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Permanent link (DOI): https://doi.org/10.7939/R3Q23R530

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Development of leptin responses in the Magel2-null mouse model of Prader-Willi syndrome Open Access

Descriptions

Other title
Subject/Keyword
Hyperphagia
Obesity
Energy Homeostasis
POMC
Leptin
Melanocortins
PWS
Prader-Willi Syndrome
Arcuate Nucleus
Treatment
Melanotan II
Animals
MC3R
Neurons
MTII
Genetics
Calcium Imaging
Humans
Electrophysiology
Adiposity
Weight Gain
EGFP
Mice
Pro-Opiomelanocortin
Immunohistochemistry
MC4R
Magel2
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Pravdivyi, Igor
Supervisor and department
Wevrick, Rachel (Medical Genetics)
Examining committee member and department
Funk, Greg (Physiology)
Eisenstat, David (Medical Genetics)
Colmers, William (Pharmacology)
Wevrick, Rachel (Medical Genetics)
Department
Medical Sciences-Medical Genetics
Specialization

Date accepted
2014-09-29T10:59:33Z
Graduation date
2014-11
Degree
Master of Science
Degree level
Master's
Abstract
An individual’s body weight is tightly regulated by balancing food intake with energy expenditure. This is accomplished in part by secretion of the hormone leptin by adipocytes, an excess of which signals to reduce appetite and increase activity through action in the hypothalamic region of the brain. This signalling pathway is disrupted in an obese and underactive mouse model of Prader-Willi syndrome (PWS), which lacks the gene Magel2. Although loss of several genes may result in PWS-like features, we have strong evidence that MAGEL2 plays a vital role in the development of obesity in PWS. In Magel2-null mice, a population of anorexigenic hypothalamic cells, which make pro-opiomelanocortin (POMC), fail to respond to leptin stimulation. Consequently, mutant POMC neurons do not secrete a factor called alpha-melanocyte-stimulating hormone (alpha-MSH), resulting in their inability to effectively regulate energy balance. The aim of my project was to further characterize the nature of faulty leptin signalling in our mutant mice and to determine whether administration of an alpha-MSH-like agonist molecule, melanotan II (MTII) can restore the energy balance. Through immunohistochemical analysis I discovered that unlike in adults, young mutant mice have a normal number of POMC neurons. These cells are able to sense leptin at the appropriate cell surface receptor and initiate a downstream signalling cascade through phosphorylation of the nuclear transcription factor, STAT3. Further examination of cellular function using electrophysiology and calcium imaging, revealed that POMC neurons of Magel2-null mice are responsive to leptin at a young age but lose this capability when the mice become adults. Peripheral injection of MTII into mutant mice revealed increased sensitivity to the compound as compared to wildtype mice, which manifested itself in significantly elevated food intake. Although not apparent at 3 weeks of age, this effect was first detected in 4 week old mice. A pilot study testing the efficacy of long-term MTII treatment on adult mutant mice failed to produce diminished food intake or body weight in the long run. These results indicate that mice lacking Magel2 have leptin-responsive POMC neurons at birth but lose this functionality by adulthood. Thus, they are not resistant to leptin as neonates, but rather develop insensitivity during postnatal life. The existence of a period where POMC neurons are responsive to leptin may provide a window of opportunity for preventative treatment using therapeutic agents. PWS pathology seen in humans may follow closely what we observe in our mouse model in terms of progression of leptin signalling impairments. If such is the case, results from this study may be extended to better understand the causes and origins of PWS in humans and to design drugs that counteract obesity and other related clinical manifestations of PWS.
Language
English
DOI
doi:10.7939/R3Q23R530
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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