There are numerous potential mechanisms that could link obesity with SNS activation in humans (). Chronic activation of supra-bulbar subcortical noradrenergic neurons has been suggested to contribute to peripheral SNS activation in heart failure (Lambert et al., 1995
), essential hypertension (Ferrier et al., 1992
), and aging (Esler et al., 2002
). Thus, it is possible that this may also be a potential mechanism contributing to SNS activation in obesity. Unfortunately, the available evidence (Lambert et al., 1999
) suggests this is not the case. However, whether brain NE spillover is increased in individuals with visceral obesity has not been determined to our knowledge.
Figure 6 Potential mechanisms contributing to sympathetic nervous system activation in obesity (Davy and Hall, 2004). AGT=Angiotensinogen; Ang II=Angiotension II; ACTH=Adrenocorticotropin hormone. Used with permission. (from Davy KP, Hall JE. 2004. Obesity and (more ...)
Insulin circulates in proportion to body fat stores and acts on key brain regions to reduce food intake and increase energy expenditure (via sympathetically mediated thermogenesis) (Schwartz and Porte, 2005
). Obesity, particularly visceral obesity, is frequently associated with hyperinsulinemia and, as such, insulin could contribution to elevated MSNA in these individuals. However, several lines of evidence suggest otherwise. First, fasting insulin concentrations have been related to MSNA in some (Scherrer et al., 1994
, Monroe et al., 2000
, Weyer et al., 2000
) but not all studies (Alvarez et al., 2004
). Second, intranasal delivery of insulin, which does not accumulate systemically, appears not to increase MSNA (Benedict et al., 2005
). Third, acute insulin infusions increase MSNA in humans (Anderson et al., 1991
), but the potential confound of baroreflex-mediated adjustments to systemic vasodilatation render these findings inconclusive. Finally, Scherrer et al. (Scherrer and Owlya, 1996
) reported that MSNA was not increased in an insulinoma patient whose fasting insulin concentrations were dramatically elevated. In addition, surgical removal of the insulinoma did not reduce MSNA despite normalization of fasting insulin concentrations. Therefore, the role of endogenous hyperinsulinemia in producing tonically elevated MSNA in obesity remains unclear.
Leptin, the product of the OB gene, is another potential neurohumoral signal that could contribute to the elevated kidney or skeletal muscle SNS activity observed in obese humans. Leptin, which is secreted from adipocytes in proportion to fat mass, acts on hypothalamic neuronal targets to reduce energy intake and increase energy expenditure (Ahima and Flier, 2000
). In rodents, leptin exerts influences on cardiovascular and renal function that are sympathetically-mediated (Haynes, 2000
, Hall, 2003
). In addition, acute infusions of leptin in rodents produces large increases in SNS outflow to brown adipose tissue, the kidney and lumbar vascular beds (Haynes, 2000
). Chronically, leptin infusions produce significant sympathetically mediated blood pressure elevations in experimental animals (Hall, 2003
). However, whether hyperleptinemia could be a potential mechanism contributing to SNS activation (and BP) elevations in obese humans is unclear. Leptin concentrations have been inconsistently related to MSNA (Snitker et al., 1997
, Monroe et al., 2000
, Alvarez et al., 2004
). In addition, expression and secretion of leptin is lower in visceral compared with subcutaneous adipocytes (Russell et al., 1998
) and circulating concentrations of the protein are similar in humans with higher compared with lower abdominal visceral fat but similar total and subcutaneous abdominal fat (unpublished observations). In addition, MSNA is similar in subcutaneous obese men and normal weight controls, despite three-fold higher leptin concentrations in the former (Alvarez et al., 2004
) (, bottom panel). Thus, the available evidence does not appear to support an obvious role for leptin signaling in mediating the SNS activation observed in human obesity.
Obesity is associated with activation of the renin-angiotensin-aldosterone system. The results of animal studies indicate that angiotensin II can act centrally to increase SNS activity (Reid, 1992
). As such, it is possible that angiotensin II could increase SNS activity in a similar manner in obese humans. Muscle sympathetic nerve activity increases with angiotensin II infusion (Matsukawa et al., 1991
) and decreases with angiotensin converting enzyme inhibition (Miyajima et al., 1999
) in normotensive humans. Furthermore, multiple components of the renin-angiotensin system are expressed in adipose tissue and angiotensinogen, the major substrate for angiotensin II formation, is expressed to a greater extent in visceral than subcutaneous adipocytes (Engeli et al., 2000
). Thus, increased angiotensin II could contribute to SNS activation in visceral obesity. Unfortunately, there is no direct experimental support for this possibility at the present time. However, the observation that angiotensin II receptor blockade reduces MSNA in obese hypertensive humans (Grassi et al., 2003
) is consistent with, but does not definitively support, this concept.
The arterial baroreflex exerts a strong tonic inhibitory influence on SNS activity. Therefore, a reduction in this inhibitory influence could contribute to the higher SNS activity to muscle and kidney in obesity. However, in contrast to previous reports (Grassi et al., 2000
), we (Alvarez et al., 2002
) recently found that sympathetic baroreflex gain was not reduced in men with visceral obesity nor associated with any measure of total or regional adiposity. Furthermore, whether sympathetic baroreflex sensitivity determined from acute pharmacological perturbations of blood pressure has any relation with the long-term tonic influence of the arterial baroreflex on SNS activity is unclear. Nonetheless, the role of baroreflex function in the SNS activation that accompanies obesity needs to be explored further.
Visceral obesity has been hypothesized to be a neuroendocrine disorder characterized by dysregulation of hypothalamic-pituitary-adrenal axis and parallel activation of the SNS (Bjorntorp et al., 2000
). Whether dysregulation of the HPA axis is critical to the activation of the SNS in the context of obesity is unclear. Acute infusion of adrenocorticotropin, a pro-opiomelanocortin hormone, increases MSNA in humans (Dodt et al., 1998
) and one week of dexamethasone treatment produces greater reductions in MSNA in obese compared with nonobese individuals (Grassi et al., 2001
). However, it is important to emphasize that the specific sites of action of dexamethasone are unclear.
Obesity is an important risk factor for obstructive sleep apnea (Young et al., 2002
) and obstructive sleep apnea appears to be more closely associated with visceral obesity than total adiposity (Vgontzas et al., 2003
). Narkiewicz et al. (Narkiewicz et al., 1998
) reported that obesity, in the absence of obstructive sleep apnea, was not associated with elevated MSNA. Subsequently, Grassi et al. (Grassi et al., 2005
) demonstrated, in a much larger sample, that MSNA was significantly increased in obese compared with nonobese subjects without sleep apnea. Therefore, while the presence of obstructive sleep apnea appears sufficient to produce, even augment, SNS activation in obese humans, its presence does not appear necessary for the full expression of the sympathoexcitatory phenotype observed in “uncomplicated” obesity.