Food availability, physical activity and body weight : Role of dopamine, neuropeptide Y and orexin

Sammanfattning: During the last decades our knowledge about neuroendocrine control of energy balance has increased tremendously. Numerous neuropeptides and hormones with pronounced effects on feeding and body weight have been identified and put into schemes as anorexic or orexigenic signals. So far this has not rendered new insights into how to explain or treat human pathology such as obesity or anorexia nervosa. Although different in many aspects, obese patients and patients suffering from anorexia nervosa share the feature of abnormal body weight. In this thesis I try to elucidate the role of NPY, orexin and dopamine all three known to have pronounced effects on ingestive behavior and body weight under different experimental conditions, with emphasis on availability of food and physical activity. The aim is to get a better understanding of human body weight pathology such as anorexia nervosa and obesity. If food supply is restricted to only 1 hour each day, rats that have access to running wheels run excessively and lose control over body weight, which rapidly falls. This provides a model of activity based anorexia. In this model NPY mRNA is up regulated in the arcuate nucleus. We show that treatment with NPY increases the fall in body weight by increasing wheel running and decreasing food intake in this model. While appetitive ingestive behavior is complex, with a wide representation in the central nervous system, consummatory ingestive behavior is stereotyped and involves mainly the brainstem. The intra oral intake test separates the consummatory phase of ingestive behavior. We use this test to characterize the effects of NPY on ingestive behavior and compare the effect of NPY to the known effects of CCK on ingestive behavior and on c-fos pattern in the brainstem. While CCK decreases both appetitive and consummatory ingestive behavior NPY decreases the consummatory phase (an effect additive to that of CCK), and increases the appetitive phase. Both peptides activate neurons in the nucleus of the solitary tract, also indicating similar effects on consummatory ingestive behavior, but there is no evidence that they interact at this level. To evaluate the role of dopamine D1 and D5 receptors on two major readouts of energy expenditure, namely physical activity and core temperature, two full dopamine D1 receptor family agonists, the isochroman A 68930 and the benzazepine SKF 82958 were compared. The compounds differ in several behavioral aspects and in the pattern of immediately early gene expression they induce. Quantitative receptor autoradiography shows that A 68930 is more potent than SKF 82958 at displacing the selective dopamine D1 antagonist [3H]SCH 23390. This difference agrees with the difference observed in cAMP formation in cells transfected with the D1 receptor. In contrast, SKF 82958 is more potent than A 68930 in cells transfected with the D5 receptor. We suggest that the balance between signaling via dopamine D1 and D5 receptors determines the functional effects of agonists at D1/D5 receptors. The increased activity seen in activity based anorexia predominantly occurs during the normally sedentary light phase of a 24 h light-darkness cycle. Treatment with the D1 antagonist SCH 23390 prevented the development of this running pattern and also prevented the c-fos and orexin induction in the lateral hypothalamus typically seen in activity based anorexia. Quantitative receptor autoradiography shows [3H]SCH 23390 binding in the lateral hypothalamus and we propose that the D1 antagonist, by acting in in this brain structure, alters orexin signaling and thereby reduces light phase running. The experiments in this thesis show that the effects of NPY, dopamine and orexin are highly dependent upon environmental factors. Labeling them as anorexic or orexigenic is therefore in most cases an over-simplification. Developing new treatment strategies for diseases like obesity and anorexia nervosa will require a deeper knowledge about how the environment, and especially the availability of food and need for physical activity, influences ingestive behavior, energy expenditure and body weight.