GLP-1R-GIPR-PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice
Résumé
ability of PPARγ to decrease ectopic lipid deposition by stimulating adipocyte differentiation and fatty acid uptake 10,11,23 . Expression of PPARγ is also found in hypothalamic nuclei that govern energy metabolism 24 , and viral-mediated overexpression of hypothalamic PPARγ decreases food intake in diet-induced obese (DIO) mice 25 . In agreement with this, we recently showed that GLP-1-mediated delivery of the PPARα/γ co-agonist tesaglitazar (Tesa) decreases body weight and food intake with increased efficacy compared with GLP-1R agonism in DIO mice 26 . Nonetheless, the role of PPARγ in regulating food intake remains controversial, since studies have shown discrepant results depending on the models used and experimental conditions 10,11,23 . PPARδ shows high expression in the brain, where its activation has neuroprotective and anti-apoptotic effects in animal models of cerebral ischemia and Parkinson's Disease 27 . Germline deletion of PPARδ is embryonically lethal 28,29 , but its overexpression in the adipose tissue improves lipid metabolism and leads to resistance to diet-induced obesity 30 . Although PPARα/γ co-agonists have shown metabolic benefits in clinical trials, many have been discontinued owing to adverse cardiovascular and/or renal effects 10,11,23 . The PPARα/γ/δ triple agonist lanifibranor (Lani) is currently in clinical phase 3 trials for the treatment of MASH. In phase 2b, Lani decreased liver fibrosis and MASH, but led to body weight gain, anaemia and fluid retention (peripheral oedema) 3 .
Here we report the design and preclinical evaluation of a unimolecular quintuple agonist, which via covalent binding of Lani to a GLP-1R-GIPR co-agonist allows for its targeted delivery into cells that express the receptor for GLP-1 or GIP. This approach enabled the use of Lani at doses 6,898-fold lower than the dose (30 mg kg -1 ) required preclinically to improve liver metabolism 31 . In vitro, GLP-1-GIP-Lani is indistinguishable from its GLP-1R-GIPR co-agonist backbone in relation to incretin receptor signalling and glucose-stimulated insulin secretion, and is equally effective as Lani for inducing PPARα/γ/δ target gene expression in the presence of the incretin receptors. In vivo, however, GLP-1-GIP-Lani outperforms GLP-1R-GIPR co-agonism and semaglutide to further decrease body weight, food intake and hyperglycaemia in mice with diet, or genetically-induced obesity. Consistent with the incretin-mediated delivery of the PPARα/γ/δ agonist, the metabolic effects of GLP-1-GIP-Lani were blunted in DIO mice with pharmacological or genetic inhibition of GLP-1R, GIPR or PPARδ, and vanished in double-incretin receptor knockout (DIR-KO) mice. Together, these results indicate that GLP-1-GIP-Lani has value for the treatment for obesity and type 2 diabetes.
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