role of leptin and tumor necrosis factor- (tnf-) in mechanisms of anorexia during endotoxin infection in mice

Background: Anorexia and loss of body weight are hallmark of infection. The actual
mechanisms by which infection induces anorexia are still unknown. Several proinflammatory
cytokines, most notably tumor necrotic factor- (TNF-), known to
initiate and modulate the host response to infection have been shown to induce
anorexia and weight loss in healthy animals. Leptin is a protein hormone produced by
adipose tissue. It is considered to be a satiety factor as it decreases food intake and
increases energy expenditure. Administration of bacterial endotoxin (LPS) or TNF-
induced increase in serum leptin levels, and leptin has been shown to act in an
endocrine fashion to decrease food intake and body weight. This suggests that leptin
may be one of the mechanisms by which anorexia is induced during infection. The
present study aimed to investigate the effect of endotoxin (LPS) and TNF-, on food
intake, body weight and serum leptin levels in mice. Also, to explain the different
possible mechanisms which can cause anorexia during infection and if leptin is
involved in these mechanisms. Methods: The study included 36 adult female mice
which were divided into 6 groups, 6 mice each. Group I: “control group”, received
single intraperitoneal (i.p) injection of normal saline. Group II, III, IV and V: “LPS
treated groups”, received a single i.p. injection of different doses of LPS, (0.1g, 1g,
10g and 100g/100g. body weight respectively). Group VI: “TNF- treated group”,
injected i.p. with TNF- in a dose of 17g/100g BW. Food intake and body weight
were measured over the next 18, 42, 66 and 90 h for animals of control and LPS
treated groups. Food intake by TNF- injected group was measured 18 h after
injection. Blood sample from each mouse of all studied animal groups was collected
18 h after different injections, then serum leptin level was assessed using mouse leptin
ELISA kits. Results: The study showed a significant (p is<0.001), dose dependent
decrease in food intake and body weight 18 h after injection in all LPS injected
groups (except for group II which showed a non significant decrease) when compared
with that of control group. Gradual recovery of food intake and body weight gaining
over the next 3 days occurred in low doses treated groups (groups II & III), while as
mice treated with large doses, (group VI & V), showed no food intake nor weight gain
over the subsequent 42 h. Thereafter, group IV began to increase their food intake
and body weight till the end of the study, whereas group V remained anorectic and
losing weight till the end of the study. TNF- injected group showed a significant
decrease in food intake, ( p is<0.001) as compared to the control one, that decrease
in food intake after TNF- injection is nearly similar to that induced by LPS 
injection even in high doses injected groups (groups III & IV). Serum leptin levels
showed significant increase 18 h after LPS and TNF- injection in all injected groups
in a dose related manner, compared to that of the control group. The highest dose of
LPS injection to group V “100 g / 100 g BW” showed increased serum leptin levels
nearly 4 folds to that level of control group. The increase in serum leptin levels after
TNF- injection, did not reach the same levels of increase as after LPS injections
specially for the high doses of LPS “groups IV and V”. Conclusion: The present
study showed that both of LPS and TNF- can induce anorexia and increased leptin
level. The decrease in food intake is inversely proportional to the increase in serum
leptin. These data suggest a role for leptin in anorexia during LPS infection. Also, the
study revealed some possible mechanisms for anorexia during infection through the
cooperation between immune activation mediators (cytokines) and some hormonal
changes which can induce different host’s immune and metabolic response during
infection. As anorexia plays a critical role in chronic inflammatory diseases, it is
possible that development of leptin antagonists may play a useful role in decreasing
anorexia and wasting of chronic infections such as AIDS.