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The situation following anti-obesity drug termination is rarely investigated, eventhough a decrease in body weight needs to be sustained. Therefore, this study examined the impact of twice-daily peripheral administration of 5 mg/kg [N-palm-γGlu-Lys¹¹] prolactin-releasing peptide 31 (palm¹¹-PrRP31) in mice with diet-induced obesity (DIO from consuming a high-fat diet) after 28 days of treatment (palm¹¹-PrRP31 group) and after 14 days of peptide treatment followed by 14 days of discontinuation (palm¹¹-PrRP31 + saline group). At the end of the treatment, cumulative food intake, body weight and subcutaneous fat weight/body weight ratio and leptin plasma level were reduced significantly in both the palm¹¹-PrRP31 group and the palm¹¹-PrRP31 + saline group compared to the saline control group. This reduction correlated with significantly increased FOSB, a marker of long-term neuronal potentiation, in the nucleus arcuatus and nucleus tractus solitarii, areas known to be affected by the anorexigenic effect of palm¹¹-PrRP31. Moreover, activation of leptin-related hypothalamic signaling was registered through an increase in phosphoinositide-3-kinase, increased phosphorylation of protein kinase B (PKB, AKT) and enhanced extracellular signal-regulated kinase 1/2 phosphorylation. Besides, lowered apoptotic markers c-JUN N-terminal kinase and c-JUN phosphorylation were registered in the hypothalami of both palm¹¹-PrRP31-treated groups. This study demonstrates that palm¹¹-PrRP31 positively affects feeding and leptin-related hypothalamic signaling, not only after 28 days of treatment but even 14 days after the termination of a 14-day long treatment without the yo-yo effect.

Lack of leptin production in ob/ob mice results in obesity and prediabetes that could be partly reversed by leptin supplementation. In the hypothalamus, leptin supports the production of prolactin-releasing peptide (PrRP), an anorexigenic neuropeptide synthesized and active in the brain. In our recent studies, the palmitoylated PrRP analog palm¹¹-PrRP31 showed a central anorexigenic effect after peripheral administration. This study investigates whether PrRP could compensate for the deficient leptin in ob/ob mice. In two separate experiments, palm¹¹-PrRP31 (5 mg/kg) and leptin (5 or 10 μg/kg) were administered subcutaneously twice daily for 2 or 8 weeks to 8- (younger) or 16-(older) week-old ob/ob mice, respectively, either separately or in combination. The body weight decreasing effect of palm¹¹-PrRP31 in both younger and older ob/ob mice was significantly powered by a subthreshold leptin dose, the combined effect could be then considered synergistic. Leptin and palm¹¹-PrRP31 also synergistically lowered liver weight and blood glucose in younger ob/ob mice. Reduced liver weight was linked to decreased mRNA expression of lipogenic enzymes. In the hypothalamus of older ob/ob mice, two main leptin anorexigenic signaling pathways, namely, Janus kinase, signal transducer and activator of transcription-3 activation and AMP-activated protein kinase de-activation, were induced by leptin, palm¹¹-PrRP31, and their combination. Thus, palm¹¹-PrRP31 could partially compensate for leptin deficiency in ob/ob mice. In conclusion, the results demonstrate a synergistic effect of leptin and our lipidized palm¹¹-PrRP31 analog.