Abstract Body (Do not enter title and authors here): Background: The cardiac hormone atrial natriuretic peptide is the endogenous ligand for the guanylyl cyclase A (GC-A) receptor. The ANP/GC-A/cGMP pathway is a key regulator of cardiorenal and metabolic homeostasis. Beyond its classical natriuretic and vasodilatory roles, emerging evidence reveals that ANP via GC-A stimulates lipolysis in human adipocytes and modulates insulin secretion. Notably, the ANP gene variant rs5068, which enhances ANP production, is associated with reduced risk of obesity and metabolic syndrome in humans. We recently engineered CRRL191, a novel best-in-class GC-A agonist, with superior receptor activation and greater resistance to degradation by neprilysin and insulin degrading enzyme resulting in greater blood pressure lowering and natriuretic effects than ANP. Given the metabolic properties of GC-A signaling, we investigated CRRL191’s metabolic effects on lipolysis and insulin secretion in pancreatic, including its interaction with GLP-1.
Hypothesis: CRRL191 exerts potent lipolytic and insulinotropic effects and synergizes with GLP-1 to enhance insulin secretion.
Methods: Human visceral adipocytes were treated with CRRL191 (10^-8-10^-6M) for 6 hrs. Lipolysis was assessed by measuring glycerol and non-esterified fatty acids (NEFA) in supernatants. Rat pancreatic beta cells (INS-1) were stimulated treated with CRRL191 (10^-10-10^-6M), GLP-1 (10^-10-10^-6M) alone or their combination for 1 hr. Insulin secretion was quantified by ELISA.
Results: CRRL191 stimulated lipolysis in human visceral adipocytes (10^-8 -10^-6M), increasing glycerol and NEFA release. CRRL191 induced greater glycerol release than GLP-1 across all tested doses, with low dose CRRL191 (10^-10M) notably enhancing NEFA production. In INS-1 cells, CRRL191 dose dependently increased insulin secretion under hyperglycemic conditions, demonstrating superior potency at lower concentrations (10^-10 and 10^-8M) compared to GLP-1. Remarkably, co-administration of CRRL191 with GLP-1 amplified insulin release beyond levels achieved by either peptide alone.
Conclusion: CRRL191 is a potent GC-A agonist that robustly stimulates lipolysis in visceral adipocytes and enhances insulin secretion in pancreatic beta cells. Its synergistic interaction with GLP-1 highlights a novel therapeutic avenue targeting the GC-A/cGMP pathway for integrated treatment of cardiometabolic diseases. These findings support further evaluation of CRRL191 as a promising candidate for cardiometabolic drug development.