ANGPTL4 mediates shuttling of lipid fuel to brown adipose tissue

27 Brown adipose tissue (BAT) activation via cold exposure is increasingly scrutinized as a 28 potential approach to ameliorate cardio-metabolic risk. Transition to cold temperatures 29 requires changes in the partitioning of energy substrates, re-routing fatty acids to BAT to fuel 30 non-shivering thermogenesis. However, the mechanisms behind the redistribution of energy 31 substrates to BAT remain largely unknown. Angiopoietin-like 4 (ANGPTL4), a protein that 32 inhibits lipoprotein lipase (LPL) activity, is highly expressed in BAT. Here, we demonstrate 33 that ANGPTL4 is part of a shuttling mechanism that directs fatty acids derived from 34 circulating triglyceride-rich lipoproteins to BAT during cold. Specifically, we show that cold 35 markedly down-regulates ANGPTL4 in BAT, likely via activation of AMPK, enhancing LPL 36 activity and uptake of plasma triglyceride-derived fatty acids. In contrast, cold up-regulates 37 ANGPTL4 in WAT, abolishing a cold-induced increase in LPL activity. Together, our data 38 indicate that ANGPTL4 is an important regulator of plasma lipid partitioning during sustained 39 cold. 40