A Novel Non-agonist Peroxisome Proliferator-activated Receptor γ (PPARγ) Ligand UHC1 Blocks PPARγ Phosphorylation by Cyclin-dependent Kinase 5 (CDK5) and Improves Insulin Sensitivity

Choi, Sooyoung; Kim, Eun Sun; Koh, Minseob; Lee, Soojin; Lim, Donghyun; Yang, Yong Ryoul; Jang, Hyun‐Jun; Seo, Kyung-Ah; Min, Sang‐Hyun; Lee, In Hee; Park, Seung Bum; Suh, Pann‐Ghill; Choi, Jang Hyun

doi:10.1074/jbc.m114.566794

Cited by 82 publications

(89 citation statements)

References 40 publications

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“…Interestingly, SR1664 and SR1824 were structurally very similar to the above-mentioned telmisartan [74], a well-characterized selective modulator of PPARg ( Figure 3, Table 1). A derivative of SR1664, UHC1, was later suggested as a more efficient antidiabetic and anti-inflammatory molecule [78]. Recently, using virtual screening methods tailored for PPARg [79], further selective agonists that inhibit phosphorylation of PPARg at serine 273 were shown to produce antidiabetic effects in vivo, such as the compounds F12016 [80] and L312 [81].…”

Section: Junmentioning

confidence: 99%

Ligands for the Nuclear Peroxisome Proliferator-Activated Receptor Gamma

Sauer

2015

Trends in Pharmacological Sciences

101

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Nuclear receptors are ligand-activated transcription factors, which represent a primary class of drug targets. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is a key player in various biological processes. PPARγ is widely known as the target protein of the thiazolidinediones for treating type 2 diabetes. Moreover, PPARγ ligands can induce anti-inflammatory and potentially additional beneficial effects. Recent mechanistic insights of PPARγ modulation give hope the next generation of efficient PPARγ-based drugs with fewer side effects can be developed. Furthermore, chemical approaches that make use of synergistic action of combinatorial ligands are promising alternatives for providing tailored medicine. Lessons learned from fine-tuning the action of PPARγ can provide avenues for efficient molecular intervention via many other nuclear receptors to combat common diseases.

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Section: Junmentioning

confidence: 99%

Ligands for the Nuclear Peroxisome Proliferator-Activated Receptor Gamma

Sauer

2015

Trends in Pharmacological Sciences

101

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“…This paradigm has already been explored as a potential therapeutic target for T2D using the non-agonist PPAR gamma ligand UHC1, which exclusively prevents the phosphorylation of S273 on PPAR gamma. As a result, UHC1 treatment not only improved insulin sensitivity but also reduced diet-induced obesity, which is quite different from the TZDs (Choi, et al 2014b). In addition to providing mechanistic insight into how TZDs and PPAR gamma are involved in the progression of diabetes, these studies also implicate Thrap3 and CDK5 as prospective anti-diabetic targets as well.…”

Section: Ppar Gamma: New Mechanisms For Generating Insulin-sensitizinmentioning

confidence: 92%

Nuclear receptors and AMPK: can exercise mimetics cure diabetes?

Wall

Atkins

et al. 2016

Journal of Molecular Endocrinology

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Endurance exercise can lead to systemic improvements in insulin sensitivity and metabolic homeostasis, and is an effective approach to combat metabolic diseases. Pharmacological compounds that recapitulate the beneficial effects of exercise, also known as “exercise mimetics,” have the potential to improve disease symptoms of metabolic syndrome. These drugs, which can increase energy expenditure, suppress hepatic gluconeogenesis, and induce insulin sensitization, have accordingly been highly scrutinized for their utility in treating metabolic diseases including diabetes. Nevertheless, the identity of an efficacious exercise mimetic still remains elusive. In this article, we will highlight several nuclear receptors and cofactors that are putative molecular targets for exercise mimetics, and review recent studies that provide advancements in our mechanistic understanding of how exercise mimetics exert their beneficial effects. We will also discuss evidence from clinical trials utilizing these compounds in human subjects to evaluate their efficacy in treating diabetes.

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“…These differences in ERK activation could possibly explain some of the efficacy and safety differences among existing synthetic TZDs. Recently, several PPARγ ligands have been found that promote insulin sensitization with fewer side effects in T2DM rodent models (123, 124). Whether these ligands can activate GPR40 or/and ERK has not been reported.…”

Section: Gpr40 and Pparγ An Integrated Two-receptor Signaling Patmentioning

confidence: 99%

PPARγ signaling and emerging opportunities for improved therapeutics

Wang

Dougherty

Danner

2016

Pharmacological Research

170

105

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Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism, endothelial function and inflammation. Rosiglitazone (RGZ) and other thiazolidinedione (TZD) synthetic ligands of PPARγ are insulin sensitizers that have been used for the treatment of type 2 diabetes. However, undesirable side effects including weight gain, fluid retention, bone loss, congestive heart failure, and a possible increased risk of myocardial infarction and bladder cancer, have limited the use of TZDs. Therefore, there is a need to better understand PPARγ signaling and to develop safer and more effective PPARγ-directed therapeutics. In addition to PPARγ itself, many PPARγ ligands including TZDs bind to and activate G protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor 1. GPR40 signaling activates stress kinase pathways that ultimately regulate downstream PPARγ responses. Recent studies in human endothelial cells have demonstrated that RGZ activation of GPR40 is essential to the optimal propagation of PPARγ genomic signaling. RGZ/GPR40/p38 MAPK signaling induces and activates PPARγ co-activator-1α, and recruits E1A binding protein p300 to the promoters of target genes, markedly enhancing PPARγ-dependent transcription. Therefore in endothelium, GPR40 and PPARγ function as an integrated signaling pathway. However, GPR40 can also activate ERK1/2, a proinflammatory kinase that directly phosphorylates and inactivates PPARγ. Thus the role of GPR40 in PPARγ signaling may have important implications for drug development. Ligands that strongly activate PPARγ, but do not bind to or activate GPR40 may be safer than currently approved PPARγ agonists. Alternatively, biased GPR40 agonists might be sought that activate both p38 MAPK and PPARγ, but not ERK1/2, avoiding its harmful effects on PPARγ signaling, insulin resistance and inflammation. Such next generation drugs might be useful in treating not only type 2 diabetes, but also diverse chronic and acute forms of vascular inflammation such as atherosclerosis and septic shock.

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A Novel Non-agonist Peroxisome Proliferator-activated Receptor γ (PPARγ) Ligand UHC1 Blocks PPARγ Phosphorylation by Cyclin-dependent Kinase 5 (CDK5) and Improves Insulin Sensitivity

Cited by 82 publications

References 40 publications

Ligands for the Nuclear Peroxisome Proliferator-Activated Receptor Gamma

Ligands for the Nuclear Peroxisome Proliferator-Activated Receptor Gamma

Nuclear receptors and AMPK: can exercise mimetics cure diabetes?

PPARγ signaling and emerging opportunities for improved therapeutics

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