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.