Synergistic effect of leptin and lipidized PrRP on metabolic pathways in ob/ob mice

in Journal of Molecular Endocrinology

Correspondence should be addressed to L Maletínská: maletin@uochb.cas.cz
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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.

Supplementary Materials

    • Suppl. Fig. 1. Open field test of WT and ob/ob mice in EXPERIMENT 2 (A) Distance travelled before experiment: groups of WT saline and ob/ob saline mice. (B) Distance travelled after two-month treatment: groups of WT saline and ob/ob saline mice. (C) Distance travelled after two-month treatment: groups of ob/ob mice treated with saline, leptin, palm11-PrRP31 and leptin + palm11-PrRP31. (D) Wall distance: groups of WT saline and ob/ob saline mice. (E) Wall distance two-month treatment: groups of WT saline and ob/ob saline mice. (F) Wall distance two-month treatment: groups of ob/ob mice treated with saline, leptin, palm11-PrRP31 and leptin + palm11-PrRP31. Data are means ± SEM (n= 8-10). Significance is *** p<0.001, **** p<0.0001 vs ob/ob saline (t-test or One-way ANOVA + Bonferroni post-hoc test).
    • Suppl. Fig. 2. mRNA expression in liver in EXPERIMENT 2 Ob/ob mice were treated with saline, leptin. palm11-PrRP31 and leptin + palm11-PrRP31: (A) Acaca. (B) Fasn. (C) SREBP-1. (D) Pck-1. (E) Cpt-1a. (F) PPAR-alfa. (G) PPAR-gamma. (H) G6pc. Data are means ± SEM (n= 8-10). Significance is * p<0.05, ** p<0.01, *** p<0.001 vs ob/ob saline (t-test or One-way ANOVA + Bonferroni post-hoc test).
    • Suppl. Fig. 3. UCP-1 mRNA expression in BAT in EXPERIMENT 1 and in EXPERIMENT 2 (A) UCP-1 mRNA expression in Experiment 1. There were no significant differences among group. (B) UCP-1 mRNA expression in Experiment 2. The difference between phenotypes (ob/ob saline versus WT saline) was significant but the treatment did not cause any significant change compared to ob/ob saline. Data are means ± SEM (n= 8-10). Significance is * p<0.05, ** p<0.01, *** p<0.001 vs ob/ob saline (t-test or One-way ANOVA + Bonferroni post-hoc test).

 

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