Retinoic acid-related orphan receptors α and γ: key regulators of lipid/glucose metabolism, inflammation, and insulin sensitivity

Jetten, Anton M.; Kang, Hong Soon; Takeda, Yukimasa

doi:10.3389/fendo.2013.00001

Cited by 123 publications

(131 citation statements)

References 91 publications

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“…REV-ERBs and RORs function respectively as negative and positive transcription factors competing for binding to RORE promoter elements, playing important roles in circadian rhythms, metabolism and inflammation (Gerhart-Hines et al, 2013; Jetten et al, 2013; Kojetin and Burris, 2014). In a previous screen for inhibitors of RORγt, NOB was among a number of primary screen hits that instead activated RORγt and consequently were not validated further (Huh et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome

et al. 2016

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SUMMARY Dysregulation of circadian rhythms is associated with metabolic dysfunction, yet it is unclear whether enhancing clock function can ameliorate metabolic disorders. In an unbiased chemical screen using fibroblasts expressing PER2::Luc, we identified Nobiletin (NOB), a natural polymethoxylated flavone, as a Clock amplitude-Enhancing small Molecule (CEM). When administered to diet-induced obese (DIO) mice, NOB strongly counteracted metabolic syndrome and augmented energy expenditure and locomotor activity in a Clock gene-dependent manner. In db/db mutant mice, the clock is also required for the mitigating effects of NOB on metabolic disorders. In DIO mouse liver, NOB enhanced clock protein levels and elicited pronounced gene expression remodeling. We identified retinoid acid receptor-related orphan receptors (RORs) as direct targets of NOB, revealing a pharmacological intervention that enhances circadian rhythms to combat metabolic disease via the circadian gene network.

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Section: Resultsmentioning

confidence: 99%

The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome

et al. 2016

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“…Although weight loss of the magnitude documented in this study is sufficient to substantially improve glycaemic control [8], weightindependent effects of MetAP2 inhibition also likely play a key role. For example, MetAP2 inhibition attenuates activity of extracellular signal regulated kinase (ERK1/2) [9] and downstream factors such as retinoic acid-related orphan receptor α (RORα) that influence the development of insulin resistance, inflammation and other metabolic disorders [10].…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of methionine aminopeptidase 2 inhibition in type 2 diabetes: a randomised, placebo-controlled clinical trial

et al. 2018

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Aims/hypothesis This multicentre randomised double-blind placebo-controlled clinical trial assessed the efficacy and safety of a methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib, in individuals with obesity (BMI ≥30 kg/m 2 ) and type 2 diabetes (HbA 1c 53-97 mmol/mol [7-11%] and fasting glucose <15.6 mmol/l). Methods Participants were randomised (via a centralised interactive web response system) to placebo, 1.2 or 1.8 mg beloranib s.c. twice weekly for 26 weeks. Participants, investigators and the sponsor were blinded to group assignment. The primary endpoint was the change in weight from baseline to week 26. The trial was terminated early when beloranib development was stopped because of an imbalance of venous thromboembolism events in beloranib-treated individuals vs placebo that became evident during late-stage development of the drug. Results In total, 153 participants were randomised, 51 to placebo, 52 to 1.2 mg beloranib and 50 to 1.8 mg beloranib. In participants who completed week 26, the least squares mean ± SE weight change (baseline 111 kg) was −3.1 ± 1.2% with placebo (n = 22) vs −13.5 ± 1.1% and −12.7 ± 1.3% with 1.2 and 1.8 mg beloranib, respectively (n = 25; n = 19; p < 0.0001). The change in HbA 1c (baseline 67 mmol/mol [8.3%]) was −6.6 ± 2.2 mmol/mol (−0.6 ± 0.2%) with placebo vs −21.9 ± 2.2 mmol/mol (−2.0 ± 0.2%) or −21.9 ± 3.3 mmol/mol (−2.0 ± 0.3%) with 1.2 or 1.8 mg beloranib (p < 0.0001), respectively. The most common beloranib adverse events were sleep related. One beloranib-treated participant experienced a non-fatal pulmonary embolism.Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-018-4677-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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“…Additionally, the lack of healthy controls hampered the interpretation of the results. Circulating TNFα levels are affected by various metabolic and pathological conditions in addition to MDD (McArdle, Finucane, Connaughton, McMorrow, & Roche, 2013; Sinha et al, 2015). Moreover, plasma TNFα levels may be affected by anesthesia during ECT series (Stelzhammer et al., 2011).…”

Section: Discussionmentioning

confidence: 99%

Low tumor necrosis factor‐α levels predict symptom reduction during electroconvulsive therapy in major depressive disorder

et al. 2018

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ObjectiveChanges in the tumor necrosis factor‐α (TNFα) have been associated with major depressive disorder (MDD). Findings concerning the effects of electroconvulsive therapy (ECT) on the TNFα level have been contradictory. The aim was to examine the immediate and long‐term changes in the TNFα level and their associations with symptom reduction in patients with MDD during ECT.MethodThe study included 30 patients with MDD. Their TNFα levels were measured at baseline and 2 and 4 hr after the first, fifth and last ECT session. Depressive symptoms were assessed with the Montgomery‐Asberg Depression Rating Scale (MADRS).ResultsThe TNFα level decreased from baseline to the 2‐ and 4‐hr measurements. There was a correlation between the first ECT session TNFα levels and the relative symptom reduction according to the MADRS score after the ECT series. Both the first (baseline) ECT and 4‐hr TNFα levels were lower in responders than in nonresponders.Conclusion ECT consistently induced a decrease in the TNFα level after each studied session. A low TNFα level at the first ECT appeared to predict a symptom reduction. These findings suggest that TNFα might have a role in the pathogenesis in MDD and in the mechanism of action of ECT.

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Retinoic acid-related orphan receptors α and γ: key regulators of lipid/glucose metabolism, inflammation, and insulin sensitivity

Cited by 123 publications

References 91 publications

The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome

The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome

Efficacy and safety of methionine aminopeptidase 2 inhibition in type 2 diabetes: a randomised, placebo-controlled clinical trial

Low tumor necrosis factor‐α levels predict symptom reduction during electroconvulsive therapy in major depressive disorder

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