The 5:2 diet induces male-specific weight loss and sex-independent enhancement of lipid storage in mice via activation of GHSR.

Introduction: Despite its popularity and reported benefits in humans, preclinical characterization of the broader physiological impact of the 5:2 diet and potential mechanisms of action are lacking. Methods: To address this deficit, male and female wild-type (WT) mice and mice lacking the receptor for ghrelin (GHSR) were subjected to the 5:2 diet for 3 or 6 weeks with growth and metabolic outcomes assessed. Results: The 5:2 diet reduced weight gain in adolescent male mice by 31% and induced minor weight loss in adult males without affecting body weight in females. Tibial growth rate in adolescent male and female mice was elevated by 9-13%, with marrow adiposity doubled in adolescent males and halved in adolescent females. While these effects in adolescent males were abolished in mice lacking GHSR, adult male weight loss was maintained. Adolescent mice showed rebound hyperphagia on refeeding days without elevating cumulative food intake. The 5:2 diet elevated circulating free fatty acids by 30-57% independent of GHSR. However, inguinal white fat mass was elevated in adolescent males, by 51%, with interscapular brown fat mass elevated in males and females by 37%. The latter was accompanied by increased saturated fatty acid storage, in line with the inverse of thermogenic activity. The hepatic lipid profile was altered without impacting liver weight. Discussion: Thus, our data imply that while the 5:2 diet is an effective weight loss strategy in males, it has no impact on body weight in females. Despite elevating skeletal growth and lipolysis in line with the activity of the growth hormone-IGF-1 axis, this is countered by the bi-weekly ghrelin surges to increase fat mass in ghrelin sensitive depots. This combination of metabolic effects is undesirable, especially in the absence of obesity.