A synergic GLP-1/Acylethanolamide-based combined therapy for MAFLD: Studies in rat models.

Obesity remains a major epidemic in developed countries, with metabolic-associated fatty liver disease (MAFLD) as one of its main hepatic consequences. Pharmacological treatments for MAFLD are limited, but modulation of glucagon-like peptide-1 (GLP-1) or acylethanolamide signalling offers promising therapeutic potential, while exerting anti-obesity effects. This study evaluated the effects of a combined therapy using a dual ligand targeting peroxisome proliferator-activated receptor alpha (PPARα) and peripheral cannabinoid receptor 1 (CB1) (OLHHA, acting as a PPARα agonist and CB1 antagonist) in combination with the GLP-1 receptor agonist liraglutide. Our aim was to assess their potential as a multitarget therapy to ameliorate liver dysfunction in an obesity animal model. In Wistar rats, we evaluated the effects of administering 3 mg/kg OLHHA and 25  µg/kg liraglutide, both acutely and chronically (daily for 42 days), in the context of exposure to a high-fat/high-fructose diet. Although both OLHHA and liraglutide individually ameliorated certain hepatic alterations induced by MAFLD, our findings demonstrate that their combined administration was significantly more effective in promoting body weight loss, improving lipid profiles and transaminase levels, and exerting robust antisteatotic effects in obese rats. This enhanced efficacy was evidenced by a marked reduction in hepatic fat content, downregulation of lipogenesis-related enzymes, and upregulation of proteins involved in lipid oxidation. Moreover, OLHHA, either alone or in combination with liraglutide, efficiently restored redox balance disrupted by MAFLD in obese rats. Collectively, these results highlight the potential of this multitarget therapeutic strategy for the treatment of obesity, MAFLD, and their associated comorbidities.