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A New Paradigm in the Understanding and Treatment of the Metabolic Syndrome, Part 2

Jan 12, 2017

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Elevated sympathetic tone is a major driver of insulin resistance syndrome and increased cardiovascular disease risk in humans


Reduction of neuronal dopaminergic activity at the hypothalamic clock pacemaker (suprachiasmatic nuclei; SCN) induces increases in sympathetic tone and hypothalamo-pituitary-adrenal axis activity to precipitate insulin resistance syndrome

As concluded in the previous newsletter in this series, “Evolutionary selection for insulin resistance in a cyclic environment: brain clocks and control of peripheral metabolism” the brain is equipped with circadian neurophysiological mechanisms to induce (and reverse) the insulin resistant state that evolved as a survival strategy against ensuing environmental stresses such as prolonged (seasonal) lack of food availability.  A central facilitator of this insulin resistance induction is a diminution of the circadian peak in dopaminergic activity at the SCN.  Neurotoxin induced destruction of these dopaminergic projections to the clock of insulin sensitive animals induces marked insulin resistance and glucose intolerance without alterations in food consumption [1, 2] (Figure 12).

What do we know of how this circadian dopaminergic activity peak at the SCN functions to regulate metabolism?

The loss of the circadian dopaminergic peak activity at the clock signals the clock to adjust its output signaling that regulates peripheral metabolism to drive an insulin resistant condition.  Such alterations in output signaling to induce insulin resistance include specific neurophysiological changes at the ventromedial hypothalamus (VMH) and hypothalamic paraventricular nuclei (PVN) to potentiate increases in sympathetic nervous system (SNS) tone and the hypothalamic-pituitary-adrenal (HPA) axis activity [3,4].  Decreased circadian peak dopaminergic activity at the SCN is coupled to and manifests an increase in noradrenergic (and serotonergic) activity at the VMH [5-10] (Figure 3), which in turn induces the insulin resistance syndrome in seasonal and laboratory animals via its output signals to the autonomic and endocrine systems. This effect is characterized by hyperinsulinemia, hyperglucagonemia, hyperleptinemia, insulin resistance, glucose intolerance, and the hypertensive – elevated sympathetic tone state [11-14] (Figure 4, 5, 6).  Concurrent with such VMH alterations induced by a diminution of hypothalamic dopaminergic activity are elevations in PVN corticotropin releasing hormone (CRH) and neuropeptide Y (NPY) levels.  Such simultaneous increases in PVN CRH and NPY activities potentiate an increase in sympathetic tone, HPA axis activity, and beta cell hypersecretory response to glucose (leading to hyperinsulinemia) (reviewed in [15]).  Consequently, such changes in PVN and VMH activities potentiated by the reduction of dopaminergic circadian peak activity at the clock facilitate the induction and maintenance of the obese-insulin resistant- hypertensive state without any alteration of food consumption.  The composite of these changes at the SCN, VMH, and PVN are sufficient to “lock” the animal in the insulin resistant state even while maintained on a low fat diet.

What is the relevance of this programmable hypothalamic circuitry to human insulin resistance syndrome?

The literature is now replete with clinical studies indicating a causative role for elevated sympathetic nervous system tone in the induction of both insulin resistance syndrome and increased CVD event rate (see reference list on elevated sympathetic tone in human metabolic syndrome, [16-42]).  Increased SNS tone induces increased free fatty acid mobilization, inflammation, and inflammatory cytokine secretion from adipose, increased hepatic insulin resistance, inflammation, and inflammatory cytokine secretion, muscle insulin resistance, and postprandial dysglycemia and dyslipidemia that all in turn act on the vasculature (including kidney vasculature) to precipitate arteriosclerosis (vessel stiffness and inflammation).  Importantly, these studies indicate that elevated SNS tone contributes to CVD risk at the level of the vasculature not only by increasing vascular resistance (hypertension) [24,33,43-48], but more forcefully by directly inducing reactive oxygen species (ROS) generation and inflammation in the vasculature and myocardium [49-52].

Similarly a mounting body of scientific literature is amassing that implicates elevated HPA axis activity (particularly aberrant elevations in the circadian rhythm of plasma cortisol level) as potentiating insulin resistance syndrome [53-60].  The combination of elevated SNS tone and HPA axis activity can be a powerful and persistent pathophysiology for the induction and maintenance of metabolic syndrome and CVD in that each pathophysiology facilitates the existence of the other (reviewed in [4,61]).

A simple means of reversing the VMH and PVN neurophysiology that initiates and maintains elevated SNS and HPA axis activities is the administration of a dopamine (D2) receptor agonist (e.g., bromocriptine) at the appropriate circadian time of day to reinstate the normal circadian peak of dopaminergic activity at the biological clock SCN.  Such treatment reduces overactive VMH NE and S activities and PVN NPY and CRH levels and reverses the metabolic syndrome [4,10,62,63]  (Figure 7, 8, 9).



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