Weaning in mammals is associated with a shift in the metabolism, driven by the differences in the macronutrient composition of milk and post-weaning diet. Milk has a higher fat content compared with the carbohydrate-enriched solid food. Malnutrition during this stage could affect this transition with long-term adverse effects. The role of micronutrients during this transition is not well understood.

We used mice lacking a functional vitamin D receptor (VDR) to study the role of vitamin D signalling in the metabolic transition during weaning.

We demonstrate that after weaning, VDR knockout mice exhibit systemic energy deprivation and higher lipolysis in inguinal white adipose tissue, probably due to increased norepinephrine signalling via protein kinase A (PKA) and extracellular signalling-regulated kinase (ERK) pathways. The energy deprivation in vdr−/− mice is associated with defective liver glycogenolysis, characterized by increased expression of protein phosphatase-1 alpha and decreased glycogen phosphorylase activity. However, restoration of serum calcium and phosphate levels by a rescue diet is sufficient to restore energy metabolism in vdr−/− mice. Interestingly, maintaining a high-fat-containing milk-based diet post-weaning could prevent the onset of energy deprivation, liver glycogen storage defect, and adipose atrophy in these mice.

Our data show that vitamin D-signalling is essential for the adaptation of mice to the dietary shift from high-fat-containing milk to post-weaning carbohydrate-enriched diets. It also reveals a novel macronutrient–micronutrient interaction that shapes the metabolic flexibility of the individual based on the dietary composition of nutrients.