Obesity and adipokines: effects on sympathetic overactivity

Abstract

Excess body weight is a major risk factor for cardiovascular disease, increasing the risk of hypertension, hyperglycaemia and dyslipidaemia, recognized as the metabolic syndrome. Adipose tissue acts as an endocrine organ by producing various signalling cytokines called adipokines (including leptin, free fatty acids, tumour necrosis factor-α, interleukin-6, C-reactive protein, angiotensinogen and adiponectin). A chronic dysregulation of certain adipokines can have deleterious effects on insulin signalling. Chronic sympathetic overactivity is also known to be present in central obesity, and recent findings demonstrate the consequence of an elevated sympathetic outflow to organs such as the heart, kidneys and blood vessels. Chronic sympathetic nervous system overactivity can also contribute to a further decline of insulin sensitivity, creating a vicious cycle that may contribute to the development of the metabolic syndrome and hypertension. The cause of this overactivity is not clear, but may be driven by certain adipokines. The purpose of this review is to summarize how obesity, notably central or visceral as observed in the metabolic syndrome, leads to adipokine expression contributing to changes in insulin sensitivity and overactivity of the sympathetic nervous system.

Figure 1. The cellular effects of adipokines on insulin signalling

Leptin has been shown to decrease phosphorylation of protein kinase C (PKC) which causes a failure of GLUT-4 translocation which then cannot bring glucose (glu) into the cell. C-reactive protein (CRP) can act in concert with interleukin-6 (IL-6) to decrease protein kinase B (PKB) phosphorylation, which will result in decreased GLUT-4 translocation. IL-6 can also inhibit the activation of insulin receptor substrate (IRS) by phosphatidylinositol 3-kinase (PI3K) and down-regulate the expression of the suppressor of cytokine signalling (SOCS) protein which normally serves a protective role in the effect of cytokines on cellular signalling. It is important to note that IL-6 only demonstrates deleterious effects on insulin signalling when chronically released. Free fatty acids (FFA) can impair one of the first steps in insulin signalling, tyrosine phosphorylation (TP) and impair activation of IRS by PI3K. Tumour necrosis factor-α (TNF-α) can impair insulin signalling by up-regulating serine/threonine phosphorylation, which has been associated with a decrease in GLUT-4 translocation, or by inhibiting phosphorylated tyrosine binding to IRS.

Figure 2. Specific pathways by which adipokines augment sympathetic outflow in obesity

Leptin is preferentially expressed in peripheral fat cells and both free and protein-bound leptin can impair glucose transporter-4 (GLUT-4) which creates a hyperinsulinaemic state and results in a co-activation of the sympathetic nervous system (SNS). Leptin can also act through a central mechanism. Free fatty acids (FFA) are equally expressed in central and peripheral obesity and in addition to causing a decrease in GLUT-4 translocation, can increase blood sugar and ultimately insulin levels through up-regulating gluconeogenesis in the liver. There is also evidence FFA can stimulate the SNS by a central mechanism. TNF-α is preferentially expressed in central obesity and through interacting with several key steps of insulin transduction, can cause a decrease in GLUT-4 translocation and ultimately increase blood glucose levels. Interleukin-6 (IL-6) is preferentially expressed in central obesity and stimulates neural SNS hyperactivity through effects on insulin signalling, direct HPA activation and in positive feedback fashion with β₂- and β₃-adrenoceptors on adipocytes. C-reactive protein (CRP) acts by impairing insulin signalling causing the resultant hyperinsulinaemia and co-activation of the neural SNS. Angiotensinogen expression is up-regulated in obesity which, in concert with the observed increase in renal SNS and resultant renin release, may act through mass action to cause a vasoconstriction and activation of the SNS by angiotensin II (ANG II) formation.

Figure 3. Co-expression and mechanisms of adipokines in obesity

In obesity, key adipokines which can result in sympathetic overdrive are dysregulated (angiotensinogen, tumour necrosis factor-α, adiponectin, leptin, free fatty acids, interleukin-6 and C reactive protein) and can act as endocrine and paracrine hormones to up-regulate expression of other adipokines. In the case of TNF-α they can sensitize angiotensin II receptors which, when activated, can cause sympathetic outflow through a central mechanism. These adipokines then work to increase sympathetic outflow either through their effects on insulin sensitivity, or through central cardiovascular control centres directly.