The Effect of PPAR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math>, PPAR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>δ</mml:mi></mml:math>, PPAR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math>, and PPARpan Agonists on Body Weight, Body Mass, and Serum Lipid Profiles in Diet-Induced Obese AKR/J Mice

Harrington, W. Wallace; Britt, Christy S.; Wilson, Joan G.; Milliken, Naphtali; Binz, Jane G; Lobe, David C.; Oliver, William R.; Lewis, Michael C.; Ignar, Diane M.

doi:10.1155/2007/97125

Cited by 65 publications

(69 citation statements)

References 77 publications

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“…3C). Interestingly, a recent study of PPAR agonists described a synergistic effect from stimulating PPAR␣ and PPAR␦, which resulted in a significantly enhanced weight loss effect over action on the individual receptors in mice (22). Our data suggests that this is not a mouse-specific observation, and that appropriate stimulation of the 3 PPARs can result in weight loss in both rodents and primates, in addition to beneficial effects on glucose, insulin, and lipid profiles in various models.…”

Section: Treatment Results In Weight Loss In Obese Hamsters and Monkeysmentioning

confidence: 46%

Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent

Artis¹,

Lin²,

Zhang³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

132

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In a search for more effective anti-diabetic treatment, we used a process coupling low-affinity biochemical screening with highthroughput co-crystallography in the design of a series of compounds that selectively modulate the activities of all three peroxisome proliferator-activated receptors (PPARs), PPAR␣, PPAR␥, and PPAR␦. Transcriptional transactivation assays were used to select compounds from this chemical series with a bias toward partial agonism toward PPAR␥, to circumvent the clinically observed side effects of full PPAR␥ agonists. Co-crystallographic characterization of the lead molecule, indeglitazar, in complex with each of the 3 PPARs revealed the structural basis for its PPAR pan-activity and its partial agonistic response toward PPAR␥. Compared with full PPAR␥-agonists, indeglitazar is less potent in promoting adipocyte differentiation and only partially effective in stimulating adiponectin gene expression. Evaluation of the compound in vivo confirmed the reduced adiponectin response in animal models of obesity and diabetes while revealing strong beneficial effects on glucose, triglycerides, cholesterol, body weight, and other metabolic parameters. Indeglitazar has now progressed to Phase II clinical evaluations for Type 2 diabetes mellitus (T2DM).adiponectin ͉ diabetes ͉ partial agonist ͉ PPAR pan-agonist ͉ Scaffold-based drug discovery T herapeutic approaches to Type 2 diabetes mellitus (T2DM), which currently affects Ϸ6% of adults in the United States (US Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, GA; 2005), are generally polypharmaceutical in nature, targeting effects on insulin sensitivity and elements of the coincident dyslipidemia and cardiovascular diseases (1). However, polypharmacy in these treatment regimens has been cited as a potential additional risk factor (2), with many patients on 4 or more concomitant medications. A more effective strategy would be to use a single agent that possesses combined benefits from simultaneous inhibition or stimulation of several related targets, without the risks associated with combination therapy. However, optimizing activities against several targets is a complex design problem that necessitates judicious choice of targets and requires new ways in which therapeutic agents are generated.Two classes of marketed therapeutics, the fibrates (as lipidlowering agents) and the glitazones (as insulin-sensitizing drugs) target related receptors known as PPAR␣ and PPAR␥, respectively, whereas a third member of the subfamily, PPAR␦, has been the target of intense preclinical interest as an avenue for treatment of dyslipidemia (3). A pan-agonist, capable of stimulating the 3 peroxisome proliferator-activated receptors (PPARs) as a group, would be expected to be particularly useful in the treatment of T2DM from the standpoints of both efficacy and reduction in the additional risk factors associated with polypharmacy. Despite the close structural relationship between these 3 receptors, the search for compounds whi...

