Lipopolysaccharide-induced anorexia following hepatic portal vein and vena cava administration.

To examine the role of the liver in lipopolysaccharide (LPS)-induced hypophagia, we investigated the effect of hepatic portal and vena cava infusions (1 mL/30 min) of LPS (100 microg/kg of body weight) on feeding in rats. LPS infusion significantly reduced food intake when administered via either the hepatic portal vein or the vena cava. Both the magnitude and time course of this hypophagia were similar regardless of the infusion route. As in previous experiments of ours in which LPS was administered by intraperitoneal (i.p.) injection, LPS reduced food intake by decreasing meal frequency, without affecting meal size or duration. The results suggest that peripherally administered LPS does not act primarily in the liver to reduce food intake.

Effects of age on the feeding response to moderately low dietary protein in rats.

Moderately low levels of dietary protein are associated with increased food intake and body fat. We propose that the generation of this feeding signal is dependent on the level of dietary protein relative to the protein requirement of the animal, that is, that protein-dependent feeding is maximized when the level of dietary protein is around the animal's protein requirement. One of the factors that affects an animal's protein requirement is age. We predict that young, growing animals are more responsive to a moderately low level of dietary protein than are mature animals. The feeding response to moderately low dietary protein (10% casein) was determined in young ( approximately 190 g) and more mature ( approximately 340 g) Sprague-Dawley rats for 12 days. As an index of amino acid deamination, serum urea nitrogen concentrations were determined, as was the in vitro release of neuropeptide Y (NPY) from hypothalamic tissue containing the paraventricular nucleus. Young rats were more responsive to the feeding effects of moderately low dietary protein than mature animals. In young rats, cumulative food intake was inversely correlated with serum urea nitrogen concentration. No correlation was found in mature animals. Although the amount of NPY remaining in hypothalamic tissue after incubation was significantly greater (p = 0.04) in young rats fed 10% casein as compared with rats fed the standard 20% casein diet, no dietary difference in K(+)-stimulated NPY release was observed. We hypothesize that the signal for low-protein-induced hyperphagia is a reduction in a compound whose production is coupled to the level of amino acid deamination in the brain.

Protein selection, food intake, and body composition in response to the amount of dietary protein.

Though not universally observed, moderately low-protein diets have been found to increase caloric intake and body fat. It appears that animals overeat in calories in order to obtain more dietary protein. For animals to control protein intake, they must be able to distinguish between two isocaloric diets containing different percentages of protein and make the appropriate dietary selection on the basis of their previous history of protein intake. Experiment 1 examined the 24-h diet selection (5 vs. 35% casein) of Sprague-Dawley rats that had been previously fed diets containing various percentages of dietary protein (5, 10, 20, 35, or 60% casein). Animals fed 5, 10, or 20% dietary protein showed a preference for the higher protein selection diet. In contrast, no significant diet preference was found in animals pre-fed the two higher levels of dietary protein (35 or 60% casein). In this study, daily food intake and body fat of rats fed the low-protein diets (5 and 10% casein) were similar to rats fed the 20% casein diet. Experiment 2 examined the effects of the level of methionine supplementation on rats fed 10% casein. In this study, food intake and body fat were increased by approximately 20% in rats fed 10% casein diets, regardless of the level of methionine supplementation (0.3 vs. 0.15%). Together, the results suggest that the presence of low-protein-induced hyperphagia helps maintain body protein levels in the face of moderately low dietary protein and promotes an increase in the amount of body fat and energy.

TNF-alpha tolerance blocks LPS-induced hypophagia but LPS tolerance fails to prevent TNF-alpha-induced hypophagia.

To investigate the role of tumor necrosis factor-alpha (TNF-alpha) in bacterial lipopolysaccharide (LPS)-induced hypophagia, we tested whether a cross tolerance between LPS and TNF-alpha exists with respect to their anorectic effects. Only the first of three subsequent intraperitoneal injections of LPS (100 micrograms/kg body wt) given every second day at dark onset (12:12-h light-dark cycle) led to a significant reduction of food intake in male rats. Likewise, intraperitoneal injections of human recombinant TNF-alpha (150 micrograms > or = 3 x 10(6) U/kg body wt) also resulted in tolerance to its hypophagic effect. LPS tolerance did not alter the hypophagic response to subsequently injected TNF-alpha (n = 14). However, TNF-alpha pretreatment completely blocked the hypophagic response to LPS (n = 14). The results demonstrate that tolerance to the hypophagic effect of exogenous TNF-alpha is sufficient to eliminate LPS-induced hypophagia. This is consistent with the hypothesis that endogenous TNF-alpha plays a major role in LPS-induced hypophagia. The ineffectiveness of LPS tolerance to attenuate TNF-alpha-induced hypophagia is compatible with findings demonstrating that reduced TNF-alpha production is an important feature of LPS tolerance.

Inhibition of TNF-alpha production contributes to the attenuation of LPS-induced hypophagia by pentoxifylline.

Cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) are assumed to mediate anorexia during bacterial infections. To improve our understanding of the role that these two cytokines serve in mediating infection during anorexia, we investigated the ability of pentoxifylline (PTX), a potent inhibitor of TNF-alpha production, to block the anorectic effects of the bacterial products lipopolysaccharide (LPS) and muramyl dipeptide (MDP) in rats. Intraperitoneally injected PTX (100 mg/kg body wt) completely eliminated the anorectic effect of intraperitoneally injected LPS (100 microg/kg body wt) and attenuated the anorectic effect of a higher dose of intraperitoneally injected LPS (250 microg/kg body wt). Concurrently, PTX pretreatment suppressed low-dose LPS-induced TNF-alpha production by more than 95% and IL-1beta production 39%, as measured by ELISA. Similarly, high-dose LPS-induced TNF-alpha production was reduced by approximately 90%. PTX administration also attenuated the tolerance that is normally observed with a second injection of LPS. In addition, PTX pretreatment attenuated the hypophagic effect of intraperitoneally injected MDP (2 mg/kg body wt) but had no effect on the anorectic response to intraperitoneally injected recombinant human TNF-alpha (150 ug/kg body wt). The results suggest that suppression of TNF-alpha production is sufficient to attenuate LPS- and MDP-induced anorexia. This is consistent with the hypothesis that TNF-alpha plays a major role in the anorexia associated with bacterial infection.

Vagal and splanchnic afferents are not necessary for the anorexia produced by peripheral IL-1beta, LPS, and MDP.

We investigated the extrinsic gut neural mediation of the suppression of food intake in male Sprague-Dawley rats induced by peripheral intraperitoneal administration of 2 microg/kg interleukin-1beta (IL-1beta), 100 microg/kg bacterial lipopolysaccharide (LPS), and 2 mg/kg muramyl dipeptide (MDP). Food intake during the first 3 and 6 h of the dark cycle was measured in rats with subdiaphragmatic vagal deafferentation (n = 9), celiac superior mesenteric ganglionectomy (n = 9), combined vagotomy and ganglionectomy (n = 9), and sham deafferentation (n = 9). IL-1beta, LPS, and MDP suppressed food intake at 3 and 6 h in all surgical groups. The results demonstrate that neither vagal nor nonvagal afferent nerves from the upper gut are necessary for the feeding-suppressive effects of intraperitoneal IL-1beta, LPS, or MDP in the rat and suggest that peripheral administration of immunomodulators produces anorexia via a humoral pathway.