Jawla Neha, Khare Shubhi, Yadav Nidhi, Nanda Ranjan Kumar, Arimbasseri G Aneeshkumar
Molecular Genetics Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110067, India.
Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, 110067, India.
Mol Metab. 2025 Jul;97:102158. doi: 10.1016/j.molmet.2025.102158. Epub 2025 Apr 26.
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.
哺乳动物断奶与新陈代谢的转变相关，这种转变由母乳和断奶后饮食中常量营养素组成的差异所驱动。与富含碳水化合物的固体食物相比，母乳的脂肪含量更高。此阶段的营养不良可能会影响这一转变，并产生长期不良影响。人们对微量营养素在此转变过程中的作用了解不足。
我们使用缺乏功能性维生素D受体（VDR）的小鼠来研究维生素D信号在断奶期间代谢转变中的作用。
我们证明，断奶后，VDR基因敲除小鼠表现出全身能量缺乏以及腹股沟白色脂肪组织中更高的脂肪分解，这可能是由于通过蛋白激酶A（PKA）和细胞外信号调节激酶（ERK）途径的去甲肾上腺素信号增加所致。vdr-/-小鼠的能量缺乏与肝脏糖原分解缺陷有关，其特征是蛋白磷酸酶-1α的表达增加以及糖原磷酸化酶活性降低。然而，通过补充饮食恢复血清钙和磷水平足以恢复vdr-/-小鼠的能量代谢。有趣的是，断奶后维持高脂母乳饮食可以预防这些小鼠出现能量缺乏、肝脏糖原储存缺陷和脂肪萎缩。
我们的数据表明，维生素D信号对于小鼠适应从高脂母乳到断奶后富含碳水化合物饮食的饮食转变至关重要。它还揭示了一种新的常量营养素与微量营养素的相互作用，这种相互作用基于营养素的饮食组成塑造了个体的代谢灵活性。
