Changes in Macronutrients during Dieting Lead to Weight Cycling and Metabolic Complications in Mouse Model

Weight cycling is a major challenge in obesity management. Caloric restriction is known to promote this phenomenon, but the impact of macronutrient changes during dieting remains unclear. This study aimed to determine the role of macronutrient changes in weight maintenance without caloric restriction by alternating between two hypercaloric diets: a high-carbohydrate, high-fat Western diet (WD) and a low-carbohydrate, high-fat diet (LCHDF). Obesity was induced in 8-week-old C57BL/6 male mice by 10 weeks of WD feeding. Then, the mice were subjected to 12 weeks of LCHFD interspersed with WD (I-WD), 3 periods of 2-week LCHFD followed by 2 periods of 3-week WD, or 12 weeks of continuous WD (C-WD). C-WD and I-WD mice were compared to standard diet (SD) mice. In the I-WD group, each LCHFD period decreased weight gain, but mice regained weight after WD resumption. I-WD mice exhibited obesity, dyslipidemia, and glucose intolerance, similarly to the C-WD mice. I-WD mice also developed nonalcoholic steatohepatitis, associated with an increase in type-III collagen gene expression and a decrease in FGF21 protein levels, in comparison with SD. I-WD mice developed weight cycling despite maintaining a high caloric consumption, suggesting that changes in macronutrients during dieting are also a trigger of weight regain.