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Regulation of adipogenesis and adipose maintenance by the mammalian TOR complex 1

Polak, Pazit. Regulation of adipogenesis and adipose maintenance by the mammalian TOR complex 1. 2008, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_8394

Abstract

mTOR, an atypical serine/threonine kinase, is a central component of a highly conserved
signal transduction cascade that controls cell growth. It functions as part of two distinct
multiprotein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
mTORC1 contains mTOR, raptor, mLST8, and PRAS40, and is sensitive to the
immunosuppressive and anti‐cancer drug rapamycin. mTORC1 controls protein
synthesis via phosphorylation of two well characterized effectors, the kinase S6K and
the translational repressor 4E‐BP1. mTORC2 contains mTOR, mLST8, rictor and mSin1,
and is not directly inhibited by rapamycin, although long term rapamycin treatment can
inhibit mTORC2 indirectly in certain cell types. It controls organization of the actin
cytoskeleton. Both complexes are conserved in structure and function from yeast to
human.
The mTOR signaling pathway is controlled by nutrients, cellular energy status, and
growth factors such as insulin. Since mTOR is regulated by metabolic signals, we
focused our research on the roles of the mTOR signaling pathway in metabolic tissues, in
particular adipose tissue. My research project concentrated on studying how mTORC1
signaling affects adipocytes, in tissue culture and in mice.
Adipose tissue functions mainly as a long term fat storage depot. However, it is also
an important endocrine organ, which secretes hormones, cytokines and complement
factors. In this thesis, I first present evidence confirming that mTORC1 is required for
the differentiation and maintenance of adipocytes in vitro. In tissue culture, inhibition
of mTORC1 caused a decrease in the expression of adipose transcription factors, which
led to a decreased expression of genes related to fat metabolism and storage. This
resulted in de‐differentiation of the cells, manifested as loss of intracellular triglycerides.
I further focused my research on the key adipogenic transcription factor PPARγ, and
tried to elucidate the molecular mechanism by which mTORC1 regulates its activity. The
results suggested that rapamycin treatment acts to inhibit PPARγ downstream of its
ligands.
To investigate a role of adipose mTORC1 in regulation of adipose and whole body
metabolism, we generated mice with an adipose‐specific knockout of raptor (raptorad‐/‐).
Compared to control littermates, raptorad‐/‐ mice had substantially less adipose tissue,
were protected against diet‐induced obesity and hypercholesterolemia, and exhibited
improved insulin sensitivity. Leanness was despite reduced physical activity and
unaffected caloric intake, lipolysis, and absorption of lipids from the food. White
adipose tissue of raptorad‐/‐ mice displayed enhanced expression of genes encoding
mitochondrial uncoupling proteins characteristic of brown fat. Leanness of the raptorad‐
/‐ mice was attributed to elevated energy expenditure due to mitochondrial uncoupling.
These results suggest that adipose mTORC1 is a regulator of adipose metabolism and
thereby controls whole body energy homeostasis.
Advisors:Hall, Michael N.
Committee Members:Rüegg, Markus A.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
Item Type:Thesis
Thesis no:8394
Bibsysno:Link to catalogue
Number of Pages:114
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:41
Deposited On:13 Feb 2009 16:36

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