Low-protein and methionine, high-starch diets increase energy intake and expenditure, increase FGF21, decrease IGF-1, and have little effect on adiposity in mice.

Low-protein diets most often induce increased energy intake in an attempt to increase protein intake to meet protein needs with a risk of accumulation as fat of the excess energy intake. In female adult BALB/c mice, a decrease in dietary casein from 20% to 6% and 3% increased energy intake and slightly increased adiposity, and this response was exacerbated with soy proteins with low methionine content. The effect on fat mass was however limited because total energy expenditure increased to the same extent as energy intake. Lean body mass was preserved in all 6% fed mice and reduced only in 3% casein-fed animals. Insulin response to an oral glucose tolerance test was reduced in soy-fed mice and in low-protein-fed mice. Low-protein diets did not affect uncoupling protein 1 and increased fibroblast growth factor 21 (FGF21) in brown adipose tissue and increased FGF21, fatty acid synthase, and cluster of differentiation 36 in the liver. In the hypothalamus, neuropeptide Y was increased and proopiomelanocortin was decreased only in 3% casein-fed mice. In plasma, when protein was decreased, insulin-like growth factor-1 decreased and FGF21 increased and plasma FGF21 was best described by using a combination of dietary protein level, protein-to-carbohydrate ratio, and protein-to-methionine ratio in the diet. In conclusion, reducing dietary protein and protein quality increases energy intake but also energy expenditure resulting in an only slight increase in adiposity. In this process, FGF21 is probably an important signal that responds to a complex combination of protein restriction, protein quality, and carbohydrate content of the diet.