies of pure autonomic failure and glial inclusions of multiple system atrophy.  The function of this protein in normal cells is not known and it is unclear why "-synuclein precipitates in these disorders.  "-synuclein contains a serine in position 129 that can be subject to phosphorylation, and Fujiwara et al. postulated that this process is involved in the precipitation of "-synuclein.  Using antibodies that selectively recognize the phosphorylated form of "-synuclein they found that the phosphorylated form is present in synucleopathy lesions.  This finding was confirmed by mass spectrometry analysis of detergent-insoluble brain extracts from patients.  Furthermore, phosphorylation of "-synuclein at serine 129 promoted fibril formation in vitro.  Phosphorylation of "-synuclein, therefore, appears to be involved in the pathogenesis of these neurodegenerative disorders.
            Fujiwara H, Hasegawa M, Dohmae N, et al (2002) "-Synuclein is phosphorylated in synucleinopathy lesions.  Nature Cell Biol 4:160-64.

Local Inhibition of Sympathetic Vasoconstriction in Exercising Muscle
            Strenuous exercise triggers sympathetic activation and increases blood pressure.  The increased perfusion pressure would benefit the exercising muscle, but only if it is protected from sympathetically-mediated vasoconstriction.  It is proposed that local metabolites, produced by the exercising muscle, are responsible for this “metabolic sympatholysis”.  To explore this hypothesis, Tchakosky et al. used Doppler ultrasound of the brachial artery to measured forearm blood flow, and induced local sympathetic vasoconstriction by infusing tyramine into the brachial artery to evoke the release of endogenous norepinephrine.  Exercise induced forearm which greatly blunted tyramine-induced sympathetic vasoconstriction.  Vasodilation with intrabrachial adenosine was not as effective in blunting tyramine-induced vasoconstriction, and nitroprusside was moderately effective.  These results are consistent with the existence of metabolic sympatholysis, and suggest that nitric oxide contributes to this phenomenon. It should be noted that tyramine evokes non-vesicular release of norepinephrine.  Therefore, this approach only evaluates factors that may inhibit the postsynaptic actions of norepinephrine.  Metabolites may be released by exercise that induce presynaptic inhibition of norepinephrine release, a mechanism that can also contribute to metabolic sympatholysis.  The authors acknowledged that this alternative mechanism was not investigated in this study.
            Tschakovsky ME, Sujiratanawimol K, Ruble SB, Valic Z, Joyner MJ (2002) Is sympathetic neural vasoconstriction blunted in the vascular bed of exercising human muscle? J Physiol 541:623-635.

Impaired Baroreflex-Mediated vasoconstriction in Syncope
            Maintenance of upright posture depends of baroreflex-mediated vasoconstriction.  Cooper and Hainsworth examined whether impaired carotid baroreflex contribute to orthostatic intolerance during tilt testing in patients referred for syncope.  Whereas previous studies have focused on heart rate changes to carotid baroreflex stimulation, these investigators examined also vascular changes.  Carotid baroreflex was stimulated by neck suction and pressure, and forearm blood flow was measured by Doppler ultrasound of the brachial artery.  Carotid-cardiac baroreflex was similar between patients and controls, both supine and during tilt.  Carotid-vascular responses were similar in the supine position.  Vascular responses to carotid baroreflex stimulation were enhanced in the upright posture in controls and in patients with a normal response to tilt, but were blunted in patients with a history of syncope and a positive tilt table test.  These results suggest that failure of the normal postural increase in sensitivity of the carotid baroreceptor/vascular resistance reflex may contribute to neurogenic syncope.  These findings may also explain the impaired sympathetic activation induced by upright tilt in patients with neurogenic syncope (Mosqueda-Garcia, J Clin Invest 1997;99:2736).
            Cooper VL, Hainsworth R (2002) Effects of head-up tilting on baroreceptors control in subjects with different tolerances to orthostatic stress. Clin Sci 103:221-226