Intake inhibition by neuropeptide Y

Abstract

This thesis is an attempt to elucidate some neuroendocrine concomitants to Anorexia Nervosa (AN), an eating disorder that develops in women. In particular, the thesis has examined the effect of neuropeptide Y (NPY) on food intake under experimental conditions in male and female rats. We aimed at exploring the role of NPY in the two phases of ingestive behavior: appetitive ingestive behavior (approaching and handling of food) and consummatory ingestive behavior (chewing and swallowing). Patients with AN engage excessively in various appetitive ingestive behaviors but consume only little food.

NPY is generally regarded as a potent stimulator of food intake; the reverse is true for leptin. A number of experiments were conducted to study the effect of central administration of NPY on ingestive and sexual behavior. NPY was found to increase appetitive ingestive behavior, tested by the number of times a rat visited a bottled filled with sucrose, and, interestingly, decrease consummatory ingestive behavior, tested by intake of sucrose from intraoral infusion. Leptin had the opposite effects. NPY suppressed sexual behavior in the presence of a sucrose-filled bottle, but had only a minor effect in the absence of a bottle. Leptin markedly stimulated male sexual behavior.

Suppression of consummatory ingestive behavior and sexual behavior by central administration of NPY was not reversed if an aversive taste, such as that of quinine, was added to a sucrose-filled bottle. However, the aversive taste suppressed appetitive ingestive behavior and intake from the bottle. The effects of NPY on ingestive behavior were independent of taste evaluation since NPY treatment did not affect taste responses to a palatable or an aversive taste. Hence, inhibition of consummatory ingestive behavior by NPY is a specific behavioral effect.

Some NPY-containing neurons that provide input to hypothalamic nuclei, thought to be involved in feeding, co-localise norepinephrine (NE). Lesioning the NEprojections from the locus coeruleus to the forebrain with the neurotoxin DSP-4 reduced the intraoral intake of sucrose and pre-injection of NE restored intake. The combined addition of NPY and NE in this model markedly reduced intraoral intake. Thus, NPY might exert its inhibitory influence on consummatory ingestive behavior via the NE- projections to the forebrain.

Both intracerebroventricular injection of NPY and intraperitoneal injection of the satiety peptide cholecystokinin octapeptide (CCK-8) reduced intraoral intake of a sucrose solution. The combined treatment with NPY and CCK-8 had an additive inhibitory effect on intraoral intake. In line with previous studies, NPY increased intake from a bottle and CCK-8 had the opposite effect. The inhibitory effect of CCK-8 on bottle intake was enhanced in animals treated with NPY. Treatment with CCK-8 or NPY significantly increased c-fos like immunoreactivity in the nucleus of the solitary tract (NTS), a brainstem relay mediating inhibition of feeding. The results support the suggestion that NPY and CCK-8 inhibit consummatory ingestive behavior in a similar manner, perhaps acting through the NTS.

Patients with AN show increased physical activity and eat only little food. Yet their peripheral levels of leptin are low and their brain levels of NPY are up-regulated. The results of the previous experiments in this thesis suggested that NPY stimulates appetitive ingestive behavior and inhibits the actual intake of food. We therefore hypothesized that NPY may accelerate the development of activity-based anorexia in rats with access to a running wheel and limited access to food. Food restriction increased physical activity and elevated the levels of mRNA NPY in the hypothalamic arcuate nucleus. Exogenous supply of NPY accelerated running activity, decreased food intake and, hence, reduced body weight in rats with restricted access to food, but had marginal effects in rats fed ad libitum.

In situations of limited supply of food in experimental animals, NPY, therefore, may stimulate appetitive aspects of ingestive behavior at the expense of food consumption in a manner that mimicks the clinical situation in AN.As a conclusion the following hypothesis is offered. Food deprivation leads to fat depletion, a decrease in leptin levels and release of NPY in the brain. This neuroendocrine state helps directing the attention of an animal or a human to foodrelated stimuli including development of food anticipatory activities. As a consequence, the animal or human being searches for food rather than eats food.