Phosphodiesterase-4 Inhibition as a Potential Therapeutic Strategy in the Management of Obesity: a Review

Phosphodiesterase 4 (PDE4) inhibitors, originally developed for chronic inflammatory diseases, have shown unexpected metabolic benefits, including weight reduction and improved glycemic control in both preclinical and clinical studies. Weight loss typically occurs within the first 6-12 months of treatment and may be sustained over several years. While the underlying mechanisms remain incompletely understood, preclinical findings suggest that PDE4 inhibition may increase circulating levels of glucagon-like peptide 1 (GLP-1), enhance lipolysis and thermogenesis, and promote energy expenditure via stimulation of mitochondrial biogenesis. Additionally, PDE4 inhibitors reduce markers of systemic inflammation and may influence key obesity-related comorbidities, including steatotic liver disease and impaired glucose metabolism. Despite these promising findings, the weight-reducing potential of PDE4 inhibitors has not been systematically evaluated in individuals with obesity, and clinical studies to date have primarily involved individuals with inflammatory conditions. This review summarizes the current evidence on the metabolic effects of PDE4 inhibition, with a particular focus on body weight regulation. PDE4 inhibitors may represent a novel adjunctive pharmacological approach to obesity treatment, with potential to address multiple dimensions of obesity pathophysiology. However, dedicated trials in individuals with obesity are warranted to clarify their therapeutic efficacy and role in metabolic disease management.