Procalcitonin (PCT), the precursor of calcitonin (CT), is a 116-amino-acid peptide, but PCT itself has no known activity. However, although the C cells of the thyroid gland are the dominant source of circulating CT, PCT and its free bioactive amino-terminal fragment (N-PCT) have been localized in adipocytes and neuroendocrine cells as well as in some hypothalamic regions of primary importance in the regulation of feeding and energy balance. These findings together with the coelaboration of N-PCT and CT, and N-PCT's sequence conservation during evolution, suggest that N-PCT has a critical, and as yet undefined, physiological function. We demonstrate here that intracerebroventricular administration of N-PCT significantly decreased food intake and body weight gain for at least 48 h in conscious, freely moving, and unstressed rats fed ad libitum. These effects were accompanied by a transitory increase in body temperature and a decrease in locomotor activity. Moreover, after intracerebroventricular N-PCT administration, Fos protein, a marker of neuronal activation, was found in regions of primary importance in the integration of hormonal signals for energy homeostasis and feeding. In contrast, ip administration of N-PCT did not elicit any anorectic or catabolic effects. Furthermore, PCT was found in key feeding areas such as the arcuate nucleus of free-feeding rats, and its level was significantly reduced after fasting. These results suggest that N-PCT can function as an endogenous ligand for the CT receptor and may act as a catabolic signaling molecule in the central regulation of feeding behavior and energy homeostasis.

Severe sepsis and septic shock are an important cause of mortality and morbidity. These illnesses can be triggered by the bacterial endotoxin LPS (lipopolysaccharide) and pro-inflammatory cytokines, particularly TNF-α (tumour necrosis factor-α) and IL (interleukin)-1β. Severity and mortality of sepsis have also been associated with high concentrations of N-PCT (aminoprocalcitonin), a 57-amino-acid neuroendocrine peptide derived from ProCT (procalcitonin). Previous studies in a lethal model of porcine polymicrobial sepsis have revealed that immunoneutralization with IgG that is reactive to porcine N-PCT significantly improves short-term survival. To explore further the pathophysiological role of N-PCT in sepsis, we developed an antibody raised against a highly conserved amino acid sequence of human N-PCT [N-PCT-(44-57)]. This sequence differs by only one amino acid from rat N-PCT. First, we demonstrated the specificity of this antibody in a well-proven model of anorexia induced in rats by central administration of human N-PCT-(1-57). Next we explored further the therapeutic potential of anti-N-PCT-(44-57) in a rat model of lethal endotoxaemia and determined how this immunoneutralization affected LPS-induced lethality and cytokine production. We show that this specific antibody inhibited the LPS-induced early release of TNF-α and IL-1β and increased survival, even if treatment began after the cytokine response had occurred. In addition, anti-N-PCT-(44-57) may increase long-term survival in LPS-treated rats by up-regulating the late production of counter-regulatory anti-inflammatory mediators such as ACTH (adrenocorticotropic hormone) and IL-10. In conclusion, these results support N-PCT as a pro-inflammatory factor in both the early and the late stages of lethal endotoxaemia, and suggest anti-N-PCT as a candidate for septic shock therapy.

Gram-negative and gram-positive infections have been considered the most important causes of morbidity and mortality in patients with leukopenia following chemotherapy. However, discrimination between bacterial infections and harmless fever episodes is difficult. Because classical inflammatory signs of infection are often absent and fever is frequently the only sign of infection, the aim of this study was to assess the significance of serum interleukin-6 (IL-6), IL-10, macrophage inflammatory protein-2 (MIP-2), procalcitonin (PCT), and C-reactive protein (CRP) patterns in identifying bacterial infections during start of fever in normal and cyclophosphamide-treated (leukopenic) rats following an injection of lipopolysaccharide (LPS) or muramyl dipeptide (MDP) as a model for gram-negative and gram-positive bacterial infections. We found that, compared to normal rats, immunosuppressed animals exhibited significantly higher fevers and lesser production of all mediators, except IL-6, after toxin challenge. Moreover, compared to rats that received MDP, both groups of animals that received an equivalent dose of LPS showed significantly higher fevers and greater increase in serum cytokine levels. Furthermore, in contrast to those in immunocompetent rats, serum levels of IL-6 and MIP-2 were not significantly changed in leukopenic animals after MDP injection. Other serum markers such as PCT and CRP failed to discriminate between bacterial stimuli in both groups of animals. These results suggest that the use of the analyzed serum markers at an early stage of fever could give useful information for the clinician for excluding gram-negative from gram-positive infections.

