Changes in Farr radioimmunoassay and EliA fluorescence immunoassay anti-dsDNA in relation to exacerbation of SLE.

Measuring anti-dsDNA levels could support treatment adjustment during follow-up of patients with systemic lupus erythematosus (SLE). We investigated whether patients with exacerbations of SLE showed changes in anti-double-stranded DNA (anti-dsDNA) levels prior to the exacerbation using the Farr and EliA assay and examined which assay showed highest specificity and predictive value for exacerbations. Changes in anti-dsDNA of ≥ 25% prior to exacerbation were considered of clinical significance. Exacerbations were retrospectively abstracted from medical records. Eighteen of 48 patients showed one or more exacerbations. We found 22 exacerbations with complete lab work-up, all accompanied by ≥ 25% change in anti-dsDNA in one or both assays. Only 10 exacerbations showed concordant changes in anti-dsDNA in both assays. Changes in anti-dsDNA had a low predictive value for exacerbations of SLE, but the specificity of anti-dsDNA changes for patients with exacerbations was higher for EliA than Farr. We conclude that despite the limited relation between anti-dsDNA changes and exacerbations of SLE, anti-dsDNA testing could still support clinical decision making when used in the correct setting. We conclude that EliA is preferable over Farr for assaying anti-dsDNA during follow-up of patients with SLE because of higher specificity, less "hands-on" time and absence of radioactivity.

Neurobiology driving hyperactivity in activity-based anorexia.

Hyperactivity in anorexia nervosa is difficult to control and negatively impacts outcome. Hyperactivity is a key driving force to starvation in an animal model named activity-based anorexia (ABA). Recent research has started unraveling what mechanisms underlie this hyperactivity. Besides a general increase in locomotor activity that may be an expression of foraging behavior and involves frontal brain regions, the increased locomotor activity expressed before food is presented (food anticipatory behavior or FAA) involves hypothalamic neural circuits. Ghrelin plays a role in FAA, whereas decreased leptin signaling is involved in both aspects of increased locomotor activity. We hypothesize that increased ghrelin and decreased leptin signaling drive the activity of dopamine neurons in the ventral tegmental area. In anorexia nervosa patients, this altered activity of the dopamine system may be involved not only in hyperactivity but also in aberrant cognitive processing related to food.

Hepatic-portal vein infusions of glucagon-like peptide-1 reduce meal size and increase c-Fos expression in the nucleus tractus solitarii, area postrema and central nucleus of the amygdala in rats.

We recently reported that brief, remotely controlled intrameal hepatic-portal vein infusions of glucagon-like peptide-1 (GLP-1) reduced spontaneous meal size in rats. To investigate the neurobehavioural correlates of this effect, we equipped male Sprague-Dawley rats with hepatic-portal vein catheters and assessed (i) the effect on eating of remotely triggered infusions of GLP-1 (1 nmol/kg, 5 min) or vehicle during the first nocturnal meal after 3 h of food deprivation and (ii) the effect of identical infusions performed at dark onset on c-Fos expression in several brain areas involved in the control of eating. GLP-1 reduced (P < 0.05) the size of the first nocturnal meal and increased its satiety ratio. Also, GLP-1 increased (P < 0.05) the number of c-Fos-expressing cells in the nucleus tractus solitarii, the area postrema and the central nucleus of the amygdala, but not in the arcuate or paraventricular hypothalamic nuclei. These data suggest that the nucleus tractus solitarii, the area postrema and the central nucleus of the amygdala play a role in the eating-inhibitory actions of GLP-1 infused into the hepatic-portal vein; it remains to be established whether activation of these brain nuclei reflect satiation, aversion, or both.

Leptin's effect on hyperactivity: potential downstream effector mechanisms.

Up to 80% of patients with Anorexia Nervosa (AN) demonstrate hyperactivity. Hyperactivity counteracts weight gain during treatment and is associated with poor outcome of the disease. We hypothesized that hyperactivity in AN patients has a neurobiological basis and used an animal model-based translational approach to gain insight in mechanisms underlying this hyperactivity. Previously we and others showed that leptin treatment attenuates hyperactivity in the rat activity-based anorexia (ABA) model. The mechanisms involved in this process are, however, unknown. Here we describe potential downstream effector mechanisms involved in the attenuation of hyperactivity by leptin treatment in ABA rats.

The impact of hyperactivity and leptin on recovery from anorexia nervosa.

In anorexia nervosa (AN), hyperactivity is observed in about 80% of patients and has been associated with low leptin levels in the acute stage of AN and in anorexia animal models. To further understand the importance of this correlation in AN, we investigated the relationship between hypoleptinaemia and hyperactivity in AN patients longitudinally and assessed their predictive value for recovery. Body weight, activity levels, and serum leptin levels were assessed in adolescents and adult AN patient groups at the start and during treatment, up to a year. In the adolescent group, initial leptin and activity levels were correlated. This negative correlation changes over time into a positive correlation with physiological recovery. Treatment outcome in both groups could be predicted by initial BMI and leptin levels but not by activity levels. No major relationship of activity with the course of recovery was detected, suggesting that in contrast to the acute stage of the disease, leptin and activity levels during the recovery process are dissociated.

