Obesity-induced increases in sympathetic nerve activity: Sex matters
Introduction
Obesity is a rapidly escalating epidemic that often leads to hypertension, due in part to increased sympathetic nerve activity (SNA) to muscle (MSNA) and the kidneys [for reviews, see Davy and Orr, 2009, Esler et al., 2006, Lambert et al., 2010b]. Moreover, elevated SNA may accelerate the progression of end organ damage (vascular, metabolic, cardiac, renal), independently of any rise in arterial pressure (AP) (Lambert et al., 2010a, Schlaich et al., 2009, Fisher et al., 2009). Thus, SNA may also contribute to the co-morbidities of insulin resistance, type II diabetes mellitus, obstructive sleep apnea, and cardiovascular disease commonly present in obese individuals. However, much of the current information documenting obesity-induced increases in SNA and AP has been obtained from male human and animal subjects. In this brief review, we highlight recent work beginning to explore potential sex differences and raise the question: does obesity increase SNA and AP in females, and if not, why not? As a basis for this discussion, we first provide a brief overview of what is known about sex differences in resting SNA and AP in non-obese healthy subjects.
Section snippets
Sex differences in SNA and AP
In young healthy lean subjects, women typically have lower levels of MSNA, directly measured via microneurography, compared to men (Hogarth et al., 2007, Ng et al., 1993, Seals and Esler, 2000). Likewise, young women tend to have lower resting AP than young men, and systemic blockade of the sympathetic nervous system decreases AP less in young women (Christou et al., 2005, Schmitt et al., 2010), suggestive of lower tonic sympathetic support of AP. Surprisingly, however, in both young men and
Sex differences and obesity-induced sympathoexcitation
Several studies have reported increased SNA with human obesity, often as MSNA directly measured using microneurography, but also as organ-specific norepinephrine release measured indirectly via the spillover technique [for reviews, see Davy and Orr, 2009, Smith and Minson, 2012, Lambert et al., 2010b, Esler et al., 2006]. Elevations in SNA have also been detected in animal models of obesity, beginning soon after a high fat diet has been initiated (Muntzel et al., 2012, Armitage et al., 2012).
Adipose tissue
Several recent excellent reviews have detailed the numerous sex differences in the distribution, morphology, and content or activity of adipose tissue (Power and Schulkin, 2008, Richard et al., 2012, Lovejoy and Sainsbury, 2009, Fuente-Martin et al., 2013, Mauvais-Jarvis et al., 2013, Tchernof and Despres, 2013). Chief among these is that adult females accrue more white and brown adipose tissues than males and that, in women compared to men, more white fat is distributed in the subcutaneous
Sex differences in vascular responses to heightened SNA
Given that obesity increases SNA in males, the next question is whether this sympathoexcitation uniformly translates into vasoconstriction and hypertension development. In both humans and animals, it appears that obesity (before development of metabolic syndrome) simultaneously impairs sympathetically- or alpha-adrenergic-mediated vasoconstriction (Belin de Chantemele et al., 2011, Jerez et al., 2012, Romanko and Stepp, 2005, Agapitov et al., 2008), which tends to minimize increases in AP.
Summary and conclusions
We have highlighted data suggesting that the sympathoexcitatory and hypertensive consequences of obesity that have been well established in males may be muted in females. We considered sex differences in the levels and central actions of factors implicated in males to raise SNA and AP as possible explanations for the apparent protection afforded by the female sex. Even in the lean state, sex differences are evident, with females exhibiting less visceral adiposity, lower SNA and SNA-induced
Acknowledgments
This work was supported in part by NIH grant HL088552 (vlb) and Grants-in-Aid from the American Heart Association (12GRNT11550018, vlb and 14GRNT20160072, pjf); swh was supported by NIH training grant 5T32AR048523-09.
References (126)
- et al.
Sympathetic activity and response to ACE inhibitor (enalapril) in normotensive obese and non-obese subjects
Arch. Med. Res.
(2004) The source of cerebral insulin
Eur. J. Pharmacol.
(2004)- et al.
Transport of insulin across the bloodābrain barrier: saturability at euglycemic doses of insulin
Peptides
(1997) - et al.
Selective, physiological transport of insulin across the bloodābrain barrier: novel demonstration by species-specific radioimmunoassays
Peptides
(1997) - et al.
Sex differences in inflammatory markers: what is the contribution of visceral adiposity?
Am. J. Clin. Nutr.
(2009) - et al.
Visceral adipose tissue differences in black and white women
Am. J. Clin. Nutr.
(1995) - et al.
Sympathetic nervous system behavior in human obesity
Neurosci. Biobehav. Rev.
