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Persistence of the Hypertriglyceridemic Effect of Tumor Necrosis Factor Despite Development of Tachyphylaxis to Its Anorectic/Cachectic Effects in Rats¹

Metabolism and Cardiology Sections, Medical Service, Veterans Administration Medical Center, San Francisco, and Department of Medicine, University of California, San Francisco, California 94121

The administration of a single injection of tumor necrosis factor (TNF) produces a variety of acute and sustained biological effects, including hyperlipidemia, stimulation of hepatic lipogenesis, decreases in adipose tissue lipoprotein lipase activity, and anorexia with weight loss. Chronic administration of a fixed dose of TNF produces tachyphylaxis to the anorectic/cachectic effects of TNF. We now report that the hyperlipidemic effect of TNF persists during chronic TNF administration in the absence of any cachectic effect of TNF. Sprague-Dawley rats injected with TNF (250 µg/kg) show a significant decrease in weight over the next 24 h which can be accounted for by decreases in food and water intake accompanied by an increase in urine output. With subsequent daily injections of TNF, treated rats begin eating and rapidly regain weight. Hypertriglyceridemia persists for up to 10 days of daily injections of TNF. After three daily injections of TNF, no decreases were seen in lipoprotein lipase activity in a wide variety of tissues. De novo hepatic lipogenesis remained increased in TNF-treated animals after four daily injections, but by the fifth day hepatic lipogenesis returned to normal. After 5 days of TNF treatment the acute incorporation of labeled glycerol into serum triglycerides remained elevated. These data indicate that hyperlipidemia persists during multiple daily injections of TNF and that TNF induced hypertriglyceridemia is not inevitably linked to the syndrome of cachexia.

¹ This work was supported in part by grants from the Veterans Administration, the NIH (DK37102), and the University of California Universitywide Task Force on AIDS. Portions of this manuscript were submitted by H. W. in partial fulfillment of the degree of Master of Science in Clinical Science at the Center for Advanced Medical Technology of San Francisco State University.

² Clinical Investigator at the Veterans Administration. To whom correspondence should be addressed, at Metabolism Section (111F), Veterans Administration Medical Center, 4150 Clement Street, San Francisco, California 94121.

³ Current address: Applied ImmuneSciences, 200 Constitution Drive, Menlo Park, CA 94025.

Received 11/10/88. Revised 2/14/89. Accepted 2/20/89.

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