title: The PDE4 inhibitor roflumilast reduces weight gain by increasing energy expenditure and leads to improved glucose metabolism.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Möllmann
authors.affiliation: Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Kahles
authors.affiliation: Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Lebherz
authors.affiliation: Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany.|Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Ben
authors.initials: B
authors.lastname: Kappel
authors.affiliation: Department of Internal Medicine III, University Hospital Aachen, Aachen, Germany.
authors.forename: Christer
authors.initials: C
authors.lastname: Baeck
authors.affiliation: Department of Internal Medicine III, University Hospital Aachen, Aachen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
authors.affiliation: Department of Internal Medicine III, Saarland University Medical Centre, Homburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Werner
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Federici
authors.affiliation: Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Marx
authors.affiliation: Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lehrke
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects; D003521:Cyclopropanes / Q000494:pharmacology; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000209:etiology; D015398:Signal Transduction / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects*
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; C424423:Roflumilast; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose
keywords: energy expenditure; glucose metabolism; hepatic steatosis; insulin resistance; mitochondria