Conversion of human-selective PPARα agonists to human/mouse dual agonists: a molecular modeling analysis

Wang, Minmin; Winneroski, Leonard L.; Ardecky, Robert; Brooks, Dawn A.; Etgen, Garret J.; Hutchison, D. R.; Kauffman, Raymond F.; Kunkel, Aaron; Mais, Dale E.; Montrose‐Rafizadeh, Chahrzad; Ogilvie, Kathleen M.; Oldham, Brian A.; Peters, Mary A.; Rito, Christopher J.; Rungta, Deepa; Tripp, Allie E.; Wilson, Sarah Beth; Xu, Yanping; Zink, Richard W.; McCarthy, James R.

doi:10.1016/j.bmcl.2004.09.031

Cited by 12 publications

(4 citation statements)

References 12 publications

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“…It is known that humans and rodents show great species differences in response to PPAR␣ agonist on transactivation assay (41,42). It has been demonstrated that two amino acid residues in helix 3 of the LBDs of PPAR␣ are major contributors to species differences in response to a PPAR␣ agonist (21,30).…”

Section: Discussionmentioning

confidence: 99%

A novel PPARα agonist ameliorates insulin resistance in dogs fed a high-fat diet

Tsunoda¹,

Kobayashi²,

Ide³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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Tsunoda M, Kobayashi N, Ide T, Utsumi M, Nagasawa M, Murakami K. A novel PPAR␣ agonist ameliorates insulin resistance in dogs fed a high-fat diet. Am J Physiol Endocrinol Metab 294: E833-E840, 2008. First published January 22, 2008 doi:10.1152/ajpendo.00627.2007.-Agonism of peroxisome proliferator-activated receptor (PPAR) ␣, a key regulator of lipid metabolism, leads to amelioration of lipid abnormalities in dyslipidemic patients. However, whether PPAR␣ agonism is an effective form of therapy for obesity-related insulin resistance associated with lipid abnormalities is unclear. The present study investigated the effects of a potent and subtype-selective PPAR␣ agonist, KRP-101, in a nonrodent insulin-resistant animal model under pair-fed conditions. Beagle dogs were fed a high-fat diet for 24 wk to induce insulin resistance. During the final 12 wk, 0.03 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 KRP-101 (n ϭ 5) or vehicle (n ϭ 5) was administered orally once a day. KRP-101 administration resulted in a significantly lower weight of overall visceral fat, which is associated with increased adiponectin and decreased leptin in serum. KRP-101 administration improved hyperglycemia and hyperinsulinemia as well as dyslipidemia in dogs fed a high-fat diet. Oral glucose tolerance test showed that KRP-101 administration improved glucose intolerance. The KRP-101 group showed a markedly lower hepatic triglyceride concentration. Lipid oxidation was increased in the liver and skeletal muscles of the KRP-101 group. These findings in the dog model suggest that the use of potent and subtype-selective PPAR␣ agonists as a potentially relevant therapeutic approach to treat human insulin resistance associated with visceral obesity.

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Section: Discussionmentioning

confidence: 99%

A novel PPARα agonist ameliorates insulin resistance in dogs fed a high-fat diet

Tsunoda¹,

Kobayashi²,

Ide³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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“…The large ligand-binding pocket of PPARa, which is able to accommodate a wide variety of fatty acid-derived molecules, is presumably the reason underlying such ligand promiscuity (Wang et al, 2004).…”

