Obesity is increasingly prevalent and associated with decreased longevity and adverse health conditions. Although intentional weight loss (WL) is conjectured to increase longevity, most epidemiologic studies find WL associated with decreased longevity. However, these nonexperimental studies remain open to multiple interpretations and unable to convincingly resolve questions about WL and mortality. A randomized controlled trial (RCT) of intentional WL and longevity is needed. However, an RCT in humans powered to detect effects on mortality would require enormous resources (were it possible at all). The conjecture that WL will increase longevity is bolstered by animal research showing that caloric restriction (CR) increases longevity even if started in mid-life. However, the effects of CR resulting in WL have not been established in animals after the development of obesity. Although extrapolating from rodents to humans is open to question, for the near future, such models may be the only way to experimentally test the effect of WL among obese organisms on mortality. This study is an RCT of the effects of intentional WL on mortality among obese rats.
Specific aims are: 1) test the hypothesis that WL induced by CR among obese rats will reduce mortality rate; 2) evaluate the extent to which WL reduces mortality rate to that of never-obese animals; 3) evaluate the extent to which any WL induced reduction in mortality with WL is dependent on low fat diet composition; and 4) establish a protocol for testing the effects of intentional WL that can be used in future research to evaluate the conditions under which intentional WL does or does not reduce mortality rate. At weaning, 50 Sprague-Dawley rats will be randomized to a high fat (HF; 45 percent of kcal as fat) diet but have their energy intake restricted so that they remain non-obese. Another 50 will be randomized to a low-fat diet and also have their intake restricted to remain non-obese. An additional 225 rats will be fed the HF diet ad lib until 9 months of age to induce obesity. Following obesity induction, the 150 heaviest males and females will be randomized to: 1) a control group which continues to consume the HF diet ad lib; 2) a high-fat WL which receives the high-fat diet but will has their intake restricted to induce a 20 percent reduction in body weight; or 3) a low-fat WL group which is switched to a low-fat diet and has their intake restricted to induce a 20 percent reduction in body weight. Animals will be followed until death or 33 months of age. Differences in mortality rates among groups will be tested via Cox proportional hazards regression. This study will, for the first time, allow a rigorous experimental test of the hypothesis that among obese organisms, WL promotes longevity.
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