Recent evidence suggests that the free amino-terminal fragment of procalcitonin (N-PCT) plays a role in the central control of feeding behavior and energy homeostasis. However, little is known about the mechanisms through which N-PCT works. Here we report that intracerebroventricular administration of N-PCT to free-feeding male rats induced a significant decrease of longer-term food intake and body weight gain. Conversely, N-PCT increased body temperature. We also show that intracerebroventricular administration of N-PCT induced a marked neuronal activation in key thermoregulatory and feeding areas of the hypothalamus. We further show that N-PCT increases the responsiveness of proopiomelanocortin anorexigenic neurons in the arcuate nucleus of the hypothalamus, and that stimulation of the de novo synthesis of prostaglandins is crucial for the central effects induced by N-PCT. Results support the role of N-PCT to the central control of feeding behavior and suggest that N-PCT, acting probably through the eicosanoid cyclooxygenase pathway, may act as a signaling molecule in the hypothalamus by regulating the activity of anorexigenic neurons in the hypothalamus.

BackgroundThe multiligand receptor megalin controls the brain uptake of a number of ligands, including insulin and leptin. Despite the role of megalin in the transport of these metabolically relevant hormones, the role of megalin at the blood–brain-barrier (BBB) has not yet been explored in the context of metabolic regulation.MethodsHere we investigate the role of brain endothelial megalin in energy metabolism and leptin signaling using an endothelial cell-specific megalin deficient (EMD) mouse model.ResultsWe found megalin is important to protect mice from developing obesity and metabolic syndrome when mice are fed a normal chow diet. EMD mice developed neuroinflammation, by triggering several pro-inflammatory cytokines, displayed reduced neurogenesis and mitochondrial deregulation.ConclusionsThese results implicate brain endothelial megalin expression in obesity-related metabolic changes through the leptin signaling pathway proposing a potential link between obesity and neurodegeneration.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0800-2) contains supplementary material, which is available to authorized users.

During myelosuppressive chemotherapy, Gram-negative bacterial infection with consequent exposure to lipopolysaccharide (LPS) is one of the most important causes of persistent fever. The classical model of the pathogenesis of fever suggests that pro-inflammatory cytokines, produced by leucocytes in the bloodstream in response to exogenous pyrogens such as bacterial LPS, represent the distal mediators of the febrile response. Neutrophils are the first effectors cells and the most prominent leucocyte population involved in acute bacterial infection. Macrophage inflammatory protein (MIP)-2 plays a crucial role in influencing early cell trafficking and neutrophil activation during pathophysiological processes and serves the same chemotactic function as human interleukin-8. In the present study, we investigated the role of MIP-2 in the development of a febrile response induced by LPS in immunocompetent and leukopenic rats. Intraperitoneal injection of LPS in leukopenic rats elicited a biphasic febrile response of rapid onset, the magnitude and duration of which were significantly greater than in immunocompetent animals. The febrile responses to LPS were accompanied by a pronounced induction of serum MIP-2 levels at 1, 2 and 4 h compared with their respective controls. In both normal and leukopenic rats, neutralization of endogenous MIP-2 bioactivity by systemic administration of antirat MIP-2 antibody caused a significant attenuation of the early phase of LPS fever. However, in contrast with normal rats, the second phase of fever was unimpaired by anti-MIP-2 in leukopenic rats. These findings suggest that circulating MIP-2 is involved in the generation of the early phase of LPS fever that contributes to the maintenance of the later phase of fever in immunocompetent, but not leukopenic, rats. Our data support a regulatory role for endogenous MIP-2 in initiating the fever responses to LPS. Furthermore, these results provide evidence that different cellular and humoral mechanisms are implicated in the development of a febrile response triggered by Gram-negative bacterial infections in leukopenic hosts.

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