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Section: Treatment Results In Weight Loss In Obese Hamsters and Monkeysmentioning

confidence: 46%

Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent

Artis¹,

Lin²,

Zhang³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

132

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“…The acute actions of MLR-1023 suggest that MLR-1023 regulated blood glucose levels by mechanisms that were independent of the transcriptional events required for rosiglitazone activity. Second, in contrast to rosiglitazone and other PPAR agonists, MLR-1023 did not produce an acceleration of weight gain (Harrington et al, 2007). The absence of an MLR-1023-mediated increase in weight gain is consistent with MLR-1023 not affecting PPARs.…”

Section: Ochman Et Almentioning

confidence: 66%

The Lyn Kinase Activator MLR-1023 Is a Novel Insulin Receptor Potentiator that Elicits a Rapid-Onset and Durable Improvement in Glucose Homeostasis in Animal Models of Type 2 Diabetes

Ochman¹,

Lipinski²,

Handler³

et al. 2012

J Pharmacol Exp Ther

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MLR-1023 [Tolimidone; CP-26154; 2(1H)-pyrimidinone, 5-(3-methylphenoxy)] is an allosteric Lyn kinase activator that reduces blood glucose levels in mice subjected to an oral glucose tolerance test (J Pharmacol Exp Ther 342:15-22, 2012). The current studies were designed to define the role of insulin in MLR-1023-mediated blood glucose lowering, to evaluate it in animal models of type 2 diabetes, and to compare it to the activities of selected existing diabetes therapeutics. Results from these studies show that in an acute oral glucose tolerance test MLR-1023 evoked a dose-dependent blood glucose-lowering response that was equivalent in magnitude to that of metformin without eliciting a hypoglycemic response. In streptozotocin-treated, insulin-depleted mice, MLR-1023 administration did not affect blood glucose levels. However, MLR-1023 potentiated the glucose-lowering activity of exogenously administered insulin, showing that MLR-1023-mediated blood glucose lowering was insulin-dependent. In a hyperinsulinemic/ euglycemic clamp study, orally administered MLR-1023 increased the glucose infusion rate required to sustain blood glucose levels, demonstrating that MLR-1023 increased insulin receptor sensitivity. In chronically treated db/db mice, MLR-1023 elicited a dose-dependent and durable glucose-lowering effect, reduction in HbA1c levels and preservation of pancreatic ␤-cells. The magnitude of effect was equivalent to that seen with rosiglitazone but with a faster onset of action and without causing weight gain. These studies show that MLR-1023 is an insulin receptor-potentiating agent that produces a rapid-onset and durable blood glucose-lowering activity in diabetic animals.

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“…Moreover, genetic or pharmacological modulation of regulators of FAO, such as Sirt1 or PPARs, have an impact on dietinduced obesity (22)(23)(24)(25). Therefore, we evaluated whether loss of Pml would result in an increased predisposition to obesity.…”

Section: Pml Opposes a Metabolic Syndrome In Vivo By Favoring Fatty Amentioning

confidence: 99%

A metabolic prosurvival role for PML in breast cancer

et al. 2012

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Cancer cells exhibit an aberrant metabolism that facilitates more efficient production of biomass and hence tumor growth and progression. However, the genetic cues modulating this metabolic switch remain largely undetermined. We identified a metabolic function for the promyelocytic leukemia (PML) gene, uncovering an unexpected role for this bona fide tumor suppressor in breast cancer cell survival. We found that PML acted as both a negative regulator of PPARγ coactivator 1A (PGC1A) acetylation and a potent activator of PPAR signaling and fatty acid oxidation. We further showed that PML promoted ATP production and inhibited anoikis. Importantly, PML expression allowed luminal filling in 3D basement membrane breast culture models, an effect that was reverted by the pharmacological inhibition of fatty acid oxidation. Additionally, immunohistochemical analysis of breast cancer biopsies revealed that PML was overexpressed in a subset of breast cancers and enriched in triple-negative cases. Indeed, PML expression in breast cancer correlated strikingly with reduced time to recurrence, a gene signature of poor prognosis, and activated PPAR signaling. These findings have important therapeutic implications, as PML and its key role in fatty acid oxidation metabolism are amenable to pharmacological suppression, a potential future mode of cancer prevention and treatment.

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The Effect of PPARα, PPARδ, PPARγ, and PPARpan Agonists on Body Weight, Body Mass, and Serum Lipid Profiles in Diet-Induced Obese AKR/J Mice

Cited by 65 publications

References 77 publications

Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent

Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent

The Lyn Kinase Activator MLR-1023 Is a Novel Insulin Receptor Potentiator that Elicits a Rapid-Onset and Durable Improvement in Glucose Homeostasis in Animal Models of Type 2 Diabetes

A metabolic prosurvival role for PML in breast cancer

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