Introduction and Objective: Uncoupling protein 1 (Ucp1) activation drives potent adipose thermogenesis, yet the target is widely considered undruggable by conventional therapeutic modalities. Targeting the Ucp1 promoter with small activating RNA (saRNA) offers a novel RNA activation (RNAa) approach to overcome this barrier. We evaluated the efficacy, body composition, and durability effects of LiCO-saUcp1—an adipose-biased, lipid-conjugated oligonucleotide—in diet-induced obesity (DIO) mice.Methods: Pharmacodynamics were assessed in wild-type mice. In four DIO models (10-17 weeks on high-fat diet), subcutaneous LiCO-saUcp1 (1-30 mg/kg), semaglutide (0.04-0.1 mg/kg), or combinations were administered. Outcomes included body weight (BW), body composition, energy expenditure markers, and hepatic histology up to two months post-withdrawal.Results: In wild-type mice, a single LiCO-saUcp1 dose increased brown adipose Ucp1 mRNA 1.6-fold. In DIO mice, LiCO-saUcp1 (30 mg/kg) inhibited BW gain by 52% versus vehicle. While semaglutide caused lean mass loss (19%) and rapid weight rebound post-withdrawal, LiCO-saUcp1 specifically reduced fat mass (45%) and preserved lean mass. LiCO-saUcp1 maintained BW and 46% fat mass loss two months post-withdrawal. Combination therapy synergistically induced 69% fat mass loss versus 47% with semaglutide alone, without exacerbating lean mass depletion. LiCO-saUcp1 dose-dependently lowered liver triglycerides (up to 79%) and steatosis. On-target thermogenesis was evidenced by a 20-fold increase in inguinal white adipose Ucp1 mRNA and a 0.5°C elevation in abdominal skin temperature.Conclusion: LiCO-saUcp1 provides potent, durable weight loss by browning white adipose tissue. Its ability to selectively reduce fat, preserve lean mass, and prevent post-withdrawal weight rebound presents a highly differentiated therapeutic mechanism that complements incretin-based therapies.
J. Wang: Employee; Current; Ractigen Therapeutics. J. Chen: Employee; Current; Ractigen Therapeutics. F. Xu: Employee; Current; Ractigen Therapeutics. X. Zhou: Employee; Current; Ractigen Therapeutics. W. Lin: Employee; Current; Ractigen Therapeutics. M. Kang: Other – I hold shares in Ractigen Therapeutics and a named inventor in patent applications related to the work presented in the abstract.; Current; Ractigen Therapeutics. L. Li: Other – I hold shares in Ractigen Therapeutics and a named inventor in patent applications related to the work presented in the abstract.; Current; Ractigen Therapeutics.
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