Very long-chain ceramides promote energy expenditure in brown adipose tissue

Abstract Ceramides are increased in the blood in metabolic diseases, including cardiovascular disease and type 2 diabetes. While their cellular roles in insulin resistance and energy metabolism are well established, the functional significance of ceramides in blood plasma remains poorly understood. To address this knowledge gap, we used the selective pressure of acute cold exposure in mice, which rapidly increases very long-chain (VLC) ceramides localized to high-density lipoprotein (HDL) particles. Through heavy labeling, we demonstrated that plasma VLC-ceramides are synthesized in the liver and taken up by brown adipocytes to promote energy expenditure. Inhibition of ceramide synthesis ablates VLC-ceramide production, driving cold intolerance. Mechanistically, HDL-associated VLC-ceramides enhance β3-adrenergic receptor signaling via a previously uncharacterized phosphorylation event, thereby increasing energy expenditure. These results reveal an inter-organ ceramide signaling axis that is dependent on lipoprotein localization and acyl chain length to regulate energy expenditure.