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Little is known about the fate of the lipolytic products produced by the action of lipoprotein lipase (LPL) on circulating triglyceride-rich lipoproteins in humans. We studied eight lean, healthy male subjects after an overnight fast. Subjects received infusions of lipid emulsions containing triolein labeled with (3)H on both the glycerol backbone and the fatty acid portion of the molecule; (14)C glycerol and (14)C oleate were coinfused to quantify the systemic and forearm release of (3)H glycerol and (3)H oleate resulting from LPL action. There was significant forearm uptake of both whole plasma triglyceride (presumed to represent primarily VLDL; extraction fraction 2.6 +/- 0.6%, P < 0.005 vs. zero) and radiolabeled triglyceride derived from the lipid emulsion (a surrogate for chylomicrons; extraction fraction 31 +/- 4%, P < 0.005 vs zero). Systemic clearance and forearm fractional extraction of glycerol was greater than that of oleate (P < 0.001 and P < 0.02, respectively). The systemic and forearm fractional release of LPL-generated glycerol were similar at 51 +/- 4 and 59 +/- 1%, respectively (NS). In contrast, the forearm fractional release of LPL-generated oleate was less than systemic fractional release (14 +/- 2 vs. 36 +/- 4%, P < 0.0001). These results indicate that there is escape, or spillover, of the lipolytic products of LPL action on triglyceride-rich lipoproteins in humans. They further suggest that LPL-mediated fatty acid uptake is an inefficient process, but may be more efficient in muscle than in adipose tissue.