Autonomic Nervous System

Measurement of ANS Function

Traditionally, whole-body sympathetic activity was most commonly assessed by measuring plasma, platelet, or 24-hour urinary levels of catecholamines and their metabolites. More recent techniques include isotope dilution-derived measurements of noradrenaline release to plasma, and microneurography, to measure muscle sympathetic nerve activity (MSNA). ANS function can also be assessed by spectral analysis of heart rate variability (HRV), which provides information regarding both sympathetic and parasympathetic (vagal) nerve activity.

Is ANS Activity Altered in Obesity?

Although it has been controversial regarding whether “obesity” (i.e., excess adipose tissue deposition) is associated with altered sympathetic neural activity, more recent studies demonstrate that a state of basal/resting sympathetic overdrive characterizes obese individuals. Some of this discrepancy between studies is likely to be due to differences in the methods used to assess ANS function in the literature. Furthermore, failure to measure and account for the demonstrated effects of central adiposity, insulin resistance, elevated fatty acid levels, and glucose intolerance on ANS tone may also explain some of this inconsistency.

In spite of increased basal sympathetic neural activity, recent data suggest that obese individuals may exhibit reduced “responsiveness” to sympathetic stimuli. For example, it has been shown that although the basal (unstimulated) LF/HF ratio (an HRV measure of sympathovagal balance) is higher in obese versus lean individuals, insulin (delivered during a hyperinsulinemic-euglycemic clamp) fails to increase the LF/HF ratio in obese subjects. Furthermore, a recent study examined the effect of physiological (meal-induced) hyperinsulinemia on the LF/HF ratio in lean and obese subjects using high- and low-carbohydrate meals. The main findings were: (1) SNS tone increased postprandially; (2) the postprandial increase in SNS tone was significantly greater following the high-carbohydrate meal compared to the low-carbohydrate meal; and (3) the carbohydrate (insulin)-induced increase in SNS tone following the meal was blunted in obese subjects.

However, it cannot be concluded from these reports that reduced sympathetic responsiveness contributes to the development of obesity, as altered sympathetic tone may be a consequence of the obese state and, perhaps, its associated comorbidities, particularly insulin resistance. To answer this question, it is imperative that ANS activity is examined prior to the onset of these disorders in pre-obese individuals. Although reports in Pima Indians provide some evidence that reduced sympathetic activity may predict weight gain, it has been argued that the unique genetic makeup of the Pima Indians makes it difficult to extrapolate these findings to other populations.

Potential Mechanisms Linking Obesity with Alterations in ANS Function

If confirmed, is it biologically plausible that alterations in autonomic neural activity (i.e., reduced sympathetic responsiveness) could contribute to the accumulation of body fat in insulin resistance? One possible mechanism is that hyperinsulinemia is an initiating factor leading to activation of basal SNS tone in insulin-resistant individuals. As there is some evidence to suggest that persistently elevated SNS activity leads to adrenoreceptor downregulation, this may, over time, lead to a blunted sympathetic response to stimuli such as insulin, which may have important implications in the postprandial state. Indeed, the SNS plays an important role in the regulation of energy balance, particularly in relation to suppressing appetite following a meal. There is also evidence from both animal and human studies that the SNS is a key regulator of adaptive thermogenesis. Furthermore, studies using pharmacological blockade of the SNS suggest that oxidation of fat in the postprandial state is particularly dependent on SNS activation.

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