Jan H. Strubbe

The temporal dynamics of the stress response.

This paper summarises the available evidence that failure of defense mechanisms in (semi)-natural social groups of animals may lead to serious forms of stress pathology. Hence the study of social stress may provide animal models with a high face validity. However, most of the animal models of human stress-disorders have concentrated on the consequences of chronic exposure to stressors. The present paper considers recent data, indicating that a single experience with a major stressor in the form of social defeat may have long-term consequences ranging from hours to days and weeks. It seems that the experience of a major stressor sensitizes the animal to subsequent stressors. The consequences of these long-term temporal dynamics of the stress response to the development of stress-related disorders and stress-vulnerability are discussed.

Increased Feeding in Response to Bilateral Injection of Insulin Antibodies in the VMH

In order to investigate the role of insulin in the VMH in regulation of food intake in the rat, a specific antibody against rat insulin was injected in the VMH. The insulin antibody caused transient hyperphagia, when administered in the nighttime. This result is discussed in view of the glucostatic theory of the regulation of food intake.

The timing of meals.

In most individuals, food intake occurs as discrete bouts or meals, and little attention has been paid to the factors that normally determine when meals will occur when food is freely available. On the basis of experiments using rats, the authors suggest that when there are no constraints on obtaining food and few competing activities, 3 levels of interacting controls normally dictate when meals will start. The first is the genetically determined circadian activity pattern on which nocturnal animals tend to initiate most meals in the dark. The second is the regularly occurring changing of the light cycle: These changes provide temporal anchors. The third relates to the size of the preceding meal, such that larger meals cause a longer delay until the onset of the next meal. Superimposed on these 3 are factors related to learning, convenience, and opportunity.

Plasma insulin and the time pattern of feeding in the rat

Abstract Blood levels of glucose and insulin during meals and between-meal-intervals were measured in virtually undisturbed rats. After a peak due to glucose absorbed from the meal blood sugar soon reverts to the pre-meal level. Insulin shows a similar peak followed by a continuing decline so that just before the next meal it is lower than at any other time. In terms of the glucostatic theory this might mean that meals are triggered by a critical drop of insulin. However, intravenous infusions of glucose, resulting in continously high insulin, do not affect timing or size of meals. Glucostatic factors probably are of minor importance in meal-to-meal regulation in the rat. However, they may subserve nutritional homeostasis on at least two other points.

Long-term biocompatibility, chemistry, and function of microencapsulated pancreatic islets

Transplantation of encapsulated living cells is a promising approach for the treatment of a wide variety of diseases. Large-scale application of the technique, however, is hampered by insufficient biocompatibility of the capsules. In the present study, we have implemented new as well as previously reported technologies to test biocompatibility issues of immunoisolating microcapsules on the long term (i.e. 2 years) instead of usually reported short time periods. When transplanted empty, the capsules proved to be highly biocompatible not only for short periods (i.e. 1 month) but also on the long term as evidenced by the absence of any significant biological response up to 2 years after implantation in rats. The immunoprotective properties of the capsules were confirmed by prolonged survival of encapsulated islet allografts up to 200 days. The surface of the applied capsule was analyzed and provides new insight in the chemical structure of true biocompatible and immunoprotective capsules applicable for transplantation of encapsulated islets in type I diabetes.

The psychobiology of meals

Meals are considered as bouts of behavior that, although necessary for supplying nutrients to the body, result in undesirable perturbations of homeostatically controlled parameters. If the environment dictates that an animal mainly eat very large meals, these meal-associated perturbations become potentially dangerous. When the opportunity to eat a very large meal is regular and predictable, animals adopt strategies that maximize the efficiency of the process while minimizing the threatening homeostatic disturbances. Hence, prior to the onset of meals, animals elevate their body temperatures, presumably to facilitate critical processes involved in ingestion and/or digestion. Temperature continues to rise during the meal, and as it approaches potentially dangerous levels, the meal is terminated and temperature falls to “safer” levels. Animals also undergo a slow decline of blood glucose prior to the initiation of meals, thus minimizing the postprandial elevation of blood glucose caused by the absorption of ingested carbohydrates. Analogously, prior to meals, animals undergo a decrease of metabolic rate, thus precluding the necessity for postprandial increases of metabolic rate to reach even higher absolute levels. These premeal changes of regulated parameters have been interpreted by others as indicating depletion of one or more energy supplies so that the animal is compelled to eat. Contrary to this, we interpret the changes as ones that enable the animal to prepare adequately to consume a large meal when the environment is predictable.

