The Effect of Drugs on Lipogenesis from Glucose and Palmitate in Human Adipose Tissue

Abstract

Several drugs were tested for their ability to inhibit lipogenesis in human adipose tissue. Only fenfluramine was found to inhibit the incorporation of T-palmitate and 14C_gtucose into neutral lipid in intact tissue. This effeet was observed at drug coneentrations above 1 mM. Fenfluramine inhibited lipogenesis in broken-cell preparations of human adipose tissue at concentrations of 1 mM and above. However, in this system the N-benzoyloxyethyl derivative of fenfluramine, S. 1513, was also found to inhibit lipogenesis. This drug was more potent than fenfluramine, a significant inhibition bdng observed at 0.4 mM. During inhibition of lipogenesis in homogenates of adipose tissue by fenfluramine radioaetitivity was found to aeeumulate in long-ehain aeyl-CoA whieh suggests that the drug may interfere with acylation of glycerol 3-phosphate. Evidence that fenfluramine may have a similar effeet in vivo was considered, but the results were not statistically significant.

Effect of Fenfluramine on Human Growth Hormone Release

“…This supports the observation that o 30 bO 90 120 in-vitro fenfluramine inhibits the metabolism of glucose to Time (min) a-glycerophosphate in adipose tissue and decreases fat synthesis sma HGH (>units/ml, means + S.E. of mean) (Wilson and Galton, 1971). cts after two periods of 20 min exercise.…”

The glycerol phosphate, dihydroxyacetone phosphate and monoacylglycerol pathways of glycerolipid synthesis in rat adipose-tissue homogenates

“…The equivalent inhibition was not obtained until about 15mM in the present work (Table 1). Wilson & Galton (1971) reported an inhibition of neutral-lipid synthesis by human adipose tissue by 2-3 mM-fenfluramine, which they attributed to an inhibition of glycerol phosphate acyltransferase. In the present work concentrations of norfenfiuramine in this range stimulated glycerol phosphate acyltransferase activity by up to 2.5-fold.…”

The Effects of Mazindol and 46-034 (Sandoz) on Glucose Oxidation and Insulin Binding by Rat Isolated Fat Cells

“…A 'leaky' cell membrane is also indicated by the rise in LDH concentration in the medium, especially in the presence of 46-034, and by the reduction in the cell-associated 3 H 2 0 space after a 10 min incubation with 46-034. The high concentrations (> 0.4 mM) of mazindol and 46-034 required to inhibit rat fat cell metabolism are similar to those of fenfluramine which inhibit U-14C-glucose oxidation in rat fat cells (Dannenburg & Kardian, 1970) and lipogenesis in human adipose tissue (Wilson & Galton, 1971) However, the peak blood level of unchanged mazindol in rats after oral administration of an appetite suppressant dose of 10 mg/kg is only of the order of 0.7 p~ (Sandoz, 1972a); in humans taking a therapeutic dose of 1 mg thrice daily it is about 0.07 PM (Sandoz, 1972b). The present results are therefore unlikely to be relevant to the antiobesity action of mazindol in man.…”