Molecular Basis of Obesity and Obesity-induced Metabolic Diseases

National Heart, Lung, And Blood Institute

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Abstract

Using a sequence-independent approach, we systematically identified pairs of conserved lncRNA metabolic regulators (fcLMRs) between humans and mice. Among them, h/mLMR1 was shown to regulate hepatic triglyceride metabolism through a nutrient-sensitive amino acid–mTOR–SREBP1 pathway. This finding established a paradigm for dissecting the physiological function of human liver lncRNAs. Building on this framework, we discovered a conserved lncRNA, GULL, that enhances systemic glucose and lipid homeostasis by binding to CRTC2 and regulating CREB- and SREBP1-dependent transcriptional programs. Importantly, we defined the minimal functional motif within GULL, termed GULF, and demonstrated that this RNA element alone confers therapeutic benefits in obese mice. These findings provide proof-of-concept for developing RNA-based therapeutics directly from human lncRNA motifs. Together, these studies establish an experimental platform for studying human lncRNAs in vivo and reveal their potential as both mechanistic drivers and therapeutic targets in obesity-associated metabolic disease.