Counteracting vitamin D receptor signaling deficiency rescues subcutaneous adipose loss in aging

Subcutaneous adipose tissue (SAT) is a type of white adipose tissue (WAT) located beneath the skin, and plays important roles in energy storage, thermal insulation, mechanical protection and endocrine. In naturally aging and Hutchinson-Gilford progeria syndrome (HGPS), a rare progeroid disorder, SAT declines, yet the underlying mechanism is still poorly understood, and the clinical intervention is limited. Here, we demonstrate that adipogenesis defect contributes to SAT decline in both naturally aging and HGPS, which is driven by vitamin D receptor (VDR) deficiency. Mechanistically, VDR signaling enables adipogenesis by upregulating commitment factor zinc-finger protease ZNF423 and adipogenesis activators while downregulating adipogenesis inhibitors, and VDR deficiency causes significant subcutaneous adipogenesis defect and SAT decline in mice. We also identify that emerin interacts with VDR. Progerin expression disrupts emerin and thus leads to VDR deficiency and drives adipogenesis defect and SAT loss in HGPS. More importantly, counteracting VDR deficiency by calcipotriol dramatically promotes adipogenesis and alleviates SAT loss in HGPS mice. Collectively, this study highlights the role of VDR in subcutaneous adipogenesis and SAT homeostasis during aging, and provides a potential strategy for SAT loss treatment.