The temporal organization of ingestive behaviour and its interaction with regulation of energy balance

Body weight of man and animals is under homeostatic control mediated by the adjustment of food intake It is discussed in this review that besides signals reporting energy deficits, optimized programs of body clocks take part in feeding behaviour as well Circadian light- and food-entrainable clocks determine anticipatory adaptive behavioural and physiological mechanisms, promoting or inhibiting food intake In fact these clocks form the constraints within which the homeostatic regulation of feeding behaviour is operating Therefore, a strong interaction between circadian and homeostatic regulation must occur. In this homeostatic control, a wide variety of regulatory negative feedback mechanisms, or satiety signals, play a dominant role. In this respect several gut hormones and body temperature function as 'short-term' satiety factors and determine meal sizes and intermeal intervals Leptin, secreted by fat cells in proportion to the size of adipose tissue mass, is probably an important determinant of the 'long-term' regulation of feeding behaviour by setting the motivational background level for feeding behaviour. Thus, initiation or termination of meals at any particular point in time, depends on the resultant of all satiety signals and on constraints imposed by circadian light- and food-entrainable oscillators. (C) 2002 Elsevier Science Ltd. All rights reserved

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

Ablation of capsaicin-sensitive afferent nerves affects insulin response during an intravenous glucose tolerance test

We investigated the role of sensory nerves in glucose tolerance in conscious Wistar rats neonatally treated with neurotoxin capsaicin or vehicle. Intravenous glucose tolerance tests (IVGTT, 150, 300 and 450 mg in 30 min) were performed to measure glucose tolerance, and glucose, insulin and glucagon levels were measured. Higher glucose concentration resulted in a greater insulin response in both capsaicin- and vehicle-treated rats. However, glucose-stimulated insulin secretion was attenuated in capsaicin-treated animals, even though glucose levels did not differ. Glucagon levels did not differ between both groups. These results show that capsaicin-sensitive nerves are involved in glucose-stimulated insulin secretion, but are not directly involved in the regulation of blood glucose levels. Moreover, they suggest that capsaicin-sensitive nerves could be involved in the regulation of insulin sensitivity. We hypothesize that sensory afferents could play a role in the aetiology of pathologies where glucohomeostatic mechanisms are disturbed, as is in type 2 diabetes mellitus. (c) 2005 Elsevier Inc. All rights reserved

Overfeeding, Autonomic Regulation and Metabolic Consequences

The autonomic nervous system plays an important role in the regulation of body processes in health and disease. Overfeeding and obesity (a disproportional increase of the fat mass of the body) are often accompanied by alterations in both sympathetic and parasympathetic autonomic functions. The overfeeding-induced changes in autonomic outflow occur with typical symptoms such as adiposity and hyperinsulinemia. There might be a causal relationship between autonomic disturbances and the consequences of overfeeding and obesity. Therefore studies were designed to investigate autonomic functioning in experimentally and genetically hyperphagic rats. Special emphasis was given to the processes that are involved in the regulation of peripheral energy substrate homeostasis. The data revealed that overfeeding is accompanied by increased parasympathetic outflow. Typical indices of vagal activity (such as the cephalic insulin release during food ingestion) were increased in all our rat models for hyperphagia. Overfeeding was also accompanied by increased sympathetic tone, reflected by enhanced baseline plasma norepinephrine (NE) levels in both VMH-lesioned animals and rats rendered obese by hyperalimentation. Plasma levels of NE during exercise were, however, reduced in these two groups of animals. This diminished increase in the exercise-induced NE outflow could be normalized by prior food deprivation. It was concluded from these experiments that overfeeding is associated with increased parasympathetic and sympathetic tone. In models for hyperphagia that display a continuously elevated nutrient intake such as the VMH-lesioned and the overfed rat, this increased sympathetic tone was accompanied by a diminished NE response to exercise. This attenuated outflow of NE was directly related to the size of the fat reserves, indicating that the feedback mechanism from the periphery to the central nervous system is altered in the overfed state.

Improved biocompatibility but limited graft survival after purification of alginate for microencapsulation of pancreatic islets

Graft failure of alginate-polylysine microencapsulated islets is often interpreted as the consequence of a non-specific foreign body reaction against the microcapsules, initiated by impurities present in crude alginate. The aim of the present study was to investigate if purification of the alginate improves the biocompatibility of alginate-polylysine microcapsules. Alginate was purified by filtration, extraction and precipitation. Microcapsules prepared from crude or purified alginate were implanted in the peritoneal cavity of normoglycaemic AO-rats and retrieved at 1, 2, 3, 6, 9, and 12 months after implantation. With crude alginate, all capsules were overgrown within 1 month after implantation. With purified alginate, however, the portion of capsules overgrown was usually less than 10%, even at 12 months after implantation. All recipients of islet allografts in capsules prepared of purified alginate became normoglycaemic within 5 days after implantation, but hyperglycaemia reoccurred after 6 to 20 weeks. With intravenous and oral glucose tolerance test, all recipients had impaired glucose tolerance and insulin responses were virtually absent. After graft failure, capsules were retrieved (80-100%) by peritoneal lavage. Histologically, the percentage of overgrown capsules was usually less than 10% and maximally 31%. This small portion cannot explain the occurrence of graft failure. The immunoprotective properties of the capsules were confirmed by similar if not identical survival times of encapsulated islet allo- and isografts. Our results show that purification of the alginate improves the biocompatibility of alginate-polylysine microcapsules. Nevertheless, graft survival was still limited, most probably as a consequence of a lack of blood supply to the encapsulated islets

Noradrenergic and cholinergic reinnervation of islet grafts in diabetic rats

Grafted islets become denervated due to the islet transplantation procedure. The aim of the present study was 1) to examine whether islet grafts in the liver, the spleen, and under the kidney capsule in rats become reinnervated following the transplantation and experimental procedures used in our laboratory, 2) whether there is any difference in reinnervation at these different sites, and 3) how these results relate to previous physiological experiments. Isogeneic isolated islets were transplanted into diabetic Albino Oxford rats, resulting in normoglycaemia. After at least 5 wk, graft-receiving organs were removed and several antibodies were employed to detect insulin, neuron-specific proteins, and cholinergic and noradrenergic nerve fibers. Islets in all three receiving organs contained viable insulin-positive B-cells. Neuron-specific enolase (NSE) as well as the growth-associated protein B-50 was observed at all sites. The cholinergic marker choline acetyltransferase (ChAT) was localized in islets grafts at all sites, but with the lowest density in the spleen. Staining for the noradrenergic markers tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) was observed in islet grafts at all sites with the lowest density in grafts under the kidney capsule. All these neurochemical substances were most frequently observed in fibers associated with blood vessels, which may be the route along which nerves grow into the graft. It can be concluded that 1) islet grafts in the liver, in the spleen and under the kidney capsule become reinnervated; 2) the innervation pattern of the islet grafts differs only slightly from that in the control pancreatic islets; and 3) in combination with our previously physiological data, we can conclude that these nerve fibers are, at least partly, functionally active