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

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

Author information

1
Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany.
2
Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
3
Department of Internal Medicine III, University Hospital Aachen, Aachen, Germany.
4
Department of Internal Medicine III, Saarland University Medical Centre, Homburg, Germany.

Abstract

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

PMID:
27917591
DOI:
10.1111/dom.12839
[Indexed for MEDLINE]

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