VLDL-VLDLR axis facilitates brown fat thermogenesis through replenishment of lipid fuels and PPARβ/δ activation.

In mammals, brown adipose tissue (BAT) is specialized to conduct non-shivering thermogenesis for survival under cold acclimation. Although emerging evidence suggests that lipid metabolites are essential for heat generation in cold-activated BAT, the underlying mechanisms of lipid uptake in BAT have not been thoroughly understood. Here, we show that very-low-density lipoprotein (VLDL) uptaken by VLDL receptor (VLDLR) plays important roles in thermogenic execution in BAT. Compared with wild-type mice, VLDLR knockout mice exhibit impaired thermogenic features. Mechanistically, VLDLR-mediated VLDL uptake provides energy sources for mitochondrial oxidation via lysosomal processing, subsequently enhancing thermogenic activity in brown adipocytes. Moreover, the VLDL-VLDLR axis potentiates peroxisome proliferator activated receptor (PPAR)β/δ activity with thermogenic gene expression in BAT. Accordingly, VLDL-induced thermogenic capacity is attenuated in brown-adipocyte-specific PPARβ/δ knockout mice. Collectively, these data suggest that the VLDL-VLDLR axis in brown adipocytes is a key factor for thermogenic execution during cold exposure. [Display omitted] • Cold stimuli promote VLDL uptake in BAT accompanied by elevation of VLDLR • VLDLR deficiency impairs thermogenic activity in BAT • VLDLR-derived VLDL provides fuel sources for thermogenesis via lysosomal processing • VLDL-VLDLR-PPARβ/δ axis facilitates thermogenic execution Shin et al. show that the thermogenic activity of brown adipocytes is regulated by lipoprotein receptors. They suggest that VLDLR-derived VLDL in thermogenic brown adipocytes plays key roles in modulating heat generation by potentiating fuel oxidation and PPARβ/δ activation. [ABSTRACT FROM AUTHOR]