Fat Gain and Cardiovascular Disease Mechanisms

Understanding the mechanisms of obesity-induced hypertension is important both for
prevention and therapy. Studies of patients with established obesity have provided valuable
information on pathophysiologic links between obesity and both blood pressure and
cardiovascular risk. However, these studies are necessarily limited by the heterogeneity of
obesity-associated disease so that the relative contribution of obesity or hypertension or
other co-existing diseases to specific regulatory abnormalities is often not clear.
Clarification of whether any abnormalities associated with increased cardiovascular risk
were present before or after the development of obesity has also been problematic.

We therefore propose a series of novel studies directed at establishing the effects of
increased body fat in otherwise healthy individuals. We will determine the distribution
patterns of increased body fat and how both increased body fat and fat distribution relate
to changes in blood pressure, and in neural, endothelial and inflammatory mechanisms which
have been implicated in the development and progression of cardiac and vascular disease.

We will study non-obese subjects with and without a family history of hypertension. These
subjects will undergo an eight-week program of overfeeding with the objective of inducing a
4 kg fat gain. We will determine the nature of fat distribution in these individuals after
the fat gain program and subsequently after an eight-week period of weight loss and
restoration of normal body weight. Measurements will be compared to those obtained in a
matched control group with and without a family history of hypertension, who will continue
their normal diets. We will test the following hypotheses:

- Individuals with a family history of hypertension will gain more visceral fat and upper
body subcutaneous fat and will have greater blood pressure increases with overfeeding-
compared with those without such a family history.

- For all overfed subjects, increases in blood pressure and insulin resistance with fat
gain will be most marked in those individuals with a predominantly upper body and
visceral fat accumulation.

- Upper body and visceral fat gain will also be associated with greater impairment in
cardiovascular function, higher nocturnal blood pressures and an increased likelihood
of sleep disordered breathing.