Food availability, physical activity and body weight : role of dopamine, neuropeptide Y and orexin
Author: Nergårdh, Ricard
Date: 2008-05-23
Location: Farmakologens föreläsningssal, Nanna Svartz väg 2, Karolinska Institutet, Solna
Time: 09.00
Department: Institutionen för fysiologi och farmakologi / Department of Physiology and Pharmacology
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Thesis (1.052Mb)
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.
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.
List of papers:
I. Nergårdh R, Ammar A, Brodin U, Bergström J, Scheurink A, Södersten P (2007). Neuropeptide Y facilitates activity-based-anorexia. Psychoneuroendocrinology. 32(5): 493-502. Epub 2007 Apr 30
Pubmed
II. Ammar AA, Nergårdh R, Fredholm BB, Brodin U, Södersten P (2005). Intake inhibition by NPY and CCK-8: A challenge of the notion of NPY as an "Orexigen. Behav Brain Res. 161(1): 82-7. Epub 2005 Feb 25
Pubmed
III. Nergårdh R, Oerther S, Fredholm BB (2005). Differences between A 68930 and SKF 82958 could suggest synergistic roles of D1 and D5 receptors. Pharmacol Biochem Behav. 82(3): 495-505. Epub 2005 Nov 28
Pubmed
IV. Nergårdh R, Ammar AA, Boersman GJ, Scheurink A, Fredholm BB, Södersten S (2008). Dopamine D1 receptor blockade reduces physical activity induced by food restriction. [Submitted]
I. Nergårdh R, Ammar A, Brodin U, Bergström J, Scheurink A, Södersten P (2007). Neuropeptide Y facilitates activity-based-anorexia. Psychoneuroendocrinology. 32(5): 493-502. Epub 2007 Apr 30
Pubmed
II. Ammar AA, Nergårdh R, Fredholm BB, Brodin U, Södersten P (2005). Intake inhibition by NPY and CCK-8: A challenge of the notion of NPY as an "Orexigen. Behav Brain Res. 161(1): 82-7. Epub 2005 Feb 25
Pubmed
III. Nergårdh R, Oerther S, Fredholm BB (2005). Differences between A 68930 and SKF 82958 could suggest synergistic roles of D1 and D5 receptors. Pharmacol Biochem Behav. 82(3): 495-505. Epub 2005 Nov 28
Pubmed
IV. Nergårdh R, Ammar AA, Boersman GJ, Scheurink A, Fredholm BB, Södersten S (2008). Dopamine D1 receptor blockade reduces physical activity induced by food restriction. [Submitted]
Issue date: 2008-05-02
Rights:
Publication year: 2008
ISBN: 978-91-7409-051-2
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