The PDE4 inhibitor roflumilast reduces weight gain by increasing energy expenditure and leads to improved glucose metabolism

Aims To investigate the metabolic effects of the phosphodiesterase‐4 (PDE4) inhibitor roflumilast, a clinically approved anti‐inflammatory drug used for the treatment of chronic obstructive pulmonary disease. Materials and methods The metabolic effects of roflumilast were investigated in C57BL/6J mice, fed a high‐fat Western‐type diet and treated with or without roflumilast for a period of 12 weeks. Results Roflumilast led to a marked reduction in body weight gain, which became apparent in the second week after treatment initiation and was attributable to a pronounced increase in energy expenditure. Furthermore, roflumilast improved glucose tolerance, reduced insulin resistance and diminished steatohepatitis in mice. Mechanistically, this was associated with hepatic protein kinase A (PKA) and cAMP response element binding protein (CREB) activation, leading to peroxisome proliferator‐activated receptor gamma coactivator‐1α (PCG‐1α)‐dependent induction of mitochondrial biogenesis. Consistently, roflumilast increased the cellular respiratory capacity of hepatocytes in a PKA‐dependent manner. Conclusion Roflumilast‐dependent PDE4 inhibition is a new target for weight loss strategies, especially in conditions of associated comorbidities such as insulin resistance and non‐alcoholic steatohepatitis.