Time-restricted feeding improved metabolic hormone levels and energy metabolism in high-fat diet-fed Leap2-/- mice

Time-restricted feeding combats obesity by restoring the insulin/growth hormone ratio. Growth hormone and appetite are stimulated by ghrelin but inhibited by Leap2. Whether time-restricted feeding reduces weight gain through Leap2 inhibition is unknown. Ten-week-old male Leap2+/+ and Leap2-/- mice were randomly divided into four groups: Leap2+/+ normal diet (n = 6), Leap2+/+ high-fat diet (n = 6), Leap2-/- normal diet (n = 8), and Leap2-/- high-fat diet (n = 8). Body weight was measured weekly. In further experiments, the Leap2-/- high-fat diet mice were randomly assigned to time-restricted feeding or control for 10 weeks. Metabolic parameters were monitored; growth hormone profiles over 6 h were obtained at week 5, and insulin and glucose tolerance tests were performed at week 8 or 9. Expression of metabolism-related genes was assessed in the liver, white adipose tissue, and brown adipose tissue after 10 weeks. Body weight was significantly increased in Leap2-/- mice fed a normal diet and was further increased in both Leap2-/- and wild-type mice by the high-fat diet, with greater weight gain in Leap2-/- mice. Time-restricted feeding decreased body weight, fat weight, and liver weight; improved growth hormone pulsatility, insulin sensitivity, and glucose tolerance; and enhanced lipid metabolism, oxygen consumption, and physical activity during the dark phase, while altering the expression of genes related to glucose and lipid utilization. It decreased adipocyte size and prevented liver fat accumulation. Although Leap2-/- mice gained more weight during high-fat diet feeding, time-restricted feeding improved growth hormone, insulin, glucose, and lipid metabolism without changing total caloric intake over the 10-week protocol, similar to that observed in wild-type mice.