From starvation to time-restricted eating: a review of fasting physiology

Abstract

We have long known that subjects with obesity who fast for several weeks survive. Calculations that assume the brain can only use glucose indicated that all carbohydrate and protein sources would be consumed by the brain within several weeks yet subjects with obesity who fasted for several weeks survived. This anomaly led to the determination of the metabolic role of ketone bodies. Subsequent studies transformed our understanding of ketone bodies and illustrated the value of challenging the norm and adapting theory to evidence. Although prolonged fasting is no longer a treatment for obesity, the early studies of starvation provided valuable insights about macronutrient metabolism and ketone body adaptations that fasting elicits. Intermittent fasting and its variants such as time-restricted eating are fasting models that are far less regimented than starvation and severe calorie restriction; yet they produce metabolic benefits. The mechanisms that produce the metabolic changes that intermittent fasting elicits are relatively unknown. In this article, we review the physiology of starvation, starvation adaptation diets, diet-induced ketosis, and intermittent fasting. Understanding the premise and physiology that these regimens induce is necessary to draw parallels and provoke thoughts on the mechanisms underlying the metabolic benefits of intermittent fasting and its variants.

Figure 1,. Time-restricted feeding and lipid metabolism in the liver.

Fasting increases adenosine monophosphate (AMP) levels which in turn activates AMP kinase. Acetyl-CoA carboxylase (ACC) catalyzes the carboxylation of acetyl-CoA to malonyl-CoA. In its phosphorylated form ACC is enzymatically inactive, which reduces the synthesis of malonyl-CoA. Additionally, time-restricted feeding increases the expression of the circadian clock repressor component Rev-erb and its direct target is the key lipogenic gene fatty acid synthase (Fasn). Increased phosphorylation of ACC and reduced mRNA expression of Fasn act synergistically to reduce fatty acid synthesis. Furthermore, malonyl-CoA allosterically inhibits carnitine palmitoyltransferase (CPT) essential for the transit of long-chain fatty acids and acylcarnitine esters into the mitochondria for β-oxidation. Reduced levels of malonyl-CoA increase availability of fatty acids to promote fat oxidation and ketogenesis. Figure created in Biorender.com