EFFECTS OF TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA) ON GLUCOSE-TRANSPORT AND LIPID-METABOLISM OF NEWLY-DIFFERENTIATED HUMAN FAT-CELLS IN CELL-CULTURE

Tumour necrosis factor alpha (TNF alpha) has been found to cause a delipidation of fat cells and a decrease of the adipose tissue mass, In the present study, we tried to elucidate some of the mechanisms responsible for this phenomenon by investigating the action of TNF alpha on specific pathways which are involved in lipid storage. Cultured stromal cells from human adipose tissue were induced to differentiate into adipose cells by exposure to adipogenic factors and subsequently used for studying the effects of TNF alpha on fat cell metabolism, Presence of 5 nmol/l TNF alpha for 24 h resulted in a complete loss of the stimulatory effect of insulin on 2-deoxy-glucose transport. This inhibitory action was paralleled by a decrease of GLUT4 protein and mRNA levels. The amount of cellular GLUT4 protein was reduced by 49 +/- 3 % after a 24-h exposure and by 82 +/- 18 % after a 72-h exposure to 5 nmol/l TNF alpha, GLUT4 mRNA was almost undetectable after a 24-h incubation with 5 nmol/l TNF alpha. In a similar time-dependent manner, TNF alpha dramatically reduced the lipoprotein lipase mRNA content of the cells. Furthermore, incubation of cultured human fat cells with TNF alpha resulted in a marked dose-dependent stimulation of lipolysis, assessed by glycerol release, by up to 400 % above controls, which became apparent after a 6-h exposure at the earliest. These data suggest that TNF alpha induces a catabolic state in human adipose tissue which includes a loss of the stimulatory effect of insulin on glucose transport. These multiple actions of TNF alpha may contribute to the loss of adipose tissue observed during cachexia in man.