Beneficial reprogramming of lipid metabolism with intermittent fasting

Caloric restriction is the most conserved behavioral intervention that prolongs lifespan in model organisms. Capturing benefits of caloric restriction, either through dietary prescription or by identifying causal pathways that can be manipulated pharmacologically, holds promise to improve cardiometabolic health. Testing whether the life-prolonging effect is translatable to humans is challenging; however, multiple studies, with various approaches to caloric restriction, have demonstrated benefits to surrogate endpoints such as weight loss, lipids, and glucose homeostasis. One important question is the degree to which benefits of caloric restriction are due to weight loss—i.e. would we all benefit from caloric restriction or are the benefits most applicable to patients who are overweight? Moreover, long-term compliance with a diet requiring daily adherence is challenging. Intermittent fasting has emerged as an alternative that does not require daily adherence and early studies suggest metabolic benefit. Our multi-disciplinary research group has focused on studying fasting because there is theoretical benefit independent of weight loss. Through coupling of clinical phenotyping with multi-omics analyses, we have defined metabolic responses as a function of fasting duration and in relationship to key physiological events, such as weight loss and changes in bone metabolism, as catabolic effects on bone are a consistent negative result of caloric restriction with weight loss. We have discovered a marked fasting shift in lipid composition— sustained even after re-feeding—characterized by reduced low carbon-content, saturated triglycerides and increased high- carbon content, unsaturated triglycerides; a triglyceride shift shown in epidemiologic studies to protect against future cardiometabolic disease and frailty. Remarkably, the beneficial shift in triglyceride quality is already evident in the first fasting day, before weight loss or negative changes in bone turnover markers. Therefore, our central hypothesis is that fasting drives cardiometabolic benefits independent of weight loss and the benefits can be captured without negative effects to bone if each fasting dose is limited to one day. We propose a mechanistic clinical study, randomizing volunteers at high risk of diabetes, to one of 3 groups: 1) Control group, 2) Fasting one day per week for 3 months, or 3) Fasting one day per week with a caloric prescription to maintain body weight. In Aim 1 we will perform metabolomics to test whether intermittent fasting beneficially reprograms lipid metabolism, whether that reprogramming predicts improved insulin sensitivity and whether these changes occur independent of weight loss. Recognizing that the most important negative consequence of any approach to caloric restriction is the catabolic effect on bone, in Aim 2 we will assess the effects on bone, including state of the art analyses of bone microarchitecture. If successful, this study will provide proof-of-concept for a once weekly fasting intervention to improve cardiometabolic health without compromising bone integrity. Moreover, by merging a randomized-control study design with rigorous clinical phenotyping and metabolomics, this project holds promise to identify novel metabolic mechanisms underpinning the benefits of fasting.