Flipping the Metabolic Switch: Understanding and Applying the Health Benefits of Fasting

Abstract

Objective: Intermittent fasting (IF) is a term used to describe a variety of eating patterns in which no or few calories are consumed for time periods that can range from 12 hours to several days, on a recurring basis. This review is focused on the physiological responses of major organ systems, including the musculoskeletal system, to the onset of the metabolic switch: the point of negative energy balance at which liver glycogen stores are depleted and fatty acids are mobilized (typically beyond 12 hours after cessation of food intake).

Results and conclusions: Emerging findings suggest that the metabolic switch from glucose to fatty acid-derived ketones represents an evolutionarily conserved trigger point that shifts metabolism from lipid/cholesterol synthesis and fat storage to mobilization of fat through fatty acid oxidation and fatty acid-derived ketones, which serve to preserve muscle mass and function. Thus, IF regimens that induce the metabolic switch have the potential to improve body composition in overweight individuals. Moreover, IF regimens also induce the coordinated activation of signaling pathways that optimize physiological function, enhance performance, and slow aging and disease processes. Future randomized controlled IF trials should use biomarkers of the metabolic switch (e.g., plasma ketone levels) as a measure of compliance and of the magnitude of negative energy balance during the fasting period.

Figure 1

Summary of the major metabolic pathways involved in the metabolic switch and responses of excitable cells to the ketone β-hydroxybutyrate (β-OHB). See text for description. AcAc, acetoacetate; ATP, adenosine triphosphate; FFA, free fatty acids; TCA, tricarboxylic acid.

Figure 2

Profiles of circulating glucose and ketone levels over 48 hours in individuals with a typical American eating pattern or two different IF eating patterns. (a) In individuals who consume three meals plus snacks every day the metabolic switch is never ‘flipped’ and their ketone levels remain very low, and the area under the curve for glucose levels is high compared to individuals on an IF eating pattern. (b) In this example, the person fasted completely on the first day and then at three separate meals on the subsequent day. On the fasting day ketones are progressively elevated and glucose levels remain low, whereas on the eating day ketones remain low and glucose levels are elevated during and for several hours following meal consumption. (c) In this example the person consumes all of their food within a 6-hour time window every day. Thus, the metabolic switch is flipped on following 12 hours of fasting and remains on for approximately six hours each day, until food is consumed after approximately 18 hours of fasting. Modified from Mattson et al 2016.(9)

Figure 3

Examples of functional effects and major cellular and molecular responses of various organ systems to IF. In humans and rodents, IF results in decreased levels of circulating insulin and leptin, elevated ketone levels, and reduced levels of pro-inflammatory cytokines and markers of oxidative stress. Liver cells respond to fasting by generating ketones and by increasing insulin sensitivity and decreasing lipid accumulation. Markers of inflammation in the intestines are reduced by IF. The insulin sensitivity of muscle cells is enhanced and inflammation reduced in muscle cells in response to the metabolic switch triggered by fasting and exercise. Emerging findings further suggest that exercise training in the fasted state may enhance muscle growth and endurance. Robust beneficial effects of IF on the cardiovascular system have been documented including reduced blood pressure, reduced resting heart rate, increased heart rate variability (improved cardiovascular stress adaptation) and resistance of cardiac muscle to damage in animal models of myocardial infarction. Studies of laboratory animals and human subjects have shown that IF can improve cognition (learning and memory); the underlying mechanisms may involve neurotrophic factors, stimulation of mitochondrial biogenesis and autophagy, and the formation of new synapses. IF also increases the resistance of neurons to stress and suppresses neuroinflammation. *Demonstrated in animal models, but not yet evaluated in humans.