Restraint stress activates nesfatin-1-immunoreactive brain nuclei in rats

Abstract

Nesfatin-1 is a newly discovered peptide that was reported to reduce food intake when injected centrally. We recently described its wide distribution in rat brain autonomic nuclei which implies potential recruitment of nesfatin-1 by stress. We investigated whether restraint, a mixed psychological and physical stressor activates nesfatin-1-immunoreactive (ir) neurons in the rat brain. Male Sprague-Dawley rats were either subjected to 30 min restraint or left undisturbed and 90 min later brains were processed for double immunohistochemical labeling of Fos and nesfatin-1. Restraint induced significant Fos expression in neurons of the supraoptic nucleus (SON), paraventricular nucleus (PVN), locus coeruleus (LC), rostral raphe pallidus (rRPa), nucleus of the solitary tract (NTS) and ventrolateral medulla (VLM). Double Fos/nesfatin-1 labeling revealed that Fos-ir neurons comprised 95% of nesfatin-1-ir cells in the SON, 90% in the VLM, 80% in the LC, 48% in the caudal NTS, 57% in the rRPa, 48% in the anterior parvicellular PVN, 27% in the medial magnocellular PVN, 18% in the lateral magnocellular PVN and 10% in the medial parvicellular PVN. These data demonstrate that nesfatin-1 neurons are part of the hypothalamic and hindbrain neuronal cell groups activated by restraint suggesting a possible role of nesfatin-1 in the response to stress.

Food-intake regulation during stress by the hypothalamo-pituitary-adrenal axis

“…(Chavez et al, 1997;Warne, 2009) leptin? (Dagogo-Jack et al, 1997;Miell et al, 1996;Newcomer et al, 1998;Slieker et al, 1996;York, 1996) CRH and Ucn 3 (Bernier, 2006;Ohata and Shibasaki, 2011;Smagin et al, 1998) CART (Kask et al, 2000;Xu et al, 2010) Nesfatin-1 (Goebel et al, 2009;Stengel et al, 2011) NPW (Beck et al, 2010) Melanocortins (Liu et al, 2007;Yamano et al, 2004) central monoaminergic systems (Gibson, 2006) autonomous nervous system (Seematter et al, 2004) Stress induces hyperphagia due to reduction of: sensor specific satiety (Ahn and Phillips, 2012;Ortolani et al, 2011) stressor aversiveness (Piazza and Le Moal, 1997) CRH signaling? (Foster et al, 2009;la Fleur et al, 2005;Pecoraro et al, 2004) due to activation of central reward pathways (Piazza and Le Moal, 1997), due to alterations in gut microbiota (Tehrani et al, 2012) Glucocorticoids induce hyperphagia (Dallman, 1993;Drapeau et al, 2003;Epel et al, 2000;Tataranni et al, 1996) due to increased signaling of: NPY (Gyengesi et al, 2010;Krysiak et al, 1999;McKibbin et al, 1992;White et al, 1994;Wilding et al, 1993), AgRP (Coll et al, 2005;Savontaus et al, 2002), Nociceptin …”

“…We assume that orexigenic effects of GCs are not expressed in response to acute and chronic stresses in laboratory rodents, because they are counteracted by other stress-induced anorexigenic mechanisms, which are not dependent on the increased GC levels, e.g. melanocortin system, CRH and Ucn 3 signaling (Bernier, 2006;Ohata and Shibasaki, 2011;Smagin et al, 1998), cocaineand amphetamine-regulated transcript (CART) (Kask et al, 2000;Xu et al, 2010), nesfatin-1 (Goebel et al, 2009;Stengel et al, 2011), neuropeptide W (NPW) (Beck et al, 2010), melanocortins (Liu et al, 2007;Yamano et al, 2004) and others, but the exact mechanism is not clear (Table 1).…”

Lipopolysaccharide Increases Gastric and Circulating NUCB2/Nesfatin-1 Concentrations in Rats

“…So far, only one study described the occurrence of mature nesfatin-1 peptide in the cerebrospinal fluid of rats, whereas in brain nuclei only full length NUCB2 was detected [24]. In all subsequent reports, only full length NUCB2 was detected by Western blot [8,27,36] or studies performing immunostaining did not distinguish between NUCB2 protein and nesfatin-1 peptide [5,6,8,10,13,14,16,18,25,32,34,42,43]. Since also full length NUCB2 exerts an anorexigenic effect it is also possible that this protein is the active circulating form.…”

Role of nesfatin-1 in the metabolism of skeletal tissues

“…Within neurons, nesfatin-1 occurs in conjunction with different neurotransmitters, including primarily melanin (MEL), cocaine-and amphetamine-regulated transcript (CART), proopiomelanocortin (POMC), α-melanocyte-stimulating hormone (α-MSH), growth hormone-releasing hormone (GHRH), thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), oxytocin (OT), vasopressin (AVP), neurotensin (NT), acetylocholine (Ach), and serotonin (SER) (6,12,14,16,31,34,39). The anatomical location of neurons expressing nesfatin-1 and its coexistence with neurotransmitters suggests that the physiological role of nesfatin-1 is not limited to the regulation of food intake, but also includes the regulation of neuroendocrine and autonomic control of internal organs and emotional reactions (14,22,34). The expression of NUCB2/nesfatin-1 mRNA was also observed in peripheral tissues, including the stomach, duodenum, pancreas, heart, adipose tissue, and testis (19,23,44,48,65).…”