POTENTIAL ROLE OF TNF-ALPHA AND LIPOPROTEIN-LIPASE AS CANDIDATE GENESFOR OBESITY

To maintain body weight, metabolic efficiency was promoted during evol ution; two candidate genes for body weight regulation are lipoprotein lipase (LPL) and tumor necrosis factor-alpha (TNF alpha). Human fat ce lls do not synthesize lipid, but rely on LPL-mediated plasma triglycer ide hydrolysis. Adipose LPL is elevated in obesity. Following weight l oss, LPL is elevated further, suggesting attempts to maintain lipid st ores during fasting and to replenish lipid stores during refeeding. Mu scle LPL is regulated inversely to adipose LPL. Thus, an increased adi pose/muscle LPL ratio would partition dietary lipid into adipose tissu e and would explain some of the variability in weight gain when humans are exposed to excess calories. Adipose tissue TNF alpha expression i s increased in obese rodents and humans and may be important in obesit y. When insulin-resistant rodents were injected with anti-TNF binding protein, insulin action improved, suggesting a link between insulin re sistance and TNF. TNF is expressed at higher levels in muscle cells of insulin-resistant subjects, and TNF may inhibit LPL expression. Overa ll, TNF may function to make the subject less obese by inhibiting LPL and rendering the animal more insulin resistant. Obesity has many comp onents, both metabolic and behavioral. However, the metabolic changes resulting from LPL and TNF likely played a role in regulating body adi pose tissue during much of human evolution and continue to affect huma n obesity today.