Roles of Adipose Tissue VLDL-VLDLR Axis in Energy Metabolism

Elevated plasma triglyceride-rich lipoprotein, such as very low-density lipoprotein (VLDL), is considered a risk factor for prevalence of obesity, type 2 diabetes mellitus, and atherosclerosis. VLDL receptor (VLDLR), one of the lipoprotein receptor family proteins, is involved in clearance of circulating VLDL. In obese animals, adipose tissue macrophages (ATMs) contain high level of lipid metabolites, which seems to be linked to pro-inflammatory responses. However, it has not been thoroughly understood whether lipid uptake via VLDLR in macrophages is involved in obesity-induced inflammatory responses and insulin resistance. In this study, we demonstrate that elevated VLDLR in ATMs could accelerate adipose tissue inflammation and glucose intolerance in obesity. Expression of VLDLR was increased in ATMs from obese mice. In VLDL-treated macrophages, the level of ceramides was elevated through VLDLR, which potentiates pro-inflammatory responses and augments M1-like macrophage polarization. Moreover, adoptive transfer of VLDLR knockout bone marrow to wild type mice relieved adipose tissue inflammation and improved insulin resistance in diet-induced obesity. Taken together, these findings suggest that increased VLDL-VLDLR axis in ATMs would aggravate adipose tissue inflammation and insulin resistance in obesity.