Institutionen för fysiologi och farmakologi / Department of Physiology and Pharmacology
Abstract
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