The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent

Caloric restriction (CR) is a nutritional intervention that reduces the risk of age-related diseases in numerous species, including humans. CR’s metabolic effects, including decreased fat mass and improved insulin sensitivity, play an important role in its broader health benefits. However, the extent and basis of sex differences in CR’s health benefits are unknown. We found that 30% CR in young (3-month-old) male mice decreased fat mass and improved glucose tolerance and insulin sensitivity, whereas these effects were blunted or absent in young female mice. Resistance to fat and weight loss in females was not explained by decreased energy expenditure compared to males. Positron emission tomography-computed tomography (PET/CT) with 18F-fluorodeoxyglucose (18F-FDG) showed that peripheral glucose uptake was comparable between sexes. Instead, CR caused a pronounced suppression of hepatic gluconeogenesis and altered liver ceramide content in males but not in females. In aged mice (18-months old), when females are anoestrus, CR decreased fat mass and improved glucose homeostasis to a similar extent in both sexes. CR-induced fat loss in humans was also sex- and age-dependent: younger females (45 years) this sex difference was absent. Collectively, these studies identify age-dependent sex differences in the metabolic effects of CR and highlight adipose tissue, the liver and oestrogen as key determinants of CR’s metabolic benefits. This has important implications for understanding the interplay between diet and health and for maximising the benefits of CR in humans.