Lipoprotein lipase is an enzyme in adipose tissue that hydrolyzes circulating triglycerides and thereby generates the fatty acids used in the synthesis of triglyceride in fat cells. To determine whether the activity and expression of lipoprotein lipase are affected by weight loss, we studied lipoprotein lipase in the adipose tissue of nine very obese subjects before and after a program of weight reduction. The subjects' mean (±SEM) initial weight was 136±7.3 kg, and the body-mass index (weight in kilograms divided by the square of the height in meters) ranged from 33.3 to 52.8 (mean, 43.0±2.5). Biopsies of adipose tissue were performed before weight loss and after it, when weight had been stable for three months. The weight reduction was achieved by a very-low-calorie diet (mean weight loss, 42.5±6.8 kg). After weight loss, the level of heparin-releasable lipoprotein lipase activity increased in all patients, from 3.8±1.1 to 7.1 ±1.6 neq of free fatty acid released per minute per 106 cells (P<0.05). In addition, the amount of lipoprotein lipase immunoreactive protein increased from 6.3±1.7 to 24.4±6.9 ng per 106 cells (P<0.05), and there was also an increase in the level of lipoprotein lipase messenger RNA as measured by Northern blotting. There was a strongly positive correlation between the initial body-mass index and the magnitude of the increase in lipoprotein lipase activity (r = 0.80, P<0.01) and immunoreactive protein (r = 0.92, P<0.01). We conclude that weight loss in very obese subjects leads to the increased activity and expression of lipoprotein lipase, thereby potentially enhancing lipid storage and making further weight loss more difficult. (N Engl J Med 1990;322:1053–9.) © 1990, Massachusetts Medical Society. All rights reserved.