Fat Gain and Cardiovascular Disease Mechanisms

DESCRIPTION (provided by applicant): We propose a series of novel studies directed at establishing the effects of increased body fat in healthy individuals. We will determine the distribution patterns of increased body fat and how both increased body fat and fat distribution may affect blood pressure, as well as neural, vascular and inflammatory mechanisms which have been implicated in cardiac and vascular disease. We will study sedentary subjects with and without a family history of hypertension. These subjects will undergo a program of overfeeding with the objective of inducing a 2 kg fat gain. We will study these individuals before and after the 4-week fat gain program and subsequently after an 8-week period of weight loss and restoration of normal weight. Measurements will also be compared to those in a matched control group with and without a family history of hypertension, who continue their normal diet. We will test the following hypotheses: 1) Individuals with a family history of hypertension will gain more visceral and upper body fat and have greater blood pressure increases with overfeeding, compared to those without such a family history. 2) For all overfed subjects, increases in blood pressure, sympathetic activity and insulin resistance with fat gain will be most marked in those individuals with a predominantly upper body and visceral fat accumulation. 3) Upper body and visceral fat gain will also be associated with greater impairment in baroreflex sensitivity, endothelial function and chemoreflex function, and an increased likelihood of abnormalities during sleep, including higher nocturnal blood pressures and sleep disordered breathing. 4) Fat gain, particularly upper body and visceral, will be accompanied by enhanced production of inflammatory mediators linked to cardiovascular risk, including adhesion molecules and C-reactive protein. 5) The above changes will resolve with subsequent loss of weight and restoration of normal body fat. These studies build on established programs, one addressing obesity, sleep disordered breathing and cardiovascular disease directed by Dr. Somers, and the other examining mechanisms regulating body fat in humans, directed by Dr. Jensen. This integrated state-of-the-art approach will enable important and novel insights into interactions between fat gain and neural, vascular, and inflammatory cardiovascular disease mechanisms.