Praliciguat, A Clinical-Stage Sgc Stimulator, Improves Insulin Sensitivity, Lipid Tolerance, And Energy Utilization In A Mouse Diet-Induced Obesity Model Housed At Thermoneutrality

Background: Praliciguat (IW-1973) is a soluble guanylate cyclase (sGC) stimulator under clinical investigation as a potential treatment for diabetic nephropathy. In animal models, praliciguat distributes broadly to tissues and elicits hemodynamic, anti-inflammatory, anti-fibrotic, and metabolic effects. Here, we assessed the metabolic effects of praliciguat in a mouse diet-induced obesity (DIO) model when housed at thermoneutrality. Methods: Six week old male C57BL/6N mice were maintained on a low-fat diet (LFD, lean mice) or put on a 60% high-fat diet (HFD, obese mice). At 14 weeks of age, one group of obese mice was maintained on HFD (obese controls) while another group of obese mice was switched to HFD formulated with praliciguat to achieve a Cmax similar to a daily oral administration of 6 mg/kg (praliciguat treatment). A group of lean mice were also included (lean controls). Indirect calorimetry was performed on days 8, 9, 20, 21, 32 and 33. On day 35, an oral lipid tolerance test (LTT) was conducted. In a second study under the same dosing paradigm, overnight fasted blood and organs were collected on day 28. Results: Compared to obese controls, energy expenditure was higher in praliciguat-treated mice throughout a 24h recording period as assessed by AUC (Day 8: +13%, Day 20: +9%, Day 21: +7%, Day 32: +5%, P<0.05) and LTT triglycerides were lower as assessed by AUC (-34%, P<0.01). In the second study, praliciguat-treated mice had lower fasting insulin (-28%, P<0.05), c-peptide (-20%, P<0.05), HOMA-IR (-26%, P<0.05) and triglycerides (-16%, P<0.01) compared to obese controls. Caloric intake, body weight and composition were unaffected by praliciguat treatment. Conclusions: In a mouse DIO model housed at thermoneutrality, praliciguat increased energy utilization, improved triglycerides in response to an oral lipid challenge, improved insulin sensitivity, and lowered plasma triglycerides. Disclosure C. Schwartzkopf: Employee; Self; Ironwood Pharmaceuticals, Inc. J. Hadcock: Employee; Self; Ironwood Pharmaceuticals, Inc. J. Roux: None. G. Liu: None. C. Shea: Employee; Self; Ironwood Pharmaceuticals, Inc. M. Currie: Employee; Self; Ironwood Pharmaceuticals, Inc. G. Milne: Employee; Spouse/Partner; Catabasis Pharmaceuticals. Employee; Self; Ironwood Pharmaceuticals, Inc. Stock/Shareholder; Spouse/Partner; Catabasis Pharmaceuticals. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc. J. Masferrer: Employee; Self; Ironwood Pharmaceuticals, Inc. J.E. Jones: None.