ABSTRACT
Metformin is the most common drug used against type 2 diabetes
mellitus. However, it was only recently shown, in human and rat
hepatocytes, that metformin-like 5-aminoimidazole-4-carboximide
ribonucleoside (AICAR), acts via activation of the AMP-activated protein
kinase (AMPK), an enzyme that plays a central role in lipid metabolism.
Although it is well known that metformin is used in the treatment of type
2 diabetes and results in significant fat loss, no study has investigated
the effects of this drug on adipocytes. In this report I studied the effects
of metformin on the formation of fat deposits in mouse 3T3-L1 preadipocytes,
as well as its effects on the activation of AMPK in these cells.
Our results suggested that metformin significantly inhibits the
transformation of pre-adipocytes into adipocytes. This is achieved via the
inhibition of intracellular lipid accumulation during adipogenesis. In
addition to its inhibition of intracellular lipid accumulation, metformin
induced a significant increase in the phosphorylation of AMPK.
It has been shown that AMPK activation with AICAR results in the
inhibition of the nuclear factor-κB (NF-κB) induced gene expression. Since
NF-κB is the key nuclear factor used by HIV-1 during the initiation of its
gene transcription, I investigated the possibility of inhibiting HIV-1
replication in U1 cells with metformin and AICAR. I observed that AICAR
and metformin inhibit HIV-1 replication in U1 cells. This inhibition wasparalleled by the accumulation of NF-κB in the cytoplasm of AICAR and
metformin treated cells, and at the same time by a significant decrease in
the concentration of this nuclear factor in the nucleus of these cells.
However, I failed to observe any phosphorylation of AMPK by metformin
and AICAR in U1 cells.
In conclusion, metformin inhibits adipogenesis in mouse adipocytes and
this inhibition is likely to take place via the activation of AMPK. AICAR and
metformin have inhibitory properties against HIV-1 replication. However,
this inhibition does not seem to be by the activation of AMPK.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/4745 |
| Date | 08 April 2008 |
| Creators | Alexandre, Kabamba Bankoledi |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 1721860 bytes, application/pdf, application/pdf |
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