Eveline Bruinstroop

Hypothalamic control of energy metabolism via the autonomic nervous system

The hypothalamic control of hepatic glucose production is an evident aspect of energy homeostasis. In addition to the control of glucose metabolism by the circadian timing system, the hypothalamus also serves as a key relay center for (humoral) feedback information from the periphery, with the important role for hypothalamic leptin receptors as a striking example. The hypothalamic biological clock uses its projections to the preautonomic hypothalamic neurons to control the daily rhythms in plasma glucose concentration, glucose uptake, and insulin sensitivity. Euglycemic, hyperinsulinemic clamp experiments combined with either sympathetic‐, parasympathetic‐, or sham‐denervations of the autonomic input to the liver have further delineated the hypothalamic pathways that mediate the control of the circadian timing system over glucose metabolism. In addition, these experiments clearly showed both that next to the biological clock peripheral hormones may “use” the preautonomic neurons in the hypothalamus to affect hepatic glucose metabolism, and that similar pathways may be involved in the control of lipid metabolism in liver and white adipose tissue.

Hypothalamic Neuropeptide Y (NPY) Controls Hepatic VLDL-Triglyceride Secretion in Rats via the Sympathetic Nervous System

Excessive secretion of triglyceride-rich very low-density lipoproteins (VLDL-TG) contributes to diabetic dyslipidemia. Earlier studies have indicated a possible role for the hypothalamus and autonomic nervous system in the regulation of VLDL-TG. In the current study, we investigated whether the autonomic nervous system and hypothalamic neuropeptide Y (NPY) release during fasting regulates hepatic VLDL-TG secretion. We report that, in fasted rats, an intact hypothalamic arcuate nucleus and hepatic sympathetic innervation are necessary to maintain VLDL-TG secretion. Furthermore, the hepatic sympathetic innervation is necessary to mediate the stimulatory effect of intracerebroventricular administration of NPY on VLDL-TG secretion. Since the intracerebroventricular administration of NPY increases VLDL-TG secretion by the liver without affecting lipolysis, its effect on lipid metabolism appears to be selective to the liver. Together, our findings indicate that the increased release of NPY during fasting stimulates the sympathetic nervous system to maintain VLDL-TG secretion at a postprandial level.

Spinal projections of the A5, A6 (locus coeruleus), and A7 noradrenergic cell groups in rats.

The pontine noradrenergic cell groups, A5, A6 (locus coeruleus), and A7, provide the only noradrenergic innervation of the spinal cord, but the individual contribution of each of these populations to the regional innervation of the spinal cord remains controversial. We used an adeno‐associated viral (AAV) vector encoding green fluorescent protein under an artificial dopamine beta‐hydroxylase (PRSx8) promoter to trace the spinal projections from the A5, A6, and A7 groups. Projections from all three groups travel through the spinal cord in both the lateral and ventral funiculi and in the dorsal surface of the dorsal horn, but A6 axons take predominantly the dorsal and ventral routes, whereas A5 axons take mainly a lateral and A7 axons a ventral route. The A6 group provides the densest innervation at all levels, and includes all parts of the spinal gray matter, but it is particularly dense in the dorsal horn. The A7 group provides the next most dense innervation, again including all parts of the spinal cord, but is it denser in the ventral horn. The A5 group supplies only sparse innervation to the dorsal and ventral horns and to the cervical and lumbosacral levels, but provides the densest innervation to the thoracic intermediolateral cell column, and in particular to the sympathetic preganglionic neurons. Thus, the pontine noradrenergic cell groups project in a roughly topographic and complementary fashion onto the spinal cord. The pattern of spinal projections observed suggests that the locus coeruleus might have the greatest effect on somatosensory transmission, the A7 group on motor function, and the A5 group on sympathetic function. J. Comp. Neurol. 520:1985–2001, 2012.

Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism: a meta-analysis

Summary.  Background : The evidence on the optimal duration of treatment in patients with an idiopathic venous thromboembolic event (VTE) is inconclusive. d‐dimer testing to predict recurrent VTE has been evaluated in several studies. Objectives: We performed a meta‐analysis of studies of patients with idiopathic VTE treated with oral anticoagulation therapy (OAT) to assess the prognostic value of elevated d‐dimer levels 1 month after discontinuation of OAT for VTE recurrence. Patients/Methods: The MEDLINE, EMBASE and Cochrane databases were searched to identify relevant studies. Studies were eligible for inclusion if they included patients with idiopathic VTE and in addition reported results for this group separately, had measured d‐dimer approximately 1 month after discontinuation of OAT and had reported on recurrence of VTE. A random‐effects model was used to pool study results. Results: Data from four studies (1539 patients) were included in the current analysis. All studies reported on the number of recurrent events in the normal and elevated d‐dimer groups. Overall, 125 of 751 patients (16.6%) with elevated d‐dimer levels experienced recurrent VTE during the period of follow‐up compared with 57 of 788 patients (7.2%) with normal d‐dimer levels. Elevated d‐dimer levels were significantly associated with recurrent VTE (odds ratio , 2.36; 95% CI, 1.65 to 3.36). Conclusions: Elevated d‐dimer levels measured 1 month after discontinuation of OAT identify patients with idiopathic VTE at higher risk of recurrence.