Blood glucose levels in portal and peripheral circulation and their relation to food intake in the rat

Rats weighing about 450 g were provided with permanent catheters in the portal vein and the right auricle. This method allows blood sampling from the portal and peripheral circulation at the same moment in the nondisturbed unanesthetized rat. In the ad lib condition the portal glucose level was higher than that in the general circulation before, during, and after the meal. After a fast of 22 hr premeal portal vein levels were equal to those of the general circulation. During the meal the portal glucose levels rose to about 150 mg per 100 ml whereas those of the general circulation did not exceed 130 mg/100 ml. Experiments with glucose infusions systemically and intraportally show that, under conditions of mild deprivation, the level of glucose in the portal vein plays no or only a very minor role in the termination of feeding.

Circadian control of insulin secretion is independent of the temporal distribution of feeding

To investigate whether there is a circadian regulation of insulin secretion, rats were adapted to a feeding regimen of six meals equally distributed over 24 h. Under these conditions basal glucose and insulin levels increased during the light phase and decreased during the dark phase. Maximal blood glucose responses were fairly similar during the six different meals, but glucose increments were clearly delayed during the last two meals consumed during the light period. Insulin increments were highest during the dark phase and clearly diminished during the second half of the light phase. This situation was reversed when the scheduled meals were replaced by i.v. glucose infusions, i.e., no significant differences were detected between insulin responses, whereas glucose increments were reduced during the dark period. These results show that there is a circadian regulation of basal blood glucose and feeding-induced insulin responses, which is independent of the temporal distribution of feeding activity.

Interaction Between Circadian and Caloric Control of Feeding Behavior in the Rat

Feeding at the beginning of the night is probably dependent on the rats immediate energy requirements while feeding at the end may have an anticipatory function. This latter feeding peak may be mainly controlled by a circadian pacemaker. The aim of this study was to investigate the relative contribution of satiety signals and circadian pacemakers in the control of feeding behavior. Food intake was monitored after infusion of liquid food into the stomach during several parts of the day-night cycle to prevent a possible influence of oral sensations. It is demonstrated that intragastric infusion is more effective in suppressing intake during daytime and the first half of the dark phase than during the second half of the dark phase. Suppressions of food intake are mainly due to delaying the first occurrence of food ingestion, whereas the size of that meal is less affected. During the last period of the night no significant delay could be brought about. These experiments suggest that in the rat a circadian pacemaker dominates feeding motivation during the end of the night thereby strongly interacting with caloric control of feeding behavior.

Hormonal and metabolic effects of paraventricular hypothalamic administration of neuropeptide Y during rest and feeding

To investigate the role of neuropeptide Y (NPY) in the paraventricular nucleus of the hypothalamus (PVN) in the regulation of autonomic outflow, hormonal (plasma insulin and catecholamines), metabolic (blood glucose and plasma free fatty acids) and cardiovascular (heart rate and main arterial pressure) indices were measured before, during, and after bilateral infusion of NPY (1.0, 0.2, 0.04 micrograms in 1 microliter synthetic CSF) into the PVN of conscious resting rats. Administration of the highest dose (1.0 microgram/microliter) caused bradycardia and reduced circulating norepinephrine levels without effecting circulating fuels, insulin or epinephrine. In a second experiment, feeding-induced changes in hormonal and metabolic indices were assessed after NPY administration (1.0 microgram/microliter) into the PVN. During and after feeding, NPY enhanced the feeding-induced insulin response (P < 0.01) and attenuated the feeding-induced norepinephrine response (P < 0.05). The results of the present study suggest that stimulation of NPY receptors in the PVN decreases sympathetic activity and increases parasympathetic activity in resting conditions, and that these effects are potentiated during feeding.