Mitochondrial metabolism and central nervous system dysregulation govern an overeating but low energy conversion efficiency response to intermittent-feeding

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The ideal type of diet is a long-sought goal that has not been fulfilled so far, both for preventive as well as therapeutic purposes. At the same time, caloric restriction has been well demonstrated to afford increase in lifespan in several species. Intermittent feeding has been used as a substitute for caloric restriction both by overweight or obese individuals (frequently without medical supervision) or, experimentally, as a mechanistical tool to understand the physiology of lifespan extension. These intermittently-fed animals, indeed display decreased body mass, but surprisingly overall caloric intake is similar to that of ad libitum-fed animals. Work performed by the CEPID-Redoxoma group led by Kowaltowski and collaborators provided a detailed analysis to unravel this paradox. The authors showed that intermittent diets, alternating 24-hour fasting and feeding periods, promote lowed body mass, while associating with overeating during fed periods. Such lower energetic efficiency of diets was linked to increased lipid oxidation during fasting days and higher metabolic rates during fed days. Mitochondrial bioenergetics was unaltered, and the lower energy conversion was not due to uncoupling of electron transport chain. Importantly, hypothalamic energy metabolism control was significantly altered, increasing hunger and energy expenditure. Evidence was provided that intermittently fasted animals present higher levels of the orexigenic hypothalamic mediators AGRP and NPY both when fed and fasted, leading to overeating when food is available. High levels of lipid oxidation on fasting days, associated with higher catabolic rates during feeding days, promote lower energy conversion efficiency leading to lower body mass in intermittent feeding. This work clarifies mechanistical pathways involved in feeding and metabolic rates after caloric restriction. While it is premature to associate these findings to human conditions, the results implicate very distinct bioenergetic consequences arising from different restrictive dietary interventions.

Comment on: Chausse B, Solon C, Caldeira da Silva CC, Masselli Dos Reis IG, Manchado-Gobatto FB, Gobatto CA, Velloso LA, Kowaltowski AJ. Intermittent fasting induces hypothalamic modifications resulting in low feeding efficiency, low body mass and overeating. Endocrinology. 2014 Jul;155(7):2456-66.

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