Diet regimens and study design. (A) Following the week 15 diet switch, the control mice remained on the same low-fat control diet, and the diet-induced obesity (DIO) mice were randomized to either remain on the DIO diet (obese) or change to 1 of 4 weight loss regimens: non-restricted low-fat diet (LFD), low-fat calorie restricted (LFCR), Mediterranean-style calorie restricted (MCR), or intermittent calorie-restricted (ICR). The control, obese, and LFD mice were fed ad libitum, with the LFD group receiving the same low-fat diet as the control group. The LFCR and MCR groups were chronically 30% calorie restricted, receiving a daily food pellet of their respective diets equal to 70% of the previous week’s average daily control mouse kcal intake. On Mondays and Thursdays, the ICR mice received the high protein 2-day ICR diet in an amount equal to 30% of the previous week’s average daily control mouse kcal intake. On the other days of the week, the ICR mice received the 5-day ICR diet in an amount equal to 87% of the average daily control mouse kcal intake. See Table 1 for the macronutrient and fatty acid content of each diet. (B) At study initiation, the mice were randomized to 2 diets: DIO or control. After 15 weeks, the DIO mice were further randomized to remain on DIO (Obese) or switch to 1 of 4 weight loss diets: non-restricted LFD, LFCR, MCR, and ICR. The mice remained on these diets for 10 weeks and were then orthotopically injected with 3.5×104 E0771 mammary tumor cells. During the 3.5-week period between tumor cell injections and euthanization, the mice continued on the same diets.