Obesity is a chronic condition that primarily develops from an
increase in body fat in the form of white adipose tissue (WAT) mass. The
resulting adiposity is a risk factor for many diseases, including type 2
diabetes (T2D), cardiovascular diseases, and some forms of cancer. Reducing
WAT mass by targeted modulation of metabolic enzymes in fat cell
metabolism is an attractive molecular therapeutic alternative to dietary
approaches. In the present study, we exogenously up-regulate a novel
respiratory uncoupling protein to increase substrate oxidation, and thereby
control adipocyte fatty acid content.
Increasing molecular evidence points to a family of uncoupling
proteins (UCPs) playing an important role in adipocyte fat metabolism. Of
specific interest is UCP1, which in brown adipocytes mediates energy
dissipation as heat by de-coupling respiration and ATP synthesis. UCP1 is
minimally expressed in white adipose tissue (WAT). We hypothesize that
controlled expression of UCP1 in WAT will result in enhanced fatty acid oxidation to compensate for reduced ATP synthesis. We used a Tet-Off
retroviral transfection system to express UCP1, with doxycycline being used
to control the extent of expression. UCP1 cDNA was cloned into pRevTRE
and was stably transfected into 3T3-L1 preadipocytes prior to differentiating
them into adipocytes. A reporter gene (EGFP) was also transfected in
parallel to optimize the transfection and preadipocyte differentiation
conditions as well as to demonstrate regulated expression. Metabolite
measurements showed that the UCP1-expressing adipocytes accumulated
83% less triglyceride and 85 % free fatty acids while maintaining constant
ATP levels. These results suggest UCP1 and other metabolic enzymes as
potential targets for development of pharmacological agents for the
treatment of obesity and related disorders.
| Identifer | oai:union.ndltd.org:tamu.edu/oai:repository.tamu.edu:1969.1/4207 |
| Date | 30 October 2006 |
| Creators | Palani, Santhosh |
| Contributors | Jayaraman, Arul |
| Publisher | Texas A&M University |
| Source Sets | Texas A and M University |
| Language | en_US |
| Detected Language | English |
| Type | Book, Thesis, Electronic Thesis, text |
| Format | 4408128 bytes, electronic, application/pdf, born digital |
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