Jacquelien J.G. Hillebrand

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.

Intrameal Hepatic Portal and Intraperitoneal Infusions of Glucagon-Like Peptide-1 Reduce Spontaneous Meal Size in the Rat via Different Mechanisms

Peripheral administration of glucagon-like peptide (GLP)-1 reduces food intake in animals and humans, but the sites and mechanism of this effect and its physiological significance are not yet clear. To investigate these issues, we prepared rats with chronic catheters and infused GLP-1 (0.2 ml/min; 2.5 or 5.0 min) during the first spontaneous dark-phase meals. Infusions were remotely triggered 2-3 min after meal onset. Hepatic portal vein (HPV) infusion of 1.0 or 3.0 (but not 0.33) nmol/kg GLP-1 reduced the size of the ongoing meal compared with vehicle without affecting the subsequent intermeal interval, the size of subsequent meals, or cumulative food intake. In double-cannulated rats, HPV and vena cava infusions of 1.0 nmol/kg GLP-1 reduced meal size similarly. HPV GLP-1 infusions of 1.0 nmol/kg GLP-1 also reduced meal size similarly in rats with subdiaphragmatic vagal deafferentations and in sham-operated rats. Finally, HPV and ip infusions of 10 nmol/kg GLP-1 reduced meal size similarly in sham-operated rats, but only HPV GLP-1 reduced meal size in subdiaphragmatic vagal deafferentation rats. These data indicate that peripherally infused GLP-1 acutely and specifically reduces the size of ongoing meals in rats and that the satiating effect of ip, but not iv, GLP-1 requires vagal afferent signaling. The findings suggest that iv GLP-1 infusions do not inhibit eating via hepatic portal or hepatic GLP-1 receptors but may act directly on the brain.

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.

Leptin treatment in activity-based anorexia

BACKGROUND Activity-based anorexia (ABA) is considered an animal model of anorexia nervosa (AN). In ABA, scheduled feeding together with voluntary access to a running wheel results in increased running wheel activity (RWA), hypophagia, and body weight loss. Previously it was shown that leptin treatment reduced semi-starvation-induced hyperactivity in rats. The present study was performed to confirm and extend this finding, to evaluate leptins effect on energy balance in ABA. METHODS The effects of chronic leptin treatment (intracerebroventricular, 4 microg/day) in ABA rats, ad libitum-fed running rats, and sedentary rats exposed to ad libitum feeding or scheduled feeding were investigated. RESULTS Leptin treatment decreased RWA in ABA rats. Additionally, leptin treatment reduced food intake and increased energy expenditure by thermogenesis in ABA rats. Ad libitum-fed running/sedentary rats or food-restricted sedentary rats did not reduce activity after leptin treatment, whereas all leptin-treated rats showed hypophagia. Body temperature was slightly increased in leptin-treated food-restricted sedentary rats. CONCLUSIONS Although leptin treatment reduced RWA in ABA rats, it also prevented hypothermia and decreased food intake. Altogether, this resulted in a stronger negative energy balance and body weight loss in leptin-treated ABA rats.

Acute and chronic suppression of the central ghrelin signaling system reveals a role in food anticipatory activity

Using the rodent activity-based anorexia (ABA) model that mimics clinical features of anorexia nervosa that include food restriction-induced hyperlocomotion, we found that plasma ghrelin levels are highly associated with food anticipatory behaviour, measured by running wheel activity in rats. Furthermore, we showed that ghrelin receptor (GHS-R1A) knockout mice do not anticipate food when exposed to the ABA model, unlike their wild type littermate controls. Likewise, food anticipatory activity in the ABA model was suppressed by a GHS-R1A antagonist administered either by acute central (ICV) injection to rats or by chronic peripheral treatment to mice. Interestingly, the GHS-R1A antagonist did not alter food intake in any of these models. Therefore, we hypothesize that suppression of the central ghrelin signaling system via GHS-R1A provides an interesting therapeutic target to treat hyperactivity in patients suffering from anorexia nervosa.

