The mitochondrial protein UCP1 has potent therapeutic effects on vascular inflammation and atherosclerosis.

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⁺ cell–specific Slug-knockout (Slug^ΔLepRb) 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^ΔLepRb than in Slug^fl/fl mice, even before their body weight divergence. Conversely, hypothalamic LepRb⁺ 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.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by excessive hepatic lipid accumulation and can progress to metabolic dysfunction-associated steatohepatitis (MASH), which is manifested with persistent liver injury, inflammation, and fibrosis, increasing the risk for cirrhosis and hepatocellular carcinoma. Aberrant epigenetic reprogramming and epitranscriptomic remodeling emerge to be a driving force for MASLD and MASH. SNAIL1 and SLUG, two related transcriptional regulators, regulate de novo lipogenesis and liver steatosis by opposing epigenetic mechanisms. RNA m6A modification regulates not only liver steatosis but also liver injury and regeneration. MASLD is associated with changes in the expression of m6A writers, erasers, and readers, which significantly influence its progression.