SUN-662 Praliciguat, a Clinical-Stage Soluble Guanylate Cyclase Stimulator, Improves Lipid Handling and Insulin Sensitivity in Diet-Induced Obese Mice

Abstract

Praliciguat (PRL) is a soluble guanylate cyclase (sGC) stimulator which in animal models distributes broadly to tissues and elicits hemodynamic, anti-inflammatory, anti-fibrotic, and metabolic effects. Here, we assessed metabolic effects of PRL in a mouse diet-induced obesity model.Six-week-old male C57BL/6N mice were maintained on a low-fat diet (LFD, lean mice) or placed on a 60% high-fat diet (HFD, obese mice). At age 14 weeks, one group of obese mice was maintained on HFD (obese controls) and one group of obese mice was switched to HFD formulated with PRL to achieve a Cmax similar to a 6-mg/kg oral dose (PRL-treated mice). After 38 days of treatment, an oral lipid tolerance test (LTT) was conducted. In a 2nd study under the same dosing paradigm, overnight fasted blood and organs were collected on day 28.As reported previously (1), compared to obese controls, PRL-treated mice had lower fasting insulin (-28%), HOMA-IR (-26%) and triglycerides (-16%) as well as lower plasma triglycerides AUC after LTT (-34%). Gene expression and phosphorylated proteins associated with insulin pathways were measured in liver, skeletal muscle and white adipose tissue. PRL treatment normalized expression of genes involved in lipid handling (liver Pnpla3, Slc27a1, Lpl; muscle Lipe; white adipose tissue Fdft1, Ppara). Expression of proinflammatory genes (liver Tnf; muscle Ccl2; white adipose tissue Akt1, Icam1) was lower in PRL-treated mice than in obese controls. Liver insulin signaling was assessed by determining pAKT (T308) and pAKT (S473), markers of PI3K pathway activity and pERK, a marker of MAPK pathway activity. Compared to lean mice, pAKT (T308) and pERK were lower in obese controls, whereas pAKT (S473) was similar; PRL-treated mice had higher pAKT (T308) and pAKT (S473) compared to obese controls while pERK was unchanged. In skeletal muscle and white adipose tissue, levels of pVASP, a key mediator of the sGC pathway, were higher in PRL-treated mice than in obese controls.In summary, PRL improved insulin sensitivity and lipids in diet-induced obese mice by affecting mechanisms of lipid handling, inflammation, and insulin signaling in key tissues associated with metabolism.1. Author information excluded, 1924-P: Praliciguat, a Clinical-Stage sGC Stimulator, Improves Insulin Sensitivity, Lipid Tolerance, and Energy Utilization in a Mouse Diet-Induced Obesity Model Housed at Thermoneutrality. Diabetes, 2019. 68(Supplement 1): p. 1924-P.