Fig. 6.
Effect of inactivating circulating A3, A8, and A3 plus A8 on rectal temperature. (A) Anti-human A8 (REGN3776; 10 mg/kg) and anti-mouse A3 (REGN1500; 10 mg/kg) or control monoclonal antibodies (CTRL IgG; RG1945) were given i.v. for 3 d to ANGPTL8hum/hum mice (n = 6 per group; age 9 wk). Values are means ± SEM. Groups were compared by using unpaired t tests. **P < 0.01. The experiment was repeated, and the results were similar. (B) Overview of postprandial TG metabolism in WAT-SQ from WT (Upper) and A3−/−A8−/− (Lower) mice. In fed WT mice, circulating dietary TGs are hydrolyzed by LPL, and FAs are taken up into adipocytes, where they are esterified and stored as TG in lipid droplets. Norepinephrine (NE) activates β3-AR, resulting in activation of ADCY6, which generates cAMP and subsequent phosphorylation and activation of protein kinase A (PKA-P). PKA-P activates both TG hydrolysis and oxidative phosphorylation; the rise in intracellular FA inhibits ADCY6, thus inhibiting these downstream pathways. In WAT-SQ from A3−/−A8−/− mice, LPL in oxidative tissues fails to be suppressed, resulting in diminished delivery of circulating TG to WAT (9). Glucose uptake and its conversion to FAs is increased in these animals. The reduced intracellular concentration of FA may fail to suppress ADCY6, accounting for the increased in cAMP levels. We hypothesize that this results in activation of PKA, causing an increase in both lipolysis and oxidative phosphorylation.