Analogues of PrRP and GLP-1 reduce obesity and promote adult neurogenesis. undefined

Hypothalamic Adult Neurogenesis (hAN) has been implicated in regulating energy homeostasis. Adult-generated neurons and adult Neural Stem Cells (aNSCs) in the hypothalamus were found to control food intake and body weight. Conversely, Diet Induced Obesity (DIO) by High Fat Diets (HFD) exerts adverse influence on hAN. However, the effects of anti-obesity compounds on hAN are not known. To fill out this knowledge gap, we administered anti-obesity compounds to mice kept on HFD and determined their role in the hAN. We used a lipidized analogue of an anorexigenic neuropeptide, Prolactin Releasing Peptide (PrRP), so-called LiPR, and an anti-obesity compound Liraglutide, an agonist of the Glucagon-like Peptide 1 receptor (GLP-1RA), which both reduce food intake and body weight under HFD. We have found that both compounds influenced hAN but with different effects. LiPR rescued HFD-induced decrease in aNSC number and increased the survival of adult-born neurons in the hypothalamus. In addition, LiPR reduced cell proliferation, which was also observed with Liraglutide. Importantly, LiPR reduced activation of aNSCs by influencing their cell cycle as determined by in vitro time-lapse imaging and RNA sequencing. In the adult hippocampus, LiPR but not Liraglutide rescued HFD-induced decrease in number of immature neurons. In human hypothalamic iPSC-derived neurons, LiPR modulates calcium dynamics suggesting it may act also in the human brain. These results show for the first time that anti-obesity compounds differentially influence adult neurogenesis and suggest that the neurogenic process can serve as a target of anti-obesity pharmacotherapy.