The MC4 receptor and control of appetite.

Mutations in the human melanocortin (MC)4 receptor have been associated with obesity, which underscores the relevance of this receptor as a drug target to treat obesity. Infusion of MC4R agonists decreases food intake, whereas inhibition of MC receptor activity by infusion of an MC receptor antagonist or with the inverse agonist AgRP results in increased food intake. This review addresses the role of the MC system in different aspects of feeding behaviour. MC4R activity affects meal size and meal choice, but not meal frequency, and the type of diet affects the efficacy of MC4R agonists to reduce food intake. The central sites involved in the different aspects of feeding behaviour that are affected by MC4R signalling are being unravelled. The paraventricular nucleus plays an important role in food intake per se, whereas MC signalling in the lateral hypothalamus is associated with the response to a high fat diet. MC4R signalling in the brainstem has been shown to affect meal size. Further genetic, behavioural and brain-region specific studies need to clarify how the MC4R agonists affect feeding behaviour in order to determine which obese individuals would benefit most from treatment with these drugs. Application of MCR agonists in humans has already revealed side effects, such as penile erections, which may complicate introduction of these drugs in the treatment of obesity.

The appetite suppressant d-fenfluramine reduces water intake, but not food intake, in activity-based anorexia.

Biochemical, genetic and imaging studies support the involvement of the serotonin (5-HT) system in anorexia nervosa. Activity-based anorexia (ABA) is considered an animal model of anorexia nervosa, and combines scheduled feeding with voluntary running wheel activity (RWA). We investigated the effect of d-fenfluramine (d-FEN) treatment on development and propagation of ABA. d-FEN is an appetite suppressant and acts on 5-HT(2C) receptors that are located on pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. Since stimulation activation of the melanocortin system stimulates ABA, we hypothesized that d-FEN treatment enhances the development and propagation of ABA. Rats were exposed to the ABA model and chronically infused with d-FEN. Unexpectedly, d-FEN-treated ABA rats did not reduce food intake or increase wheel running as compared with vehicle-treated ABA rats. Furthermore d-FEN treatment did not affect body weight loss, hypothalamus-pituitary-adrenal axis activation, or starvation-induced hypothermia in ABA rats. POMC mRNA levels in d-FEN-treated rats were not different from vehicle-treated rats after one week of exposure to the ABA paradigm. However, d-FEN-treated ABA rats showed hypodypsia and increased plasma osmolality and arginine-vasopressin expression levels in the hypothalamus. We conclude that d-FEN treatment does not enhance ABA under the experimental conditions of this study, but strongly reduces water intake in ABA rats.

Hypothalamic neuropeptide expression following chronic food restriction in sedentary and wheel-running rats.

When rats are given access to a running-wheel in combination with food restriction, they will become hyperactive and decrease their food intake, a paradoxical phenomenon known as activity-based anorexia (ABA). Little is known about the regulation of the hypothalamic neuropeptides that are involved in the regulation of food intake and energy balance during the development of ABA. Therefore, rats were killed during the development of ABA, before they entered a state of severe starvation. Neuropeptide mRNA expression levels were analysed using quantitative real-time PCR on punches of separate hypothalamic nuclei. As is expected in a state of negative energy balance, expression levels of agouti-related protein (AgRP) and neuropeptide Y (NPY) were increased 5-fold in the arcuate nucleus (ARC) of food-restricted running ABA rats vs 2-fold in sedentary food-restricted controls. The co-regulated expression of AgRP and NPY strongly correlated with relative body weight and white adipose tissue mass. Arcuate expression of pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) was reduced 2-fold in the ABA group. In second-order neurons of the lateral hypothalamic area (LHA), melanin-concentrating hormone (MCH) mRNA expression was upregulated 2-fold in food-restricted running rats, but not in food-restricted sedentary controls. Prepro-orexin, CART and corticotropin-releasing hormone expression levels in the LHA and the paraventricular nucleus (PVN) were unchanged in both food-restricted groups. From this study it was concluded that during the development of ABA, neuropeptides in first-order neurons in the ARC and MCH in the LHA are regulated in an adequate response to negative energy balance, whereas expression levels of the other studied neuropeptides in secondary neurons of the LHA and PVN are unchanged and are probably regulated by factors other than energy status alone.

Neuropeptides, food intake and body weight regulation: a hypothalamic focus.

Energy homeostasis is controlled by a complex neuroendocrine system consisting of peripheral signals like leptin and central signals, in particular, neuropeptides. Several neuropeptides with anorexigenic (POMC, CART, and CRH) as well as orexigenic (NPY, AgRP, and MCH) actions are involved in this complex (partly redundant) controlling system. Starvation as well as overfeeding lead to changes in expression levels of these neuropeptides, which act downstream of leptin, resulting in a physiological response. In this review the role of several anorexigenic and orexigenic (hypothalamic) neuropeptides on food intake and body weight regulation is summarized.