Dysregulated nitric oxide signaling and its association with arginase-2 and fatty acid synthase in obesity and related comorbidities

Abstract Obesity is a global health epidemic, projected to affect 38% of adults as overweight and 20% as obese by 2030, usually accompanied by comorbidities such as hypertension and diabetes. This study aimed to identify a disease module related to nitric oxide (NO) signaling in obesity and its comorbidities. We used computational network analysis to identify a nitric oxide synthase (NOS)-related module using NOS2 and NOS3 as seeds. A case-control study ( n = 125) categorized participants into healthy controls and four obese groups: obesity alone, and obesity with diabetes, hypertension, or both. Groups were balanced for age, gender, and smoking. Plasma NO (nitrite via colorimetry), arginase 2 (ARG2), and fatty acid synthase (FASN) were measured via ELISA. In silico analysis identified FASN and ARG2 as key proteins interacting with NOS enzymes. Clinical data revealed significant differences in plasma NO (as nitrite), ARG2, and FASN across groups. Notably, Patients with obesity, diabetes, and hypertension had the lowest median (IQR) nitrite levels at 26.09 (25.31–26.99) µmol/L ( p < 0.001). The obese-diabetic group exhibited reduced median (IQR) ARG2 [5.18 (4.49–7) mU/ml] and FASN [13.8 (10.91–15.43) ng/ml], whereas the obese-diabetic-hypertensive group showed elevated levels of both markers. Nitrite correlated negatively with ARG2 and FASN, while ARG2 and FASN correlated positively. Multivariate regression identified that plasma nitrite is significantly associated with the coexistence of obesity, diabetes, and hypertension. These findings highlight the intricate interplay between NO signaling, ARG2, and FASN in obesity-related comorbidities. Modulating these interconnected pathways may offer novel therapeutic targets for metabolic diseases.