Increased thermogenesis by a noncanonical pathway in ANGPTL3/8-deficient mice

Dietary triglyceride (TG) is the most efficient energy substrate. It is processed and stored at substantially lower metabolic cost than is protein or carbohydrate. In fed animals, circulating TGs are preferentially routed for storage to white adipose tissue (WAT) by angiopoietin-like proteins 3 (A3) and 8 (A8). Here, we show that mice lacking A3 and A8 (A3(−/−)A8(−/−) mice) have decreased fat mass and a striking increase in temperature (+1 °C) in the fed (but not fasted) state, without alterations in food intake or physical activity. Subcutaneous WAT (WAT-SQ) from these animals had morphologic and metabolic changes characteristic of beiging. O(2) consumption rates (OCRs) and expression of genes involved in both fatty acid synthesis and fatty acid oxidation were increased in WAT-SQ of A3(−/−)A8(−/−) mice, but not in their epididymal or brown adipose tissue (BAT). The hyperthermic response to feeding was blocked by maintaining A3(−/−)A8(−/−) mice at thermoneutrality or by treating with a β3-adrenergic receptor (AR) antagonist. To determine if sympathetic stimulation was sufficient to increase body temperature in A3(−/−)A8(−/−) mice, WT and A3(−/−)A8(−/−) animals were maintained at thermoneutrality and then treated with a β3-AR agonist; treatment induced hyperthermia in A3(−/−)A8(−/−), but not WT, mice. Antibody-mediated inactivation of both circulating A3 and A8 induced hyperthermia in WT mice. Together, these data indicate that A3 and A8 are essential for efficient storage of dietary TG and that disruption of these genes increases feeding-induced thermogenesis and energy utilization.