Tolerance to appetite suppression induced by peptidoglycan.

Physiologically realistic peptidoglycan (PG) fragments, derived from Neisseria gonorrhoeae, were shown previously to dose-dependently suppress food consumption and body weight gain in rats following single intraperitoneal injections. The present study, examining the effects of repeated daily injection of PG, provides additional support to our underlying hypothesis, i.e., that soluble PG fragments contribute to the loss of appetite commonly associated with bacterial infections. An initial intraperitoneal injection of purified, soluble, macromolecular, extensively O-acetylated PG fragments (S-O-PG) (240 micrograms/kg of body weight) decreased overnight food consumption in male Lewis rats (150 g) by approximately 35% relative to animals receiving diluent alone (P < 0.05). However, subsequent daily injections of S-O-PG resulted in progressively smaller effects on food consumption until, by the fourth day, rats were completely nonresponsive (tolerant) to S-O-PG-induced hypophagia. Rats that developed tolerance to the effects of S-O-PG on appetite were also tolerant to three other known hypophagic agents, lipopolysaccharide (LPS), muramyl dipeptide, and interleukin-1, when challenged one day after establishment of S-O-PG tolerance. Similarly, rats developed tolerance to repeated injections of muramyl dipeptide or LPS and were cross-tolerant to S-O-PG when challenged 1 day later. However, 30 days after establishment of S-O-PG tolerance, rats remained nonresponsive to S-O-PG but regained full responsiveness to LPS-mediated hypophagia. Thus, at least two mechanisms of tolerance to S-O-PG hypophagia exist: an early tolerance which is nonspecific and a late tolerance which is specific for S-O-PG. Late, but not early, tolerance to S-O-PG-mediated suppression of appetite was associated with an increase in specific anti-PG antibody activity as measured in an enzyme-linked immunosorbent assay.

Peptidoglycan fragments decrease food intake and body weight gain in rats.

We hypothesized that peptidoglycan (PG) fragments decrease appetite in rats. Male Lewis rats (150 g; n > or = 7) received intraperitoneal (i.p.) injections of purified soluble PG fragments that had been treated with polymyxin B-agarose to remove residual endotoxin. Food consumption and body weight gain were determined at intervals after injection. Single i.p. injections of macromolecular extensively O-acetylated PG (S-O-PG) and non-O-acetylated PG fragments (24 to 240 micrograms/kg) reduced food intake and body weight gain in a dose-dependent fashion during the first 12 h after injection. Low-molecular-weight disaccharide peptide monomers with nonreducing 1,6-anhydro-N-acetylmuramic acid ends and muramyl dipeptide (MDP; 1.6 mg/kg) were also appetite and weight gain suppressants, albeit at least 10-fold less potent than S-O-PG; however, muramidase-derived monomers and peptide cross-linked dimers with reducing muramic acid ends were inactive. Appetite suppression was not limited to the Lewis rat strain since another strain, F344, exhibited similar decreases in food intake after injection of S-O-PG or MDP. Oral administration of MDP or S-O-PG, at concentrations 3 and 20 times higher, respectively, than those that were active i.p., failed to elicit a hypophagic response. We conclude that soluble PG fragments are potent suppressants of food consumption and body weight gain in rats and that, although macromolecular PG is more potent than low-molecular-weight fragments, neither O-acetylation nor glycosidic linkage of PG fragments is required for activity. We speculate that PG fragments may contribute to loss of appetite during bacterial illness.