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

Diabetes Obes Metab. 2017 Apr;19(4):496-508. doi: 10.1111/dom.12839. Epub 2017 Feb 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / pharmacology*
  • Animals
  • Benzamides / pharmacology*
  • Cyclic AMP-Dependent Protein Kinases / drug effects
  • Cyclopropanes / pharmacology
  • Diet, High-Fat / adverse effects
  • Energy Metabolism / drug effects*
  • Glucose / metabolism*
  • Insulin Resistance
  • Liver / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / drug therapy*
  • Non-alcoholic Fatty Liver Disease / etiology
  • Signal Transduction / drug effects
  • Weight Gain / drug effects*


  • Aminopyridines
  • Benzamides
  • Cyclopropanes
  • Roflumilast
  • Cyclic AMP-Dependent Protein Kinases
  • Glucose