cell-specific deletion of Slug mitigates obesity and nonalcoholic fatty liver disease in mice

Leptin exerts its biological actions by activating the long-form leptin receptor (LepRb). LepRb signaling impairment and leptin resistance are believed to cause obesity. The transcription factor Slug--also known as Snai2--recruits epigenetic modifiers and regulates gene expression by an epigenetic mechanism; however, its epigenetic action has not been explored in leptin resistance. Here, we uncover a proobesity function of neuronal Slug. Hypothalamic Slug was upregulated in obese mice. [LepRb.sup.+] cell-specific Slug-knockout ([Slug.sup.[DELTA]LepRb]) mice were resistant to diet-induced obesity, type 2 diabetes, and liver steatosis and experienced decreased food intake and increased fat thermogenesis. Leptin stimulated hypothalamic Stat3 phosphorylation and weight loss to a markedly higher level in [Slug.sup.[DELTA]LepRb] than in [Slug.sup.fl/fl] mice, even before their body weight divergence. Conversely, hypothalamic [LepRb.sup.+] neuron- specific overexpression of Slug, mediated by AAV-hSyn-DIO-Slug transduction, induced leptin resistance, obesity, and metabolic disorders in mice on a chow diet. At the genomic level, Slug bound to and repressed the LepRb promoter, thereby inhibiting LepRb transcription. Consistently, Slug deficiency decreased methylation of LepRb promoter H3K27, a repressive epigenetic mark, and increased LepRb mRNA levels in the hypothalamus. Collectively, these results unravel what we believe to be a previously unrecognized hypothalamic neuronal Slug/epigenetic reprogramming/leptin resistance axis that promotes energy imbalance, obesity, and metabolic disease.
Introduction Hypothalamic neural circuits play an essential role in the control of energy balance, body weight, and metabolic homeostasis. GWAS reveal that approximately 95% of human obesity-associated genes and pathways [...]