Abstract Recent research highlights pivotal roles of epigenetic reprogramming in health and disease. There is evidence that epigenetic reprogramming in the hypothalamus is linked to obesity. The hypothalamus encompasses core neural circuits controlling energy balance, body weight, and metabolic homeostasis. Of note, >95% of known human obesity-related genes affect brain neural pathways and activities. However, transcription factors and epigenetic enzymes responsible for epigenetic reprogramming of hypothalamic neurons are unknown. Slug is a transcriptional repressor and known to promote epithelial-mesenchymal transition in development and cancer metastasis. Slug binds to E2 boxes via its C-terminal DNA-binding domain, and its N-terminal SNAG domain binds to EZH2 and HDAC1/2 and recruits the epigenetic enzymes to target promoters/enhancers. EZH2 is the catalytic subunit of the polycomb repressive complex 2, and catalyzes, in conjunction with EED (a structural subunit), di- and tri-methylations of histone 3 lysine-27 (H3K27me2/3), repressive epigenetic marks. We found that Slug is expressed in a subset of hypothalamic neurons and upregulated in obesity. Deletion of Slug in long-form leptin receptor LepRb-expressing neurons protects against high fat diet (HFD)-induced obesity, type 2 diabetes, and liver steatosis. Likewise, deletion of Slug in the ventromedial hypothalamus (VMH) also mitigates HFD-induced obesity. Conversely, overexpression of wild-type Slug, but not epigenetic-defective mutants, in the mediobasal hypothalamus promotes obesity and metabolic disorders. Remarkably, central injection of EZH2-selective or EED-selective inhibitors ameliorates obesity induced by either Slug overexpression or HFD feeding. Hypothalamic leptin signaling and brain-derived neurotrophic factor (BDNF) signaling are known to protect against obesity and metabolic syndromes. We observed that Slug directly binds to the LepRb promoter and induces H3K27me2/3, thereby suppressing LepRb expression. Slug also suppresses BDNF expression in the hypothalamus. Based on these findings, we hypothesize that Slug assembles EZH2/EED epigenetic complexes on the promoters/enhancers of LepRb, BDNF, and other obesity genes, which deposit H3K27me2/3 to repress the genes. Hypothalamic SLUG/EZH2/EED epigenetic reprogramming drives the development of obesity and metabolic disorders. We further propose that pharmacological reversal of the SLUG/EZH2/EED epigenetic reprogramming mitigates obesity and metabolic disease. We will test these hypotheses in three aims. Aim 1 is to determine whether VMH Slug promotes obesity by an epigenetic mechanism. Aim 2 is to determine whether EZH2/EED1 complex mediates SLUG’s pro-obesity action. Aim 3 is to determine whether EZH2 and EED inhibitors mitigate obesity and metabolic disease by reversing SLUG/EZH2/EED epigenetic reprogramming. The outcomes are expected to establish a new hypothalamic SLUG/EZH2/EED epigenetic paradigm in the field of obesity and m...