Procalcitonin N-Terminal Peptide Causes Catabolic Effects via the Hypothalamus and Prostaglandin-Dependent Pathways

Abstract

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.

Aminoprocalcitonin-mediated suppression of feeding involves the hypothalamic melanocortin system

“…N-PCT-immunoreactive fibers and cells have been observed in several areas of the adult rat brain but are found the in highest concentrations in appetite control hypothalamic nuclei expressing high density of CT-R, including the ARC and PVN (4,34,37,54,57). In the present study, we found that N-PCT is produced locally within the ARC, including within POMC neurons, astrocytes, and possibly other neurons.…”

“…To characterize cell types expressing N-PCT, hypothalamic sections were subjected to double-labeling immunohistochemistry for a neuronal nuclei (NeuN) or a glial marker [glial fibrillary acidic protein (GFAP)], as described previously (54). To determine whether POMC neurons express N-PCT, double-labeling immunohistochemistry was performed using a rabbit anti-POMC antibody (57). Briefly, after quenching of autofluorescence with 0.3 M glycine and saturation of nonspecific sites with 3% normal donkey serum (Jackson Laboratories, West Grove, CA), sections were incubated for 72 h at 4°C with a mouse anti-N-PCT monoclonal antibody (1:100; Abcam) or incubated overnight at 4°C with rabbit anti-NeuN antibody (1:500; Millipore), anti-GFAP antibody (1:500; Dakocytomation, Carpinteria, CA), or anti-POMC antibody (1:1,000; Phoenix Pharmaceuticals).…”

“…Moreover, c-Fos expression, a marker of neuronal activity, was observed primarily within the ARC and PVN after icv injection of N-PCT (54, 57). In vitro and in vivo studies suggest that N-PCT, similarly to other neuropeptides of the CT family, like amylin and CT gene-related peptides, can function as a ligand for the 55,57). Together, these findings suggest that the anorectic actions of N-PCT likely occur within the hypothalamus.…”

“…Immunohistochemical staining for c-Fos and POMC was performed by using a sequential two-color avidin-biotin immunoperoxidase complex technique according to a previously described method (16,49,57). Briefly, endogenous peroxidase activity was blocked with 3% hydrogen peroxide in methanol.…”

“…Recent findings show that N-PCT colocalized with CRH in parvocellular neurons of the PVN (54). Moreover, c-Fos expression, a marker of neuronal activity, was observed primarily within the ARC and PVN after icv injection of N-PCT (54,57). In vitro and in vivo studies suggest that N-PCT, similarly to other neuropeptides of the CT family, like amylin and CT gene-related peptides, can function as a ligand for the CT-R (47,55,57).…”