Tiffany Ngai
Bachelor of Science, University of British Columbia, 2007
Friday, April 9, 2010, 8:30 am
“The Low-density Lipoprotein Receptor Knock-out Mouse: A
Model for the Study of Energy Balance”
EXAMINING COMMITTEE
Chair: Dr. Fabio Rossi (Medical Genetics)
Supervisory Committee: Dr. William Gibson, Research
Supervisor (Medical Genetics), Dr. Louis Lefebvre (Medical Genetics) & Dr.
Neal Boerkoel (Medical Genetics)
University Examiner: Dr. Jeffrey Richards (Zoology)
ABSTRACT
The discovery of leptin and other humoral signals which
regulate food intake and energy expenditure has greatly contributed to our
understanding of molecular pathways controlling energy homeostasis. Leptin
produced by adipocytes, insulin produced by the pancreas, and ghrelin produced
by the stomach all contribute to the body’s energy balance. One question
remaining is whether the lipid transport system also plays a role.
Our hypothesis is that lipid clearance is important in the
maintenance of energy homeostasis. The low-density lipoprotein receptor (Ldlr)
is a key molecule involved with lipid clearance. The experiments presented in
this thesis used the Ldlr-/- mouse to study the Ldlr’s role in energy balance.
One aim of this thesis was to provide a detailed analysis of the energy balance
phenotype of the Ldlr-/- mouse. Another aim of this thesis was to use the
Ldlr-/- mouse to study the potential interaction between Ldlr and the leptin
signaling pathway.
Adult Ldlr-/- mice and Ldlr+/+ controls on a C57BL/6J
background were fed either a chow or a high-fat, high-sucrose Western-type diet
(WTD) for eight weeks. Physiological studies of food intake, energy
expenditure, activity, heat production, insulin sensitivity, and leptin
responsiveness were performed. As well, the effect of these diet interventions
on circulating leptin and on leptin gene expression was examined.
On the chow diet, Ldlr-/- mice had lower energy expenditure
and higher activity levels relative to controls. On the WTD, Ldlr-/- mice
gained less weight relative to Ldlr+/+ mice, specifically gaining less fat mass.
Increased thermogenesis in Ldlr-/- mice fed the WTD was detected. Additionally,
leptin responsiveness was blunted in chow-fed Ldlr-/- mice, suggesting a novel
role for the Ldlr pathway that extends to leptin’s regulation of energy
balance.
In addition to its known role in lipid transport, these
results from the Ldlr-/- mouse demonstrate the importance of the Ldlr in
regulating energy homeostasis and suggest a direct physiological link between
dyslipidemia and energy balance.
PUBLICATIONS
Ngai, YF., Chijiwa, C., Mahmutoglu, S., Stewart, L., Yong,
SL., Robinson, WP., Gibson, WT. Pseudohypoparathyroidism Type 1a and the GNAS
p.R231H Mutation: Somatic Mosaicism in a Mother with Two Affected Sons. In
press. Accepted by the American Journal of Medical Genetics. Oct 2009.
PRESENTATIONS
The Centre for Molecular Medicine and Therapeutics TGIF
Seminar Series. February 2010, Vancouver (Canada). Seminar Presentation:
Diet-Gene Interactions in the Ldlr knockout mouse.
Child & Family Research Institute Diabetes Program
Trainee Seminar. February 2009, Vancouver (Canada). Seminar Presentation:
Diet-Gene Interactions in the Ldlr knockout mouse.
UBC Medical Genetics Research Day. November 2008 & 2009,
Vancouver (Canada). Poster Presentation: Diet-Gene Interactions in the Ldlr
knockout mouse.
Child & Family Research Institute Research Forum. Vancouver,
BC. June 2009, Vancouver (Canada). Poster Presentation: Diet-Gene Interactions
in the Ldlr knockout mouse.
ACMG Annual Clinical Genetics Meeting. March 2009, Tampa,
FL. (USA). Poster Presentation: Pseudohypoparathyroidism Type 1a and the GNAS
p.R231H Mutation: Somatic and Gonadal Mosaicism in a Mother with Two Affected
Sons.
1st Annual Canadian Human Genetics Conference. April 2008,
St.-Sauveur, QC. (Canada). Poster Presentation: Pseudohypoparathyroidism Type
1a and the GNAS p.R231H Mutation: Somatic and Gonadal Mosaicism in a Mother
with Two Affected Sons.
AWARDS
Alexander Graham Bell Canada Graduate Scholarship – $17500,
NSERC. (2009)
Canucks for Kids Diabetes Research Studentship - $20000,
Canucks for Kids Fund (2009)
Trainee Travel Grant – $1200, Child and Family Research
Institute. (2009)
GRADUATE STUDIES
Courses
MEDG 520: Advances in Human Molecular Genetics, Dr. Matthew
Lorincz
MEDG 530: Human Genetics, Dr. Jan Friedman
MEDG 505: Genome Analysis, Dr. Steven Jones
MEDG 545: Current Topics in Medical Genetics Research, Dr.
Michael Kobor
MEDG 515: Mammalian Developmental Genetics, Dr. Diana Juriloff
Tiffany Ngai MSc programme (pdf)