An LRH-1 agonist reverses hepatic metabolic dysfunction in obesity

ME610, a potent LRH-1 agonist, dose-dependently induces LRH-1 target genes and reduces hepatic triglycerides in Nr5a2humLBD mice, reversing obesity-linked metabolic dysfunction.

• Why it matters: LRH-1 metabolism in vivo is hard to study because ligand responses differ between species and suitable agonists with favorable pharmacokinetics are lacking.
• What they did: The authors developed ME610 and engineered Nr5a2humLBD mice to match human LRH-1 ligand responsiveness, then tested effects in diet-induced obesity using multi-omics (transcriptomics, lipidomics, metabolomics).
• The result: In diet-induced obesity, ME610 improves insulin sensitivity and reduces liver fat, with multi-omics showing coordinated reversal of hepatic metabolic stress and peroxisomal lipid metabolism linked to treatment efficacy.

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