GLP-1R–GIPR–PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice

Apr 29, 2026Nature

Combined activation of five hormone receptors improves obesity and diabetes in mice

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Abstract

A unimolecular quintuple agonist combining GLP-1R-GIPR co-agonism and lanifibranor shows improved metabolic effects in mice.

GLP-1-GIP-lanifibranor demonstrates similar incretin receptor signaling and insulin secretion stimulation as GLP-1-GIP in isolated mouse islets.
In vivo studies indicate that GLP-1-GIP-lanifibranor significantly reduces body weight, food intake, and hyperglycemia compared to GLP-1R-GIPR co-agonism and semaglutide.
The metabolic effects of GLP-1-GIP-lanifibranor are diminished when GLP-1R, GIPR, or PPARδ are inhibited, suggesting these pathways are critical for its action.
Therapeutic potential for GLP-1-GIP-lanifibranor in obesity and diabetes is indicated by its performance in genetically modified and pharmacologically treated mice.

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There are increasing numbers of effective drugs to improve obesity-linked metabolic dysfunction; GLP-1R-GIPR co-agonism is effective in the management of obesity and type 2 diabetes, and lanifibranor-a nuclear-acting small-molecule triple agonist of PPARα, PPARγ and PPARδ-is in clinical phase 3 trials for the treatment of metabolic dysfunction-associated steatohepatitis. Here, seeking to further improve the metabolic efficacy of GLP-1R-GIPR co-agonism, we report the development of a unimolecular quintuple agonist that combines the body weight-reducing and blood glucose-lowering effects of GLP-1R-GIPR co-agonism with the insulin-sensitizing and anti-inflammatory effects of lanifibranor via its targeted delivery into GLP-1R- and GIPR-expressing cells. In vitro, GLP-1-GIP-lanifibranor is indistinguishable from GLP-1-GIP in relation to incretin receptor signalling and shows equal stimulation of insulin secretion in isolated mouse islets. In vivo, however, GLP-1-GIP-lanifibranor outperforms GLP-1R-GIPR co-agonism and semaglutide, further decreasing body weight, food intake and hyperglycaemia in obese and insulin-resistant mice through synergistic incretin and PPAR action. The metabolic action of GLP-1-GIP-lanifibranor is blunted in mice with genetic or pharmacological inhibition of GLP-1R, GIPR or PPARδ and is absent in DIO double incretin receptor-knockout mice, collectively suggesting that GLP-1-GIP-lanifibranor has substantial therapeutic value in the treatment of obesity and diabetes. 1,2 3