Sickness behaviour after lipopolysaccharide treatment in ghrelin deficient mice

Abstract

Ghrelin is an orexigenic hormone produced mainly by the gastrointestinal system and the brain. Much evidence also indicates a role for ghrelin in sleep and thermoregulation. Further, ghrelin was recently implicated in immune system modulation. Administration of bacterial lipopolysaccharide (LPS) induces fever, anorexia, and increased non-rapid-eye movement sleep (NREMS) and these actions are mediated primarily by proinflammatory cytokines. Ghrelin reduces LPS-induced fever, suppresses circulating levels of proinflammatory cytokines and reduces the severity and mortality of various models of experimental endotoxemia. In the present study, we determined the role of intact ghrelin signaling in LPS-induced sleep, feeding, and thermoregulatory responses in mice. Sleep-wake activity was determined after intraperitoneal, dark onset administration of 0.4, 2 and 10 μg LPS in preproghrelin knockout (KO) and wild-type (WT) mice. In addition, body temperature, motor activity and changes in 24-h food intake and body weight were measured. LPS induced dose-dependent increases in NREMS, and suppressed rapid-eye movement sleep, electroencephalographic slow-wave activity, motor activity, food intake and body weight in both Ppg KO and WT mice. Body temperature changes showed a biphasic pattern with a decrease during the dark period followed by an increase in the light phase. The effects of the low and middle doses of LPS were indistinguishable between the two genotypes. Administration of 10 μg LPS, however, induced significantly larger changes in NREMS and wakefulness amounts, body temperature, food intake and body weight in the Ppg KO mice. These findings support a role for ghrelin as an endogenous modulator of inflammatory responses and a central component of arousal and feeding circuits.

Keywords: Body temperature; Electroencephalogram; Food intake; Ghrelin; Sleep.

Figure 1

Non-rapid-eye-movement sleep (NREMS), rapid-eye-movement sleep (REMS), electroencephalogram slow-wave activity (SWA), body temperature and motor activity in wild-type (WT) and preproghrelin knockout mice (Ppg KO). Open symbols: saline injection, solid symbols: 0.4 µg lipopolysaccharide (LPS) administered intraperitoneally (ip). Data were analyzed in 2-h time blocks. Time “0”: time of the injections at ZT12. Dark shaded areas: dark period. Error bars: standard error. Asterisks denote significant differences between control and treatment days (post hoc Student-Newman-Keuls test).

Figure 2

NREMS, REMS, EEG SWA, body temperature and motor activity in WT and Ppg KO mice after saline injection (open symbols) and 2 µg LPS (solid symbols) administration. See legends to Figure 1 for details.

Figure 3

NREMS, REMS, EEG SWA, body temperature and motor activity in WT and Ppg KO mice after vehicle injection (open symbols) and 10 µg LPS (solid symbols) administration. See legends to Figure 1 for details.

Figure 4

Changes in the number and duration of NREMS and REMS episodes during the 12-h dark period after LPS administrations in Ppg KO (black bars) and WT (white bars) mice. Error bars: standard error. Asterisks denote significant differences between control and treatment days (paired t-test). #: significant differences between genotypes (Student t-test).

Figure 5

Changes in daily food intake (top panel) and body weight (bottom panel) after 0.4, 2 and 10 µg LPS injections in WT (white bars) and Ppg KO mice (black bars). Asterisks: significant differences between control and treatment days (paired t-test). #: significant difference between genotypes (Student t-test).