The use of D-dimer in specific clinical conditions: A narrative review

The use of D-dimer in combination with a clinical decision rule has been widely investigated in pulmonary embolism and deep venous thrombosis. Although it has been shown to be safe in excluding venous thromboembolism, the clinician is often faced with specific situations in which the use of D-dimer is controversial. We review the best available evidence on these patients. We conclude that it is not safe to use D-dimer testing in patients with symptoms of a venous thromboembolism for over 14 days, patients receiving therapeutic heparin treatment and patients with suspected deep venous thrombosis during oral anticoagulant therapy. In these populations the levels of D-dimer can be lower then expected giving rise to false-negative results. It is safe to use D-dimer testing in combination with a clinical decision rule in patients of all ages, patients presenting with a suspected recurrent venous thromboembolism or inpatients with suspected pulmonary embolism. As patients with recurrent venous thromboembolism, elderly patients and inpatients have higher levels of D-dimer, D-dimer testing has a low specificity and the need for additional radiological testing is increased.

The autonomic nervous system regulates postprandial hepatic lipid metabolism

The liver is a key organ in controlling glucose and lipid metabolism during feeding and fasting. In addition to hormones and nutrients, inputs from the autonomic nervous system are also involved in fine-tuning hepatic metabolic regulation. Previously, we have shown in rats that during fasting an intact sympathetic innervation of the liver is essential to maintain the secretion of triglycerides by the liver. In the current study, we hypothesized that in the postprandial condition the parasympathetic input to the liver inhibits hepatic VLDL-TG secretion. To test our hypothesis, we determined the effect of selective surgical hepatic denervations on triglyceride metabolism after a meal in male Wistar rats. We report that postprandial plasma triglyceride concentrations were significantly elevated in parasympathetically denervated rats compared with control rats (P = 0.008), and VLDL-TG production tended to be increased (P = 0.066). Sympathetically denervated rats also showed a small rise in postprandial triglyceride concentrations (P = 0.045). On the other hand, in rats fed on a six-meals-a-day schedule for several weeks, a parasympathetic denervation resulted in >70% higher plasma triglycerides during the day (P = 0.001), whereas a sympathetic denervation had no effect. Our results show that abolishing the parasympathetic input to the liver results in increased plasma triglyceride levels during postprandial conditions.

Hepatic denervation and dyslipidemia in obese Zucker (fa/fa) rats

Human and animal studies increasingly point toward a neural pathogenesis of the metabolic syndrome, involving hypothalamic and autonomic nervous system dysfunction. We hypothesized that increased very-low-density lipoprotein−triglyceride (VLDL–TG) secretion by the liver in a rat model for dyslipidemia, that is, the obese Zucker (fa/fa) rat, is due to relative hyperactivity of sympathetic, and/or hypoactivity of parasympathetic hepatic innervation. To test the involvement of the autonomic nervous system, we surgically denervated the sympathetic or parasympathetic hepatic nerve in obese Zucker rats. Our results show that cutting the sympathetic hepatic nerve lowers VLDL–TG secretion in obese rats, finally resulting in lower plasma TG concentrations after 6 weeks. In contrast, a parasympathetic denervation results in increased plasma total cholesterol concentrations. The effect of a sympathetic or parasympathetic denervation of the liver was independent of changes in humoral factors or changes in body weight or food intake. In conclusion, a sympathetic denervation improves the lipid profile in obese Zucker rats, whereas a parasympathetic denervation increases total cholesterol levels. We believe this is a novel treatment target, which should be further investigated.

Hormonal Control of Metabolism by the Hypothalamus-Autonomic Nervous System-Liver Axis

The hypothalamus has long been appreciated to be fundamental in the control and coordination of homeostatic activity. Historically, this has been viewed in terms of the extensive neuroendocrine control system resulting from processing of hypothalamic signals relayed to the pituitary. Through these actions, endocrine signals are integrated throughout the body, modulating a vast array of physiological processes. Our understanding of the responses to endocrine signals is crucial for the diagnosis and management of many pathological conditions. More recently, the control emanating from the hypothalamus over the autonomic nervous system has been increasingly recognized as a powerful additional modulator of peripheral tissues. However, the neuroendocrine and autonomic control pathways emanating from the hypothalamus are not separate processes. They appear to act as a single integrated regulatory system, far more subtle and complex than when each is viewed in isolation. Consequently, hypothalamic regulation should be viewed as a summation of both neuroendocrine and autonomic influences. The neural regulation is believed to be fine and rapid, whereas the hormonal regulation is more stable and widespread. In this chapter, we will focus on the hypothalamic control of hepatic glucose and lipid metabolism.

Hypothalaam Neuropeptide Y (NPY) reguleert hepatische VLDL-triglyceriden secretie in ratten via het sympathisch zenuwstelsel

SamenvattingPatiënten met type 2 diabetes hebben een verhoogde leversecretie van triglyceriden in VLDL-partikels (VLDL-TG).1 VLDL-TG-secretie wordt onder andere gereguleerd door circulerende metabolieten (vrije vetzuren) en hormonen, zoals insuline. Recent onderzoek liet daarnaast ook een rol zien voor de hersenen en het autonome zenuwstelsel bij de regulatie van VLDL-TG-secretie.