1α,25(OH)2 Vitamin D3 Signaling in Adipose Tissue: Bridging Classical and Non-Classical Pathways in Metabolic Regulation Complexity

Background: Adipose tissue is increasingly recognized as a highly dynamic endocrine and immunometabolic organ with marked functional heterogeneity. It serves as a reservoir for the active form of vitamin D3, 1α,25-dihydroxyvitamin D3 or calcitriol (1α,25-D3), since it expresses enzymes responsible for its activation and inactivation and contains the vitamin D receptor (VDR). Through both classical and non-classical mechanisms, calcitriol modulates adipocyte proliferation and differentiation, protein expression and energy metabolism. This review aims to explore the signal transduction mechanisms of calcitriol in adipocytes, detailing the classical pathways mediated by the nuclear VDR (VDRn), as well as non-classical pathways involving membrane-associated VDR (VDRm), microRNAs, AMP-activated protein kinase (AMPK), and sirtuin 1 (SIRT1). Methods: A literature search was conducted using PubMed, ScienceDirect, and MDPI-indexed journals, prioritizing studies published within the last 10 years to ensure the inclusion of up-to-date evidence. Results: This review summarizes current knowledge on both classical and non-classical signaling pathways that are activated by calcitriol and highlights key molecular targets with potential relevance for drug development and therapeutic intervention. Through VDRn, calcitriol regulates the expression of proteins involved in inflammation and energy metabolism. Additionally, it modulates cellular processes such as energy production and secretion via the AMPK/SIRT1 axis and microRNA-mediated pathways, contributing to mitochondrial function and metabolic homeostasis. Conclusions: Calcitriol plays a central role in adipocyte biology by integrating multiple signaling pathways that regulate metabolic and inflammatory responses. These mechanisms highlight its potential as a therapeutic target and biomarker in metabolic diseases. Moreover, microRNAs emerge as critical posttranscriptional regulators in these processes, reinforcing their relevance as both biomarkers and targets for future interventions.