Energy Homeostasis in children with Prader- Willi syndrome

Ohn Nyunt (2015). Energy Homeostasis in children with Prader- Willi syndrome PhD Thesis, School of Medicine, The University of Queensland. doi:10.14264/uql.2016.7

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Author Ohn Nyunt
Thesis Title Energy Homeostasis in children with Prader- Willi syndrome
School, Centre or Institute School of Medicine
Institution The University of Queensland
DOI 10.14264/uql.2016.7
Publication date 2015-12-18
Thesis type PhD Thesis
Supervisor Peter Davies
Mark Harris
Andrew Cotterill
Total pages 168
Language eng
Subjects 1103 Clinical Sciences
1114 Paediatrics and Reproductive Medicine
1101 Medical Biochemistry and Metabolomics
Formatted abstract
Introduction
Prader- Willi syndrome (PWS) is a genetic condition commonly associated with hyperphagia and obesity. PWS is thought to have hypothalamic dysfunction which is the head ganglion of autonomic nervous system (ANS). In current literature, ANS is believed to be defective in PWS. ANS may also have a role in controlling orexigenic hormone ghrelin and energy expenditure. One study reported higher resting energy expenditure adjusted for lean body mass in growth hormone naive PWS group but another study found lower activity associated energy expenditure compared to controls. Other studies found adjusted basal and sleeping metabolic rates were not different to the controls. Complete profile of energy expenditure in PWS remains unclear.
We hypothesize that there is defective ANS in PWS, as a result of hypothalamus dysfunction, and it leads to high orexigenic hormone, acyl ghrelin, and low energy expenditure that in turn cause obesity.

Methods
We compared the ANS functions, acyl ghrelin status and energy expenditure in children with PWS and controls.
We recruited 16 genetically- confirmed children with PWS and 16 controls. Exclusion criteria were diabetes mellitus, psycho-trophic medications, and other hypothalamic pathologies.
We performed a mixed meal challenge to assess ANS function and acyl ghrelin status of PWS and control groups. We used Bodystat 1500® to measure body composition. Orthostatic hypotension, due to gravity, stimulates baroreceptors and activates sympathetic nervous system to counter regulate postural drop in blood pressure by increasing pulse rate, stroke volume and vasoconstriction. We used orthostatic change in pulse rate (PR), blood pressure (BP), and mean arterial pressure (MAP) expressed as per cent change of PR (%ΔPR), BP (%ΔBP), and MAP (%ΔMAP) from lying to standing to access sympathetic nervous function. ANS was further stimulated by a mixed meal and we examined %ΔPR, %ΔBP, and %ΔMAP at 15 and 30 seconds after standing from recumbent position; at fasting, and post-prandial periods. We also measured plasma gastrin, catecholamines (Pcat) and urinary catecholamines (Ucat) at fasting and post- prandial periods to complement autonomic cardiovascular data. Using Actiheart®, we compared weight and fat free mass adjusted total, resting, activity- associated and non- exercise associated thermogenesis between two groups.

Results
PWS group was younger, shorter, and had reduced lean mass than the controls. Post-prandial %ΔPR at both 15 and 30 seconds were significantly lower in PWS group than controls. The difference in %Δ systolic BP and diastolic BP did not reach statistical significance but %ΔMAP at 60 min and 120 min after meal was significantly lower in PWS. Postprandial plasma gastrin and Ucat were higher in PWS group than controls but Pcat were not different in two groups. Fasting plasma acyl ghrelin (AG) was significantly higher in PWS but it decreased to similar level of controls at 60 and 120 minutes after a meal. The rate of fall of plasma acyl ghrelin was faster in the PWS group than the controls. Fasting AG is negatively correlated to fasting %ΔPR at 30s (r value -0.52, p= 0.04). When adjusted for both weight and fat- free- mass, PWS group had lower total, resting, activity- associated and non- exercise associated thermogenesis than the controls.

Conclusions
We report that there is dysautonomia, high fasting acyl ghrelin and low energy expenditures in children with PWS.
In PWS, there is reduction in GABA-A receptor number and its actions as a result of the deleted genes of β3, α5, and γ3 subunit of GABA-A receptors in the PWS gene region; and probable exaggerated GABA-B receptors actions due to effect of compensatory hyper-gamma- amino- butyric- acidaemia on the normal GABA-B receptors. The abnormities lead to GABA system dysfunction in PWS. GABA is the key neurotransmitter between Nucleus Tractus Solitarius and C1 neurons that connect to the thoracic spinal cord that sends efferent neurons to sympathetic ganglions. GABA system dysfunction, therefore, may be the cause of sympathetic failure. Moreover, GABA is generally an inhibitory neurotransmitter and GABA dysfunction may be the cause of poor vagal inhibitory function that lead to high post-prandial plasma gastrin production, and increased catecholamine production from adrenal medulla probably by increase chromaffin cells gap junction communications. Our findings of dysautonomia can be explained by GABA dysfunction in PWS. Dysautonomia may also be the cause of high fasting acyl ghrelin and low energy expenditures. Therefore in PWS, there is imbalance in energy intake and expenditure resulting in obesity.
Keyword Prader-Willi syndrome
PWS
Autonomic nervous system
ANS
Obesity
Hypothalamus
Gamma amino butyric acid
GABA
Nucleus tractus solitarius
Gastrin
Ghrelin
Catecholamine
Energy expenditure
Non-exercise associated thermogenesis
Activity associated thermogenesis

Document type: Thesis
Collections: UQ Theses (RHD) - Official
UQ Theses (RHD) - Open Access
 
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Created: Tue, 08 Dec 2015, 07:04:56 EST by Ohn Nyunt on behalf of Learning and Research Services (UQ Library)