Vagal Sparing Surgical Technique but Not Stoma Size Affects Body Weight Loss in Rodent Model of Gastric Bypass

BackgroundThe aim of this study was to evaluate whether gastric bypass with or without vagal preservation resulted in a different outcome.MethodsBody weight, food intake and postprandial peptide YY (PYY) and glucagon-like peptide (GLP-1) levels were compared between gastric bypass (n = 55) and sham-operated rats (n = 27) in three groups. In group 1 (n = 17), the vagal nerve was not preserved, while in group 2 the vagal nerve was preserved during gastric bypass (n = 10). In group 3, gastric bypass rats (n = 28) were randomised for either one of the two techniques.ResultsRats in which the vagal nerve was preserved during gastric bypass showed a lower body weight (p < 0.001) and reduced food intake (p < 0.001) compared to rats in which the vagal nerve was not preserved during the gastric bypass operation. Levels of PYY and GLP-1 were significantly increased after gastric bypass compared to sham-operated controls (p < 0.05), but there was no difference between gastric bypass rats with and without vagal preservation. Differences in food intake and body weight were not related to the size of the gastro-jejunostomy in gastric bypass rats. There were no signs of malabsorption or inflammation after gastric bypass.ConclusionWe propose that the vagal nerve should be preserved during the gastric bypass operation as this might play an important role for the mechanisms that induce weight loss and reduce food intake in rats. In contrast, the gastro-jejunal stoma size was found to be of minor relevance.

Mu-opioid receptor knockout mice show diminished food-anticipatory activity

We have previously suggested that during or prior to activation of anticipatory behaviour to a coming reward, µ‐opioid receptors are activated. To test this hypothesis schedule induced food‐anticipatory activity in µ‐opioid receptor knockout mice was measured using running wheels. We hypothesized that µ‐knockout mice show little food‐anticipatory activity. In wildtype mice we observed that food‐anticipatory activity increased proportional to reduced food intake levels during daily scheduled food access, and thus reflects the animals physiological need for food. µ‐Knockout mice do not adjust their schedule induced running wheel behaviour prior to and during feeding time in the same way as wildtype mice; rather than showing more running wheel activity before than during feeding, they showed an equal amount of activity before and during feeding. As food‐anticipatory activity is dependent on the mesolimbic dopamine system and µ‐opioid receptors regulate dopaminergic activity, these data suggest a change in the dopamine systems activity in µ‐knockout mice. As we observed that µ‐knockout mice tended to show a stronger locomotor activity response than wildtype mice to the indirect dopamine agonist d‐amphetamine, it appears that the dopaminergic system per se is intact and sensitive to activation. We found no differences in the expression of pro‐opiomelanocortin, a precursor of endogenous endorphin, in the arcuate nucleus between µ‐knockout mice and wildtype mice during restricted feeding, showing that the µ‐opioid receptor does not regulate endogenous endorphin levels. These data overall suggest a role for µ‐opioid receptors in adapting reward related behaviour to the requirements of the environment.

Olanzapine Reduces Physical Activity in Rats Exposed to Activity-Based Anorexia: Possible Implications for Treatment of Anorexia Nervosa?

BACKGROUND Anorexia nervosa (AN) patients often show extreme hypophagia and excessive physical activity. Activity-based anorexia (ABA) is considered an animal model of AN and mimics food restriction and hyperactivity in rats. This study investigated whether treatment with olanzapine (Zyprexa) reduces the development of ABA in rats. The effect of olanzapine treatment in AN patients was also evaluated in a small open-label study. METHODS Rats were chronically (1 week) infused with olanzapine (7.5 mg/kg) and exposed to the ABA model or ad libitum feeding. Hyperactive AN patients were followed for up to 3 months of olanzapine treatment (5 mg/kg). RESULTS Olanzapine treatment reduced development of ABA in rats by reducing running wheel activity, starvation-induced hypothermia and activation of the hypothalamus-pituitary-adrenal axis. Olanzapine treatment reduced activity levels of AN patients compared with untreated AN patients, without affecting body weight and plasma leptin levels. CONCLUSIONS Olanzapine treatment reduced wheel running and thereby diminished development of ABA in rats. Olanzapine treatment also reduced physical activity in hyperactive AN patients in a small open-label study. These data support the need for controlled studies investigating the putative beneficial effects of olanzapine treatment in AN patients.

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.

Dopamine antagonism inhibits anorectic behavior in an animal model for anorexia nervosa

Excessive physical activity is commonly described as symptom of Anorexia Nervosa (AN). Activity-based anorexia (ABA) is considered an animal model for AN. The ABA model mimics severe body weight loss and increased physical activity. Suppression of hyperactivity by olanzapine in anorectic patients as well as in ABA rats suggested a role of dopamine and/or serotonin in this trait. Here, we investigated the effect of a non-selective dopamine antagonist in the ABA model. A dose-response curve of chronic treatment with the non-selective dopaminergic antagonist cis-flupenthixol was determined in the ABA model. Treatment reduced activity levels in both ad libitum fed and food-restricted rats. Treated ABA rats reduced body weight loss and increased food intake. These data support a role for dopamine in anorexia associated hyperactivity. Interestingly, in contrast to leptin treatment, food-anticipatory activity still persists in treated ABA rats.