Section: Implications Of Ppara As a Target For Cannabinoidsmentioning

confidence: 99%

Cannabinoid activation of PPARα; a novel neuroprotective mechanism

Sun

Alexander

Garle

et al. 2007

British Journal of Pharmacology

205

172

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Background and purpose: Although CB 1 receptor activation evokes neuroprotection in response to cannabinoids, some cannabinoids have been reported to be peroxisome proliferator activated receptor (PPAR) ligands, offering an alternative protective mechanism. We have, therefore, investigated the ability of a range of cannabinoids to activate PPARa and for N-oleoylethanolamine (OEA), an endogenous cannabinoid-like compound (ECL), to evoke neuroprotection. Experimental approach: Assays of PPARa occupancy and gene transactivation potential were conducted in cell-free and transfected HeLa cell preparations, respectively. In vivo estimates of PPARa activation through fat mobilization and gene transcription were conducted in mice. Neuroprotection in vivo was investigated in wild-type and PPARa gene-disrupted mice. Key results: The ECLs OEA, anandamide, noladin ether and virodhamine were found to bind to the purified PPARa ligand binding domain and to increase PPARa-driven transcriptional activity. The high affinity synthetic CB 1/2 cannabinoid agonist WIN 55212-2 bound to PPARa equipotently with the PPARa agonist fenofibrate, and stimulated PPARa-mediated gene transcription. The phytocannabinoid D 9 tetrahydrocannabinol was without effect. OEA and WIN 55212-2 induced lipolysis in vivo, while OEA pre-treatment reduced infarct volume from middle cerebral artery occlusion in wild-type, but not in PPARa-null mice. OEA treatment also led to increased expression of the NFkB-inhibitory protein, IkB, in mouse cerebral cortex, while expression of the NFkB-regulated protein COX-2 was inhibited. Conclusions and implications: These data demonstrate the potential for a range of cannabinoid compounds, of diverse structures, to activate PPARa and suggest that at least some of the neuroprotective properties of these agents could be mediated by nuclear receptor activation.

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“…biocides, pesticides, plasticizers, flame retardants, industrial coatings, pharmaceuticals etc. ), for which the test method is intended to predict endpoint-specific toxicity (i.e., PPARα, PPARγ, adipogenesis), ii) receptor cross-talk in lipid homeostasis, and iii) be structurally relevant for the biological role of the endpoint, as shown for example with known natural or endogenous ligands, and in PPAR molecular modelling receptor ligand binding studies, as often conducted in drug discovery ( 31 , 53 – 58 ).…”

Section: Methodsmentioning

confidence: 99%

Addressing chemically-induced obesogenic metabolic disruption: selection of chemicals for in vitro human PPARα, PPARγ transactivation, and adipogenesis test methods

Ozcagli,

Kubickova,

Jacobs

2024

Front. Endocrinol.

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Whilst western diet and sedentary lifestyles heavily contribute to the global obesity epidemic, it is likely that chemical exposure may also contribute. A substantial body of literature implicates a variety of suspected environmental chemicals in metabolic disruption and obesogenic mechanisms. Chemically induced obesogenic metabolic disruption is not yet considered in regulatory testing paradigms or regulations, but this is an internationally recognised human health regulatory development need. An early step in the development of relevant regulatory test methods is to derive appropriate minimum chemical selection lists for the target endpoint and its key mechanisms, such that the test method can be suitably optimised and validated. Independently collated and reviewed reference and proficiency chemicals relevant for the regulatory chemical universe that they are intended to serve, assist regulatory test method development and validation, particularly in relation to the OECD Test Guidelines Programme. To address obesogenic mechanisms and modes of action for chemical hazard assessment, key initiating mechanisms include molecular-level Peroxisome Proliferator-Activated Receptor (PPAR) α and γ agonism and the tissue/organ-level key event of perturbation of the adipogenesis process that may lead to excess white adipose tissue. Here we present a critical literature review, analysis and evaluation of chemicals suitable for the development, optimisation and validation of human PPARα and PPARγ agonism and human white adipose tissue adipogenesis test methods. The chemical lists have been derived with consideration of essential criteria needed for understanding the strengths and limitations of the test methods. With a weight of evidence approach, this has been combined with practical and applied aspects required for the integration and combination of relevant candidate test methods into test batteries, as part of an Integrated Approach to Testing and Assessment for metabolic disruption. The proposed proficiency and reference chemical list includes a long list of negatives and positives (20 chemicals for PPARα, 21 for PPARγ, and 11 for adipogenesis) from which a (pre-)validation proficiency chemicals list has been derived.

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Conversion of human-selective PPARα agonists to human/mouse dual agonists: a molecular modeling analysis

Cited by 12 publications

References 12 publications

A novel PPARα agonist ameliorates insulin resistance in dogs fed a high-fat diet

A novel PPARα agonist ameliorates insulin resistance in dogs fed a high-fat diet

Cannabinoid activation of PPARα; a novel neuroprotective mechanism

Addressing chemically-induced obesogenic metabolic disruption: selection of chemicals for in vitro human PPARα, PPARγ transactivation, and adipogenesis test methods

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