Leptin protects against obesity and metabolic disease mainly through leptin neural circuits in the hypothalamus. Leptin binds to and activates hypothalamic leptin receptors (LepR), thereby suppressing food intake and increasing energy expenditure. Counterintuitively, obesity is associated with hyperleptinemia in rodents and humans. Moreover, leptin therapies fail to ameliorate obesity in humans. These observations support a notion that obese subjects develop leptin resistance. Multiple positive and negative regulators of LepR signaling have been identified to influence leptin sensitivity, including Sh2b1, SOCS3, and PTP1b. However, factors, which couple overnutrition states to leptin resistance, are not fully understood. Here, we observed that high fat diet (HFD) feeding markedly upregulates Slug, a nuclear epigenetic regulator, in the hypothalamus. Remarkably, LepR neuron-specific deletion of Slug (SlugΔLepR) reversed HFD-induced hyperleptinemia, energy imbalance, obesity, insulin resistance, glucose intolerance, and liver steatosis. Conversely, overexpression of Slug (MBHSlug) but not an epigenetic-defective Slug mutant in the mediobasal hypothalamus resulted in obesity, insulin resistance, glucose intolerance, and fatty liver disease in mice. We found that Slug physically binds to the LepR promoter and suppresses LepR promoter activity; accordingly, hypothalamic LepR expression was high in SlugΔLepR mice and low in MBHSlug mice. Furthermore, Slug increased the levels of LepR promoter H3K27 methylation, a repressive epigenetic mark, in the hypothalamus, presumably by recruiting H3K37 methytransferase Ezh2 to the LepR promoter. Indeed, Ezh2 inhibitor treatment blocked Slug suppression of LepR promoter activity. Collectively, we unravel a previously unrecognized Slug-elicited epigenetic reprograming of LepR pathways that couple overnutrition states to leptin resistance, obesity, and metabolic disease.


M. Kim: None. L. Jiang: None. M.G. Myers: Research Support; Self; AstraZeneca, Novo Nordisk Inc. L. Rui: None.


National Institutes of Health (F32DK120111)

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