Research has demonstrated that consumption of milk promotes weight loss and satiety, however conflicting evidence also exists. Therefore, we tested the effect of long-term milk consumption on body weight and metabolic parameters. Newly weaned mice received whole milk, low-fat milk, or water as control for 17 weeks and serum, liver, and white adipose tissue (WAT) were tested for parameters associated with obesity and diabetes. Our results show that low-fat milk leads to the same overall caloric intake and body weight as the control group. However, the whole-milk group consumed more calories and reached a higher body weight. In addition, in the low-fat milk group, cholesterol, HDL-cholesterol, triglycerides, leptin, ghrelin, insulin, corticosterone, and glucagon were not significantly different than the control group. In contrast, in the whole-milk group, cholesterol, HDL-cholesterol, triglycerides, and glucagon were high compared with the control group. Metabolism in both liver and WAT showed only slight differences between themilk groups. Whereas the whole-milk group showed reduced insulin signaling in WAT, the low-fat milk group exhibited increased insulin signaling. Whole-milk consumption leads to increased body weight and caloric intake and reduced insulin signaling in WAT, as opposed to low-fat milk consumption.