Abstract
The phenotypic stability of somatic cells is essential for the maintenance of both structural and functional organ integrity of the adult human body. Deregulated cell plasticity could result in the development of debilitating diseases such as cancer, fibrosis, atherosclerosis, obesity, and type 2 diabetes. We have previously demonstrated that a nonsense mutation in the NPC2 gene, which encodes ubiquitous, highly conserved, secretory protein with unknown function, leads to activation of human skin fibroblasts. The activated fibroblasts, also known as myofibroblasts, have the properties of mesenchymal stem cells and are able to differentiate along the mesodermal and endodermal lineages. Here we show that NPC2-null, but not the normal skin fibroblasts, possess characteristics of adipogenic progenitors as demonstrated by their specific gene expression pattern as well as the ability for efficient differentiation into white adipocytes. The presence of NPC2 in mature white adipocytes was also necessary for their maintenance because silencing NPC2 in differentiated cells by siRNA stimulated PPARG expression, which was followed by a shift toward a more favorable, brown adipocyte-like metabolic state characterized by up-regulated lipolysis and increased insulin sensitivity. It appears that NPC2 controls both the adipogenesis and the metabolic state of mature white adipocytes through a common mechanism that is linked to activation of FGFR2 that could be followed by induction of PPARG expression. Altogether, the current study highlights NPC2 as a novel intracrine/autocrine factor that controls adipocyte differentiation and function as well as potential therapeutic target for the treatment of type 2 diabetes and related metabolic disorders.