The Effect of Ghrelin upon the Early Immune Response in Lean and Obese Mice during Sepsis

Introduction It is well established that obesity-related hormones can have modulatory effects associated with the immune response. Ghrelin, a hormone mainly derived from endocrine cells of the gastric mucosa, regulates appetite, energy expenditure and body weight counteracting leptin, a hormone mainly derived from adipocytes. Additionally, receptors of both have been detected on immune cells and demonstrated an immune regulatory function during sepsis. Methods In the present study, the effect of peripheral ghrelin administration on early immune response and survival was investigated with lean mice and mice with diet-induced obesity using cecal ligation and puncture to induce sepsis. Results In the obese group, we found that ghrelin treatment improved survival, ameliorated hypothermia, and increased hyperleptinemia as compared to the lean controls. We also observed that ghrelin treatment divergently regulated serum IL-1 beta and TNF-alpha concentrations in both lean and obese septic mice. Ghrelin treatment initially decreased but later resulted in increased bacteriaemia in lean mice while having no impact upon obese mice. Similarly, ghrelin treatment increased early neutrophil oxidative burst while causing a decrease 48 hours after sepsis inducement. Conclusion In conclusion, as the immune response to sepsis temporally changes, ghrelin treatment differentially mediates this response. Specifically, we observed that ghrelin conferred protective effects during the early phase of sepsis, but during the later phase deteriorated immune response and outcome. These adverse effects were more pronounced upon lean mice as compared to obese mice

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Influence of ghrelin treatment (0.5 μg/g BW, twice a day, intraperitoneal (ip.)) on oxidative burst capacity of neutrophils after cecal ligation and puncture (CLP)-induced sepsis.

<p>Blood and peritoneal lavage were collected from controls (n = 5/timepoint), controls with ghrelin treatment (n = 5/timepoint), high fat diet (hfd) (n = 5/timepoint) and hfd with ghrelin treatment (n = 5/timepoint) before, 24h and 48h after CLP-induced sepsis. Ghrelin dependent changes of spontaneous oxidative burst capacity of neutrophils and capacity after stimulation with fMLP in serum of (A) control and (B) hfd mice and in peritoneal lavage fluid of (C) control and (D) hfd mice were measured in blood and peritoneal lavage by flow cytometric analysis (combined data from two independent experiments). All values are expressed as means ± SEM; * p < 0.05 of of two-way ANOVA for unmatched samples followed by a <i>post hoc</i> Bonferroni test for analyses between more than two groups or within groups over time.</p

Influence of ghrelin treatment (0.5 μg/g BW, twice a day, intraperitoneal (ip.)) on inflammatory mediators after cecal ligation and puncture (CLP)-induced sepsis.

<p>Serum was collected from control mice (ghrelin: n = 5–9/timepoint, untreated: n = 4–5/timepoint) and high fat diet (hfd) mice (ghrelin: n = 4–10/timepoint, untreated: n = 4–5/timepoint) before, 6h, 24h and 48h following CLP. Serum leptin levels of (A) control and (B) hfd mice, Interleukin (IL)-1ß levels of (C) control and (D) hfd mice and tumor necrosis factor (TNF)α levels of (E) control and (F) hfd mice were determined by ELISA (combined data from several independent experiments); * p < 0.05 of two-way ANOVA for unmatched samples followed by a <i>post hoc</i> Bonferroni test for analyses between more than two groups or within groups over time. All values are expressed as means ± SEM.</p

Influence of ghrelin treatment (0.5 μg/g BW, twice a day, intraperitoneal (ip.)) on peritoneal cellular immune response after cecal ligation and puncture (CLP)-induced sepsis.

<p>Peritoneal lavage fluid from control mice (ghrelin: n = 5/timepoint, untreated: n = 5–11/timepoint) and high fat diet (hfd) mice (ghrelin: n = 5/timepoint, untreated: n = 4–10/timepoint) were collected before, 24h and 48h following CLP. Numbers of neutrophils of control (A) and (B) hfd mice, natural killer (NK) cell numbers of (C) control and (D) hfd mice and γδ T cell numbers of (E) control and (F) hfd mice were were enumerated by flow cytometric analysis (combined data from two independent experiments). All values are expressed as means ± SEM; * p < 0.05 of unpaired t-test for comparison of baseline levels between two groups (hfd and control) and of two-way ANOVA for unmatched samples followed by a <i>post hoc</i> Bonferroni test for analyses between more than two groups or within groups over time.</p