VDR-calcium axis regulates the diet-driven metabolic shift during weaning

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. Mice lacking a functional vitamin D receptor (VDR) progressively develop severe skeletal muscle and adipose atrophy after weaning, suggesting a role for vitamin D signaling in the metabolic transition during weaning. Here, we demonstrate that after weaning, VDR knock-out mice exhibit systemic energy deprivation and higher lipolysis in inguinal white adipose tissue, probably due to increased norepinephrine signaling via protein kinase A (PKA) and extracellular signalling-regulated kinase (ERK) pathways. Energy deprivation in vdr-/- mice is associated with defective liver glycogenolysis, characterized by increased expression of protein phosphatase-1 and decreased phosphorylation of glycogen phosphorylase. However, restoration of serum calcium 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 without restoring serum calcium levels. Our data show that the vitamin D-calcium axis 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.