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

Möllmann, Julia; Kahles, Florian; Lebherz, Corinna; Kappel, B.; Baeck, Christer; Tacke, Frank; Werner, Christian; Federici, Massimo; Lehrke, Michael

doi:10.1111/dom.12839

Cited by 30 publications

(22 citation statements)

References 42 publications

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“…Additionally, Mollmann et al reported that PDE4 inhibition, using roflumilast, diminished steatohepatitis and improved glucose tolerance in mice fed a high-fat Western-type diet. The authors attributed this action mechanistically to cAMP activation of PKA and CREB leading to increased mitochondrial biogenesis induced by PCG-1α [166]. Mice administered roflumilast also exhibited increased energy expenditure and lower weight gain.…”

Section: Therapeutic Interventions Via Camp Signalingmentioning

confidence: 99%

Role of cAMP and phosphodiesterase signaling in liver health and disease

Wahlang

McClain

Barve

et al. 2018

Cellular Signalling

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Liver disease is a significant health problem worldwide with mortality reaching around 2 million deaths a year. Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the major causes of chronic liver disease. Pathologically, NAFLD and ALD share similar patterns of hepatic disorders ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. It is becoming increasingly important to identify new pharmacological targets, given that there is no FDA-approved therapy yet for either NAFLD or ALD. Since the evolution of liver diseases is a multifactorial process, several mechanisms involving parenchymal and non-parenchymal hepatic cells contribute to the initiation and progression of liver pathologies. Moreover, certain protective molecular pathways become repressed during liver injury including signaling pathways such as the cyclic adenosine monophosphate (cAMP) pathway. cAMP, a key second messenger molecule, regulates various cellular functions including lipid metabolism, inflammation, cell differentiation and injury by affecting gene/protein expression and function. This review addresses the current understanding of the role of cAMP metabolism and consequent cAMP signaling pathway(s) in the context of liver health and disease. The cAMP pathway is extremely sophisticated and complex with specific cellular functions dictated by numerous factors such abundance, localization and degradation by phosphodiesterases (PDEs). Furthermore, because of the distinct yet divergent roles of both of its effector molecules, the cAMP pathway is extensively targeted in liver injury to modify its role from physiological to therapeutic, depending on the hepatic condition. This review also examines the behavior of the cAMP-dependent pathway in NAFLD, ALD and in other liver diseases and focuses on PDE inhibition as an excellent therapeutic target in these conditions.

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Section: Therapeutic Interventions Via Camp Signalingmentioning

confidence: 99%

Role of cAMP and phosphodiesterase signaling in liver health and disease

Wahlang

McClain

Barve

et al. 2018

Cellular Signalling

View full text Add to dashboard Cite

show abstract

“…For example, PDE4B-null mice have been shown to be leaner, with lower fat pad weights, smaller adipocytes, and decreased serum leptin levels compared with wild-type littermates (33). Treatment with a PDE4 inhibitor reduced the body weight of mice fed a Western-type diet mediated by an increase in energy expenditure and PDE4B mRNA in white adipose tissue (34). Furthermore, chronic treatment with PDE4 inhibitors was shown to delay the progression of diabetes in an experimental animal model for obesity, diabetes, and metabolic syndrome (db/db mice) (35).…”

Section: Discussionmentioning

confidence: 99%

Placental DNA Methylation Adaptation to Maternal Glycemic Response in Pregnancy

et al. 2018

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Maternal hyperglycemia during pregnancy is associated with excess fetal growth and adverse perinatal and developmental outcomes. Placental epigenetic maladaptation may underlie these associations. We performed an epigenome-wide association study (>850,000 CpG sites) of term placentas and prenatal maternal glycemic response 2-h post oral glucose challenge at 24-30 weeks of gestation among 448 mother-infant pairs. Maternal 2-h glycemia postload was strongly associated with lower DNA methylation of four CpG sites (false discovery rate [FDR] <0.05) within the phosphodiesterase 4B gene (). Additionally, three other individual CpG sites were differentially methylated relative to maternal glucose response within the ,, and genes (FDR <0.05). DNA methylation correlated with expression of its respective genes in placental tissue at three out of four independent identified loci: ( = 0.31, < 0.01), ( = -0.24, = 0.013), and ( = 0.32, < 0.001). In an independent replication cohort ( = 65-108 samples), results were consistent in direction but not significantly replicated among tested CpG sites in and Our study provides evidence that maternal glycemic response during pregnancy is associated with placental DNA methylation of key inflammatory genes whose expression levels are partially under epigenetic control.

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“…For example, PDE4B-null mice have been shown to be leaner, with lower fat pad, smaller adipocytes, and decreased serum leptin levels compared to wild-type littermates 24 . Treatment with a PDE4 inhibitor reduced the body weight of mice fed a Westerntype diet mediated by an increase in energy expenditure and PDE4B mRNA in white adipose tissue 25 . Furthermore, chronic treatment with PDE4 inhibitors was shown to delay the progression of diabetes among an experimental animal model for obesity, diabetes and metabolic syndrome (db/db mice) 26 .…”

Section: Discussionmentioning

confidence: 99%

Placenta DNA Methylation Adaptation to Maternal Glucose Tolerance in Pregnancy

Gagné-Ouellet

Allard

Brisson

et al. 2017

Preprint

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Maternal hyperglycemia during pregnancy is associated with fetal growth and adverse perinatal and developmental outcomes. Placental epigenetic maladaptation may underlie these associations. We performed an epigenome-wide association study of term placentas and prenatal maternal glucose response 2-hour post oral glucose challenge at 24-30 weeks of gestation among 448 mother-infant pairs. Maternal glucose levels post-load were strongly associated with lower DNA methylation of 4 CpGs (FDR q<0.05) within the Phosphodiesterase 4B gene (PDE4B).

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

Abstract: 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.

Cited by 30 publications

References 42 publications

Role of cAMP and phosphodiesterase signaling in liver health and disease

Role of cAMP and phosphodiesterase signaling in liver health and disease

Placental DNA Methylation Adaptation to Maternal Glycemic Response in Pregnancy

Placenta DNA Methylation Adaptation to Maternal Glucose Tolerance in Pregnancy

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