Endothelial cell-derived stem cell factor promotes lipogenesis through c-Kit-mediated upregulation of lipogenic enzymes in brown adipocytes

Abstract: Thermogenic function of brown adipose tissue (BAT) has beneficial effects in metabolic diseases by utilizing lipids and glucose, whereas inactive BAT accumulates lipids in brown adipocytes (BAs), leading to BAT whitening. Although cellular crosstalk between endothelial cells (ECs) and adipocytes is important for fatty acid uptake in adipocytes, the roles of ECs in de novo lipogenesis (DNL) of adipocytes have been poorly understood. Using single-nucleus RNA sequencing and knock-out mice, we demonstrate that stem cell factor (SCF) from ECs promotes DNL by activating c-Kit in BAs. In the early phase of lipid accumulation induced by denervation or thermoneutrality, transiently expressed c-Kit on BAs upregulates DNL enzymes via PI3K and AKT signaling. EC-specific SCF deletion and BA-specific c-Kit deletion attenuate lipogenic enzymes and inhibit the enlargement of lipid droplets in BAs after denervation or thermoneutrality. These data provide insight into SCF/c-Kit signaling as a novel lipogenic regulator that promotes DNL in the early phase of lipid accumulation when thermogenesis is inhibited in BAT.