Central Nesfatin-1 Reduces Dark-Phase Food Intake and Gastric Emptying in Rats: Differential Role of Corticotropin-Releasing Factor2 Receptor

Abstract

Nesfatin-1, derived from nucleobindin2, is expressed in the hypothalamus and reported in one study to reduce food intake (FI) in rats. To characterize the central anorexigenic action of nesfatin-1 and whether gastric emptying (GE) is altered, we injected nesfatin-1 into the lateral brain ventricle (intracerebroventricular, icv) or fourth ventricle (4v) in chronically cannulated rats or into the cisterna magna (intracisternal, ic) under short anesthesia and compared with ip injection. Nesfatin-1 (0.05 μg/rat, icv) decreased 2–3 h and 3–6 h dark-phase FI by 87 and 45%, respectively, whereas ip administration (2 μg/rat) had no effect. The corticotropin-releasing factor (CRF)1/CRF2 antagonist astressin-B or the CRF2 antagonist astressin2-B abolished icv nesfatin-1’s anorexigenic action, whereas an astressin2-B analog, devoid of CRF-receptor binding affinity, did not. Nesfatin-1 icv induced a dose-dependent reduction of GE by 26 and 43% that was not modified by icv astressin2-B. Nesfatin-1 into the 4v (0.05 μg/rat) or ic (0.5 μg/rat) decreased cumulative dark-phase FI by 29 and 60% at 1 h and by 41 and 37% between 3 and 5 h, respectively. This effect was neither altered by ic astressin2-B nor associated with changes in GE. Cholecystokinin (ip) induced Fos expression in 43% of nesfatin-1 neurons in the paraventricular hypothalamic nucleus and 24% of those in the nucleus tractus solitarius. These data indicate that nesfatin-1 acts centrally to reduce dark phase FI through CRF2-receptor-dependent pathways after forebrain injection and CRF2-receptor-independent pathways after hindbrain injection. Activation of nesfatin-1 neurons by cholecystokinin at sites regulating food intake may suggest a role in gut peptide satiation effect.

Nesfatin-1 exerts long-term effect on food intake and body temperature

“…Most of the authors working on rats and using icv injections investigating different aspects of nesfatin-1's actions have also found the 5 --20 pmol dose range effective, higher doses only caused earlier timing of the effect, and/or enhanced the tendencies observed with lower dose. 5,22,23 We also found the 25 pmol dose as an adequate one, increasing the dose to 100 pmol did not lead to any substantially new observations. Long-lasting effects and interference with the diurnal rhythm are not exclusive among the peptides regulating energy balance.…”

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.…”

“…NUCB2/ nesfatin-1 was described in rat brain food intake regulatory nuclei and implicated in the regulation of food intake [24]. Several studies reported a reduction of food intake following central injection of nesfatin-1 in mice and rats [2,21,24,32,45] and one study after peripheral injection in mice [29]. These effects are in opposition to those of ghrelin which is well established to stimulate food intake after central [41] as well as peripheral injection in rodents [41] and humans [40].…”

Nesfatin Role as Possible New Anti Obesity Treatment

“…The possible involvement of the CRF2 receptors in the mediation of nesfatin-1's effect was investigated. The CRF2 antagonist, astressin2-B , injected intracerebroventricular completely abolished the dark phase food intake reduction induced by intracerebroventricular nesfatin-1 (Stengel et al, 2009). By contrast, a control peptide of similar structure as astressin2-B but without affinity to the CRF2 receptor did not influence intracerebroventricular nesfatin-1's action (Stengel et al, 2009).…”

“…The CRF2 antagonist, astressin2-B , injected intracerebroventricular completely abolished the dark phase food intake reduction induced by intracerebroventricular nesfatin-1 (Stengel et al, 2009). By contrast, a control peptide of similar structure as astressin2-B but without affinity to the CRF2 receptor did not influence intracerebroventricular nesfatin-1's action (Stengel et al, 2009). However as reported by Stengel et al (2009), astressin2-B injected intracerebroventricular did not modulate the rapid onset reduction of food intake observed after intracerebroventricular injection of nesfatin-1.…”