Nesfatin-130−59 Injected Intracerebroventricularly Differentially Affects Food Intake Microstructure in Rats Under Normal Weight and Diet-Induced Obese Conditions

Abstract

Nesfatin-1 is well-established to induce an anorexigenic effect. Recently, nesfatin-130−59, was identified as active core of full length nesfatin-11−82 in mice, while its role in rats remains unclear. Therefore, we investigated the effects of nesfatin-130−59 injected intracerebroventricularly (icv) on the food intake microstructure in rats. To assess whether the effect was also mediated peripherally we injected nesfatin-130−59 intraperitoneally (ip). Since obesity affects the signaling of various food intake-regulatory peptides we investigated the effects of nesfatin-130−59 under conditions of diet-induced obesity (DIO). Male Sprague–Dawley rats fed ad libitum with standard diet were icv cannulated and injected with vehicle (5 μl ddH2O) or nesfatin-130−59 at 0.37, 1.1, and 3.3 μg (0.1, 0.3, 0.9 nmol/rat) and the food intake microstructure assessed using a food intake monitoring system. Next, naïve rats were injected ip with vehicle (300 μl saline) or nesfatin-130−59 (8.1, 24.3, 72.9 nmol/kg). Lastly, rats were fed a high fat diet for 10 weeks and those developing DIO were icv cannulated. Nesfatin-1 (0.9 nmol/rat) or vehicle (5 μl ddH2O) was injected icv and the food intake microstructure assessed. In rats fed standard diet, nesfatin-130−59 caused a dose-dependent reduction of dark phase food intake reaching significance at 0.9 nmol/rat in the period of 4–8 h post injection (−29%) with the strongest reduction during the fifth hour (−75%), an effect detectable for 24 h (−12%, p < 0.05 vs. vehicle). The anorexigenic effect of nesfatin-130−59 was due to a reduction in meal size (−44%, p < 0.05), while meal frequency was not altered compared to vehicle. In contrast to icv injection, nesfatin-130−59 injected ip in up to 30-fold higher doses did not alter food intake. In DIO rats fed high fat diet, nesfatin-130−59 injected icv reduced food intake in the third hour post injection (−71%), an effect due to a reduced meal frequency (−27%, p < 0.05), while meal size was not altered. Taken together, nesfatin-130−59 is the active core of nesfatin-11−82 and acts centrally to reduce food intake in rats. The anorexigenic effect depends on the metabolic condition with increased satiation (reduction in meal size) under normal weight conditions, while in DIO rats satiety (reduction in meal frequency) is induced.

Nesfatin-1 modulates murine gastric vagal afferent mechanosensitivity in a nutritional state dependent manner

“…A nesfatin-vagal pathway for the regulation of food intake is controversial. In rats, intracerebroventricular administration of nesfatin-1 (0.3-0.9nmol/rat) causes a reduction in food intake [39]. In contrast, peripheral administration of nesfatin-1 (8-73nmol/Kg) has been shown to have no effect on food intake despite being administered at doses 30 times higher than the intracerebroventricular administered nesfatin-1 [39].…”

Nesfatin-1: functions and physiology of a novel regulatory peptide

“…In addition, an acute gavage with a high fat bolus also increased serum NUCB2/nesfatin-1 levels in mice (Mohan et al 2014). Finally, peripheral and central acute injection of nesfatin-1 midsegment reduced food intake in mice fed a high-fat diet (Shimizu et al 2009a, Prinz et al 2015, whereas leptin did not (Shimizu et al 2009a), indicating that long term exposure to high-fat diet did not cause 'nesfatin-1 resistance' analogous to the well-described leptin-resistance (Crujeiras et al 2015). Thus, nesfatin-1 could represent a valid alternative in the treatment of metabolic diseases even in the state of leptin resistance.…”

“…In mice, central administration of nesfatin-1 reduced meal size and increased inter-meal intervals indicating both satiety (meal termination) and satiation (delayed meal initiation) , whereas central injection of nesfatin-1 midsegment induced satiety without affecting satiation (Stengel et al 2012). Interestingly, in rats fed normal chow, central nesfatin-1 midsegment induced satiation, whereas satiety was induced in rats with diet-induced obesity (Prinz et al 2015). As suggested by the authors, these mixed results could be explained by differences in species, receptor-binding affinity between full-length nesfatin-1 vs its midsegment and/or the activation of different signaling pathways depending on dietary conditions (Prinz et al 2015).…”

“…Interestingly, in rats fed normal chow, central nesfatin-1 midsegment induced satiation, whereas satiety was induced in rats with diet-induced obesity (Prinz et al 2015). As suggested by the authors, these mixed results could be explained by differences in species, receptor-binding affinity between full-length nesfatin-1 vs its midsegment and/or the activation of different signaling pathways depending on dietary conditions (Prinz et al 2015). In a recent study, treatment with nesfatin-1 resulted in the upregulation of Cck (a satiation peptide) and in the downregulation of peptide Yy (PYY, a satiety peptide) mRNA and protein levels both in vitro and in vivo .…”

“…The administration of neither nesfatin-2 nor -3 was effective in terms of food intake (Oh-I et al 2006). For the biological action, the mid-segment of nesfatin-1, which corresponds to AA 24-53 of NUCB2 and nesfatin-1, is of particular relevance (Shimizu et al 2009a, Stengel et al 2012, Prinz et al 2015.…”