Review of the Structural and Dynamic Mechanisms of PPAR<i>γ</i>Partial Agonism

Kroker, Alice J.; Bruning, John B.

doi:10.1155/2015/816856

Cited by 172 publications

(148 citation statements)

References 71 publications

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“…However, their use has been hampered because of severe side effects. Partial agonists have been identified as selective PPARγ modulators with great promise for the treatment of type 2 diabetes (Higgins & Depaoli 2010, Taygerly et al 2013, Kroker & Bruning 2015. INT131 (previously AMG131) acts as one of the selective PPARγ modulators to partially activate transcriptional output, enhances insulin sensitivity with decreased side effects in preclinical models and has been tested in phase II clinic trial (Kintscher & Goebel 2009, Higgins & Depaoli 2010, Taygerly et al 2013, DePaoli et al 2014.…”

Section: Adipogenesis and Its Regulationmentioning

confidence: 99%

Adipose tissue in control of metabolism

Luo

Liu

2016

Journal of Endocrinology

503

331

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Adipose tissue plays a central role in regulating whole-body energy and glucose homeostasis through its subtle functions at both organ and systemic levels. On one hand, adipose tissue stores energy in the form of lipid and controls the lipid mobilization and distribution in the body. On the other hand, adipose tissue acts as an endocrine organ and produces numerous bioactive factors such as adipokines that communicate with other organs and modulate a range of metabolic pathways. Moreover, brown and beige adipose tissue burn lipid by dissipating energy in the form of heat to maintain euthermia, and have been considered as a new way to counteract obesity. Therefore, adipose tissue dysfunction plays a prominent role in the development of obesity and its related disorders such as insulin resistance, cardiovascular disease, diabetes, depression and cancer. In this review, we will summarize the recent findings of adipose tissue in the control of metabolism, focusing on its endocrine and thermogenic function.

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Section: Adipogenesis and Its Regulationmentioning

confidence: 99%

Adipose tissue in control of metabolism

Luo

Liu

2016

Journal of Endocrinology

503

331

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“…The hydrophobic tail moiety of Rosiglitazone may also interact with helix 3, 5, 6, 7, and the β strand, occupying arm II and arm III of the LBD, through van der Waals and hydrophobic interactions which accounts for the efficiency of binding and potency of the molecule. The central phenyl ring is accommodated beneath helix 3 by hydrophobic interactions [74]. …”

Section: Structure Activity Relationship Studies On Thiazolidinedimentioning

confidence: 99%

Targeting Peroxisome Proliferator-Activated Receptors Using Thiazolidinediones: Strategy for Design of Novel Antidiabetic Drugs

Thangavel

Bratty

Javed

et al. 2017

International Journal of Medicinal Chemistry

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Thiazolidinediones are a class of well-established antidiabetic drugs, also named as glitazones. Thiazolidinedione structure has been an important structural domain of research, involving design and development of new drugs for the treatment of type 2 diabetes. Extensive research on the mechanism of action and the structural requirements has revealed that the intended antidiabetic activity in type 2 diabetes is due to their agonistic effect on peroxisome proliferator-activated receptor (PPAR) belonging to the nuclear receptor super family. Glitazones have specific affinity to PPARγ, one of the subtypes of PPARs. Certain compounds under development have dual PPARα/γ agonistic activity which might be beneficial in obesity and diabetic cardiomyopathy. Interesting array of hybrid compounds of thiazolidinedione PPARγ agonists exhibited therapeutic potential beyond antidiabetic activity. Pharmacology and chemistry of thiazolidinediones as PPARγ agonists and the potential of newer analogues as dual agonists of PPARs and other emerging targets for the therapy of type 2 diabetes are presented. This review highlights the possible modifications of the structural components in the general frame work of thiazolidinediones with respect to their binding efficacy, potency, and selectivity which would guide the future research in design of novel thiazolidinedione derivatives for the management of type 2 diabetes.

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“…unsaturated fatty acids, eicosanoids, oxidized lipids, nitroalkenes), synthetic agonists (e.g. thiazolidinediones which are clinically useful in treatment of Type II Diabetes Mellitus) and synthetic anatagonists (currently there are no known endogenous antagonists) (Itoh et al, 2008; Fong et al, 2010; Kroker and Bruning, 2015; Sauer, 2015). The nature of the large ligand binding pocket makes PPARγ an effective sensor and transducer of environmental nutritional and inflammatory states.…”

Section: Introductionmentioning

confidence: 99%

Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy

Simeone

Matthews

Samson

et al. 2017

Experimental Neurology

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The ketogenic diet (KD) is an effective therapy primarily used in pediatric patients whom are refractory to current anti-seizure medications. The mechanism of the KD is not completely understood, but is thought to involve anti-inflammatory and anti-oxidant processes. The nutritionally-regulated transcription factor peroxisome proliferator activated receptor gamma, PPARγ, regulates genes involved in anti-inflammatory and anti-oxidant pathways. Moreover, endogenous ligands of PPARγ include fatty acids suggesting a potential role in the effects of the KD. Here, we tested the hypothesis that PPARγ contributes to the anti-seizure efficacy of the KD. We found that the KD increased nuclear protein content of the PPARγ2 splice variant by 2–4 fold (p < 0.05) in brain homogenates from wild-type (WT) and epileptic Kv1.1 knockout (KO) mice, while not affecting PPARγ1. The KD reduced the frequency of seizures in Kv1.1KO mice by ~70% (p < 0.01). GW9662, a PPARγ antagonist, prevented KD-mediated changes in PPARγ2 expression and prevented the anti-seizure efficacy of the KD in Kv1.1KO mice. Further supporting the association of PPARγ2 in mediating KD actions, the KD significantly prolonged the latency to flurothyl-induced seizure in WT mice by ~20–35% (p < 0.01), but was ineffective in PPARγ2KO mice and neuron-specific PPARγKO mice. Finally, administering the PPARγ agonist pioglitazone increased PPARγ2 expression by 2-fold (p < 0.01) and reduced seizures in Kv1.1KO mice by ~80% (p < 0.01). Our findings implicate brain PPARγ2 among the mechanisms by which the KD reduces seizures and strongly support the development of PPARγ2 as a therapeutic target for severe, refractory epilepsy.

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Review of the Structural and Dynamic Mechanisms of PPARγPartial Agonism

Cited by 172 publications

References 71 publications

Adipose tissue in control of metabolism

Adipose tissue in control of metabolism

Targeting Peroxisome Proliferator-Activated Receptors Using Thiazolidinediones: Strategy for Design of Novel Antidiabetic Drugs

Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy

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