(2009) - et al.
Men develop more intraabdominal obesity and signs of the metabolic syndrome after hyperalimentation than women
Metabolism
(2009) - et al.
Central sympathetic overactivity: maladies and mechanisms
Auton. Neurosci.
(2009) - et al.
Sex and age differences in the effect of obesity on incidence of hypertension in the Japanese population: a large historical cohort study
J. Am. Soc. Hypertens.
(2014)
Obesity-induced hypertension: role of sympathetic nervous system, leptin, and melanocortins
J. Biol. Chem.
Towards the therapeutic use of intranasal neuropeptide administration in metabolic and cognitive disorders
Regul. Pept.
Sex difference in cardiometabolic risk profile and adiponectin expression in subjects with visceral fat obesity
Transl. Res.
Nasal drug delivery: new developments and strategies
Drug Discov. Today
Estrogen signaling in hypothalamic circuits controlling reproduction
Brain Res.
Gender differences in sensitivity to adrenergic agonists of forearm resistance vasculature
J. Am. Coll. Cardiol.
Sympathetic nervous activation in obesity and the metabolic syndromeācauses, consequences and therapeutic implications
Pharmacol. Ther.
Is insulin the new intermittent hypoxia?
Med. Hypotheses
Gender-dependent differences in plasma leptin in essential hypertension
Am. J. Hypertens.
Overweight and sympathetic overactivity in black Americans
Hypertension
Dissociation between sympathetic nerve traffic and sympathetically mediated vascular tone in normotensive human obesity
Hypertension
Higher leptin is associated with hypertension: the Multi-Ethnic Study of Atherosclerosis
J. Hum. Hypertens.
Leptin is not associated independently with hypertension in Japanese-Brazilian women
Braz. J. Med. Biol. Res.
Sympathetic neural activation in visceral obesity
Circulation
Subcutaneous obesity is not associated with sympathetic neural activation
Am. J. Physiol. Heart Circ. Physiol.
Rapid onset of renal sympathetic nerve activation in rabbits fed a high-fat diet
Hypertension
Diet-induced obesity causes selective insulin resistance
FASEB J.
Glutamatergic receptor activation in the rostral ventrolateral medulla mediates the sympathoexcitatory response to hyperinsulinemia
Hypertension
Aging enhances autonomic support of blood pressure in women
Hypertension
Impact of leptin-mediated sympatho-activation on cardiovascular function in obese mice
Hypertension
Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin
J. Clin. Endocrinol. Metab.
The sympathetic response to euglycaemic hyperinsulinaemia. Evidence from microelectrode nerve recordings in healthy subjects
Diabetologia
Activation of the systemic and adipose renināangiotensin system in rats with diet-induced obesity and hypertension
Am. J. Physiol. Regul. Integr. Comp. Physiol.
AT1-receptor antagonism reverses the blood pressure elevation associated with diet-induced obesity
Am. J. Physiol. Regul. Integr. Comp. Physiol.
Inflammatory cause of metabolic syndrome via brain stress and NF-kappaB
Aging (Albany NY)
Ovarian cycle and sympathoexcitation in premenopausal women
Hypertension
Insulin acts in the arcuate nucleus to increase lumbar sympathetic nerve activity and baroreflex function in rats
J. Physiol.
Local adipose tissue renināangiotensin system
Curr. Hypertens. Rep.
Sympathetic neural activity to the cardiovascular system: integrator of systemic physiology and interindividual characteristics
Compr. Physiol.
Balance between cardiac output and sympathetic nerve activity in resting humans: role in arterial pressure regulation
J. Physiol.
Women have lower tonic autonomic support of arterial blood pressure and less effective baroreflex buffering than men
Circulation
Differential sensitivity to central leptin and insulin in male and female rats
Diabetes
Gonadal hormones determine sensitivity to central leptin and insulin
Diabetes
Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus protect against diet-induced obesity
J. Neurosci.
Race, visceral adipose tissue, plasma lipids, and lipoprotein lipase activity in men and women: the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) family study
Arterioscler. Thromb. Vasc. Biol.
Development of hypertension in a rat model of diet-induced obesity
Hypertension
Differential effects of renināangiotensināaldosterone system inhibition, sympathoinhibition and diuretic therapy on endothelial function and blood pressure in obesity-related hypertension: a double-blind, placebo-controlled cross-over trial
J. Hypertens.
Mechanisms of sympathetic activation in obesity-related hypertension
Hypertension
Effects of the ovarian cycle on sympathetic neural outflow during static exercise
J. Appl. Physiol.
Increase in muscle nerve sympathetic activity after glucose intake is blunted in the elderly
Clin. Auton. Res.
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