HOTAIR Drives Obesity-Associated Basal Lipolysis Through Epigenetic Regulation of EGR1-ATGL Axis

This is the authors' abstract. We don't add key points for this paper.

Obesity is associated with chronically elevated basal lipolysis, which raises circulating free fatty acids and drives ectopic lipid deposition and insulin resistance, yet the underlying mechanisms remain poorly defined. Here we identify the long non-coding RNA HOTAIR as an epigenetic driver of obesity-associated basal lipolysis. HOTAIR expression was elevated in visceral white adipose tissue from obese individuals, high-fat diet-fed mice, and adipocytes exposed to obesogenic hypoxic and lipid-rich conditions, and correlated with increased glycerol and FFA release together with altered intracellular triglyceride levels. Gain- and loss-of-function studies showed that HOTAIR promotes lipolysis by upregulating adipose triglyceride lipase (ATGL), the rate-limiting enzyme in triglyceride hydrolysis, without affecting β-adrenergic-stimulated lipolysis. Mechanistically, HOTAIR repressed the transcriptional repressor EGR1 through a DNMT1-associated methylation mechanism, thereby relieving EGR1-dependent inhibition of ATGL. Silencing HOTAIR with antisense oligonucleotides or inhibiting DNA methylation with 5-azacytidine restored EGR1 expression, suppressed ATGL, reduced lipid release, and improved glucose tolerance and metabolic parameters in obese mice. These findings establish HOTAIR as a key epigenetic regulator of basal lipolysis through a methylation-dependent EGR1-ATGL axis and highlight this circuit as a potential therapeutic target for restoring lipid homeostasis in obesity.