Since being overweight appears to be a risk factor in atherosclerotic cardiovascular disease (ACVD) in man and monkeys, patients are urged to reduce weight. However, the majority of these patients regain weight, usually in repeated cycles of weight loss/regain (yo-yo dieting). Single cycles of regain after weight loss cause in man and experimental animals marked increases in blood pressure, hypertensive proliferative lesions in the arterial intima (dogs, swine, rats, mice), aggravation of atherosclerosis (swine) and ACVD (man). Additionally, repeat cycles of weight loss/regain cause in lower mammals a greater metabolic efficiency resulting in a progressively less rapid weight loss, more rapid regain and a lower energy requirement to maintain excess body weight. It may well be that persistant overweight is preferable to yo-yo dieting in terms of cardiovascular risk as well as metabolic consequences, if a one- time weight reduction cannot be maintained. Clinical and post- mortem hard endpoint data on these major public health issues are urgently needed but not likely to be obtained in human studies at present. We, therefore, propose to study these issues in a closely related nonhuman primate model (Macaca fascicularis monkeys) comprising the following groups of animals: 1) normal control monkeys; 2) monkeys on a high calorie-atherogenic diet for 18 months (baseline weight gain/atherosclerosis); 3) maintenance of this high calorie diet for 30 more months; 4) severe calorie restriction after 18 months of high calorie-atherogenic diet and maintenance of a low calorie diet for 30 more months; and 5) 3 repeated cycles of severe calorie restriction (3 months) and high calorie-atherogenic diet (6 months) over a period of 30 months following the initial 18 months on high calorie-atherogenic diet. The following in vivo (clinical) and post-mortem parameters will be analyzed: metabolic efficiency; body weight and composition; body mass index; body fat distribution; plasma lipids and lipoproteins; endocrine function (glucose and insulin); blood pressure; LVH by EKG; thickness of subcutaneous fat and of skeletal muscles, muscle/fat ratios; arteries: weight, thickness and composition (morphometry, biochemistry) of intima, media and atherosclerotic lesions (coronary arteries perfusion-fixed); heart size and weight, left ventricular mass, wall thickness and myocardial composition (morphology and biochemistry). It is anticipated that: (1) loss of excessive body weight reduces ACVD if maintained while repeat weight loss/regain cycles markedly aggravate it and (2) the post-mortem endpoints can be correlated to in vivo (clinical) parameters.
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