Tolerance to appetite suppression induced by peptidoglycan

Abstract

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 g/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 SO -PG resulted in progressively smaller effects on food consumption until, by the fourth day, rats were completely nonresponsive (tolerant) to SO -PGinduced hypophagia. Rats that developed tolerance to the effects of SO -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 SO -PG tolerance. Similarly, rats developed tolerance to repeated injections of muramyl dipeptide or LPS and were cross-tolerant to SO -PG when challenged 1 day later. However, 30 days after establishment of SO -PG tolerance, rats remained nonresponsive to SO -PG but regained full responsiveness to LPS-mediated hypophagia. Thus, at least two mechanisms of tolerance to SO -PG hypophagia exist: an early tolerance which is nonspecific and a late tolerance which is specific for SO -PG. Late, but not early, tolerance to SO -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 O-Acetylation as a Virulence Factor: Its Effect on Lysozyme in the Innate Immune System

“…The direct relationship between the induction of these effects by PG and its O-acetylation was clearly demonstrated in a series of animal model studies involving strains of N. gonorrhoeae and S. aureus that varied in their levels of this modification (reviewed in [74]). Subsequent studies by the Rosenthal group demonstrated the suppression of food consumption and body weight gain in rats following intraperitoneal injections of O-acetylated gonorrheal PG [75,76]. More recently, the role that PG O-acetylation plays in the development of septic arthritis by S. aureus was clearly demonstrated [77].…”

Vertebrate and Invertebrate Animal and New In Vitro Models for Studying Neisseria Biology

“…In addition, the disseminated arthropathic properties of gonococcal peptidoglycan fragments were demonstrated in adult rats [ 245 ], and LOS could induce a recurrence of arthritis in rat joints previously injured by peptidoglycan–polysaccharide fragments [ 246 ]. Moreover, injection of rats with purified, soluble, macromolecular, extensively O-acetylated peptidoglycan fragments decreased overnight food consumption in male Lewis rats [ 247 ].…”

Attention Seeker: Production, Modification, and Release of Inflammatory Peptidoglycan Fragments in Neisseria Species

“…PG fragments have known arthropathic, somnogenic, pyrogenic, cytotoxic, and appetite suppression effects (3,4,(25)(26)(27)(28). Gonococcus-derived PG fragments as small as PG monomers stimulate arthritis when injected into rats (25).…”