Loss　of　neuron　homeostasis　in　the　arcuate　nucleus　(ARC)　is　responsible　for　diet-induced-obesity　(DIO).　We　previously　reported　that　loss　of　Rb1　gene　compromised　the　homeostasis　of　anorexigenic　POMC　neurons　in　ARC　and　induced　obesity　in　mice.　To　evaluate　the　development　of　DIO,　we　propose　to　analyze　the　transcriptomic　alteration　of　POMC　neurons　in　mice　following　high　fat　diet　(HFD)　feeding.　We　isolated　these　neurons　from　established　DIO　mice　and　performed　transcriptomic　profiling　using　RNA-seq.　In　total,　1066　genes　(628　upregulated　and　438　downregulated)　were　identified　as　differentially　expressed　genes　(DEGs).　Pathway　enrichment　analysis　with　these　DEGs　further　revealed　that　＂cell　cycle,＂　＂apoptosis,＂　＂chemokine　signaling,＂　and　＂sphingo-lipid　metabolism＂　pathways　were　correlated　with　DIO　development.　Moreover,　we　validated　that　the　pRb　protein,　a　key　regulator　of　＂cell　cycle　pathway,＂　was　inactivated　by　phosphorylation　in　POMC　neurons　by　HFD　feeding.　Importantly,　the　reversal　of　deregulated　cell　cycle　by　stereotaxic　delivering　of　the　unphosphorylated　pRb.P　in　ARC　significantly　meliorated　the　DIO.　Collectively,　our　study　provides　insights　into　the　mechanisms　related　to　the　loss　of　homeostasis　of　POMC　neurons　in　DIO,　and　suggests　pRb　phosphorylation　as　a　potential　intervention　target　to　treat　DIO.