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In mammals, the medio-basal hypothalamus (MBH) integrates photoperiodic and food-related cues to ensure timely phasing of physiological functions, including seasonal reproduction. The current human epidemics of obesity and associated reproductive disorders exemplifies the tight link between metabolism and reproduction. Yet, how food-related cues impact breeding at the level of the MBH remains unclear. In this respect, the sheep, which is a large diurnal mammal with a marked dual photoperiodic/metabolic control of seasonal breeding, is a relevant model. Here, we present a large-scale study in ewes (n = 120), which investigated the impact of food restriction (FRes) on the MBH transcriptome using unbiased RNAseq, followed by RT-qPCR. Few genes (~100) were impacted by FRes and the transcriptional impact was very modest (2-fold increase or 50% decrease for most genes). As anticipated, FRes increased expression of Npy/AgRP/LepR and decreased expression of Pomc/Cartpt, while Kiss1 expression was not impacted. Of particular interest, Eya3, Nmu and Dio2, genes involved in photoperiodic decoding within the MBH, were also affected by FRes. Finally, we also identified a handful of genes not known to be regulated by food-related cues (e.g., RNase6, HspA6, Arrdc2). In conclusion, our transcriptomics study provides insights into the impact of metabolism on the MBH in sheep, which may be relevant to human, and identifies possible molecular links between metabolism and (seasonal) reproduction.

The modulation of the kisspeptin system holds promise as a treatment for human reproductive disorders and for managing livestock breeding. The design of analogs has overcome some unfavorable properties of the endogenous ligands. However, for applications requiring a prolongation of drug activity, such as ovulation induction in the ewe during the non-breeding season, additional improvement is required. To this aim, we designed and tested three formulations containing the kisspeptin analog C6. Two were based on polymeric nanoparticles (NP1 and NP2) and the third was based on hydrogels composed of a mixture of cyclodextrin polymers and dextran grafted with alkyl side chains (MD/pCD). Only the MD/pCD formulation prolonged C6 activity, as shown by monitoring luteinizing hormone (LH) plasma concentration (elevation duration 23.4 ± 6.1, 13.7 ± 4.7 and 12.0 ± 2.4 h for MD/pCD, NP1 and NP2, respectively). When compared with the free C6 (15 nmol/ewe), the formulated (MD/pCD) doses of 10, 15 and 30 nmol/ewe, but not the 90 nmol/ewe dose, provided a more gradual release of C6 as shown by an attenuated LH release during the first 6 h post-treatment. When tested during the non-breeding season without progestogen priming, only, the formulated 30 nmol/ewe dose triggered ovulation (50% of ewes). Hence, we showed that a formulation with an adapted action time would improve the efficacy of C6 with respect to inducing ovulation during the non-breeding season. This result suggests that formulations containing a kisspeptin analog might find applications in the management of livestock reproduction but also point to the possibility of their use for the treatment of some human reproductive pathologies.