Abstract
Obesity is a risk factor for sepsis morbidity and mortality, whereas the hypothalamic–pituitary–adrenal (HPA) axis plays a protective role in the body's defence against sepsis. Sepsis induces a profound systemic immune response and cytokines serve as excellent markers for sepsis as they act as mediators of the immune response. Evidence suggests that the adipokine leptin may play a pathogenic role in sepsis. Mouse endotoxaemic models present with elevated leptin levels and exogenously added leptin increased mortality whereas human septic patients have elevated circulating levels of the soluble leptin receptor (Ob-Re). Evidence suggests that leptin can inhibit the regulation of the HPA axis. Thus, leptin may suppress the HPA axis, impairing its protective role in sepsis. We hypothesised that leptin would attenuate the HPA axis response to sepsis. We investigated the direct effects of an i.p. injection of 2 mg/kg leptin on the HPA axis response to intraperitoneally injected 25 μg/kg lipopolysaccharide (LPS) in the male Wistar rat. We found that LPS potently activated the HPA axis, as shown by significantly increased plasma stress hormones, ACTH and corticosterone, and increased plasma interleukin 1β (IL1β) levels, 2 h after administration. Pre-treatment with leptin, 2 h before LPS administration, did not influence the HPA axis response to LPS. In turn, LPS did not affect plasma leptin levels. Our findings suggest that leptin does not influence HPA function or IL1β secretion in a rat model of LPS-induced sepsis, and thus that leptin is unlikely to be involved in the acute-phase endocrine response to bacterial infection in rats.
Highlights
Sepsis is the result of an over-activation of the innate immune response against bacterial infections (Matot & Sprung 2001) and can result in fever, tachypnea, tachycardia, deregulated organ perfusion, renal failure, hypoxaemia and altered mental state (Bone et al 1989)
We investigated the direct effects of leptin on the hypothalamic– pituitary–adrenal (HPA) axis response to acute lipopolysaccharide (LPS) administration in rats, a model of the neuroimmunological changes observed in sepsis in both rodents and humans
Leptin had no effect on basal (7.77G0.714 pg/ml) or LPSstimulated (68.8G15.5 pg/ml) plasma interleukin 1B (IL1b) concentrations (Fig. 1C)
Summary
Sepsis is the result of an over-activation of the innate immune response against bacterial infections (Matot & Sprung 2001) and can result in fever, tachypnea, tachycardia, deregulated organ perfusion, renal failure, hypoxaemia and altered mental state (Bone et al 1989). Sepsis progression can result in immune dysfunction (Tschop et al 2010), which is the leading cause for mortality in non-coronary patients in non-Western countries (Arabi et al 2003), comparable with annual death rates from acute myocardial infarction in Western countries. Obesity is a risk factor for sepsis morbidity and mortality. Morbid obesity increases the risk of death by sepsis following major surgery by 50% (Prabhakar et al 2002). It is thought that the pro-inflammatory phenotype that accompanies obesity creates a context in which any additional inflammatory stimulus results in an exaggerated inflammatory response (Vachharajani 2008)
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