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.
Keywords: energy expenditure; glucose metabolism; hepatic steatosis; insulin resistance; mitochondria.
© 2016 John Wiley & Sons Ltd.