Reduced leptin levels in starvation increase susceptibility to endotoxic shock

Abstract

Malnutrition compromises immune function, reducing resistance to infection. We examine whether the decrease in leptin induced by starvation increases susceptibility to lipopolysaccharide (LPS)- and tumor necrosis factor (TNF)-induced lethality. In mice, fasting for 48 hours enhances sensitivity to LPS. Decreasing the fasting-induced fall in leptin by leptin administration markedly reduced sensitivity to LPS. Although fasting decreases basal leptin levels, LPS treatment increased leptin to the same extent as in fed animals. Fasting increased basal serum corticosterone; leptin treatment blunted this increase. Fasting decreased the ability of LPS to increase corticosterone; leptin restored the corticosterone response to LPS. Serum glucose levels were decreased in fasted mice and LPS induced a further decrease. Leptin treatment affected neither basal glucose nor that after LPS. LPS induced a fivefold greater increase in serum TNF in fasted mice, which was blunted by leptin replacement. In contrast, LPS induced lower levels of interferon-gamma and no differences in interleukin-1beta in fasted compared to fed animals; leptin had no effect on those cytokines. Furthermore, fasting increased sensitivity to the lethal effect of TNF itself, which was also reversed by leptin treatment. Thus, leptin seems to be protective by both inhibiting TNF induction by LPS and by reducing TNF toxicity.

Figure 1.

Effect of fasting on LPS-induced lethality. Mice were fed (•) or fasted (○) for 48 hours and then injected i.p. with 7.5, 15, or 25 mg/kg of LPS (n = 5 mice per group). Mortality was assessed daily for 6 days.

Figure 2.

Effect of leptin treatment during fasting on LPS-induced lethality. Mice were fed (•), fasted (○), or fasted and treated with leptin for 48 hours (▪). Leptin was administered i.p., 1 μg/g body weight, twice a day for 2 days to fasted mice. Fasted or fed mice received saline. Mice were then challenged with LPS (15 mg/kg). Mortality was assessed daily for 6 days. *P < 0.05, **P < 0.01, ***P < 0.001 versus fed by Fisher’s exact test.

Figure 3.

Serum TNF levels after LPS administration in fed, fasted, and leptin-treated fasted mice. Mice were fed, fasted, or fasted and treated with leptin for 48 hours. Leptin was administered i.p., 1 μg/g body weight, twice a day for 2 days to fasted mice. Fasted or fed mice received saline. Mice were then challenged with LPS (15 mg/kg) or saline. Blood was collected 2 hours after LPS administration and TNF levels were measured. No detectable levels of cytokine were measured in the serum of saline-treated mice. Data are means ± SEM (n = 5).

Figure 4.

Effect of leptin treatment during fasting on TNF-induced lethality. Mice were fed, fasted, or fasted and treated with leptin for 48 hours. Fasted mice treated with leptin were administered leptin i.p., 1 μg/g body weight, twice a day for 2 days. Fasted or fed mice received saline. Mice were then challenged with mTNF (0.5 mg/kg, i.v.). Mortality was assessed daily for 6 days. P < 0.001 fasted versus fed (n = 20); P < 0.05 fasted + leptin versus fasted (n = 10) by Fisher’s exact test.