| Abstract |
 HIV
infection is a health epidemic around the world. The development
of therapeutic agents that modulate HIV infection has extended
the life expectancy of HIV-1 infected individuals. Unfortunately,
with the increased survival of HIV individuals, metabolic
complications such as insulin resistance, hyperlipidemia,
central adiposity, peripheral lipodystrophy, and its ensuing
risk of morbidity and mortality has become a major concern.
Adipocytes are critical regulators of insulin resistance and
hyperlipidemia. Defects in storage of fatty acids or increased
relase of fatty acids from lipolysis, as well alterations
in the adipocyte hormones, adiponectin and leptin, are critical
modulators of insulin sensitivity and hyperlipidemia. In this
grant application, we propose to investigate several mechanisms
by which HIV infection and anti-HIV therapeutic agents disrupt
adipocyte metabolism, predisposing to the development of insulin
resistance, hyperlipidemia, and lipodystropy in HIV infected
individuals.
The specific aims of this grant are to:
- characterize the effects of interferon-alpha on human
adipocyte metabolism including measuring lipolysis, adiponectin
and leptin production, and related metabolism. Interferon
alpha has been demonstrated to alter murine adipocyte lipogenesis
and lipolysis but there is a paucity of studies using human
adipocytes. Up to 80% of individuals infected with HIV possess
elevated serum interferon alpha levels. Importantly, serum
interferon alpha levels correlate with hyperlipidemia in
HIV-1 infected individuals on monotherapy and also correlate
with the presence of lipodystrophy in patients receiving
HAART.
- To characterize the effects of indivinar and other protease
inhibitors (PI) on human adipocyte gene expression, lipolysis,
adiponectin and leptin production. Highly active antiretroviral
therapy (HAART) has been suggested to promote lipodystrophy,
insulin resistance, and hyperlipidemia. We as well as others
have previously demonstrated that indivinar modulates adipocyte
lipolysis and increases insulin resistance in a murine adipocyte
cell line. However, limited studies have been performed
using human adipocytes. We will now extend those studies
to investigate the effects of this agent on human adipocytes.
- To determine whether thiazolidinediones (TZDs) block
the actions of interferon-alpha and indivinar to alter adipocyte
metabolism. TZDs bind and activate the nuclear transcription
factor; peroxisome proliferator activated receptor (PPAR)
? which increases the expression of adipocyte specific genes.
TZDs are approved antidiabetic agents, which ameliorate
diabetes presumably primarily through its actions on adipocytes.
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