Discovery of the first-in-class dual PPARδ/γ partial agonist for the treatment of metabolic syndrome

Li, Zheng; Ren, Qiang; Zhou, Zongtao; Cai, Zongyu; Wang, Bin; Han, Jing; Zhang, Luyong

doi:10.1016/j.ejmech.2021.113807

Cited by 10 publications

(6 citation statements)

References 27 publications

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“…PPARA is a transcription factor that plays an important regulatory role in glucolipid metabolism (Li et al, 2021). PPARα has been found to suppress the ERR transcriptional pathway, resulting in the progression of various cardiovascular diseases (e.g., cardiac hypertrophy, heart failure, and diabetic cardiomyopathy) (Oka et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…In response to a high‐fat diet, the expression of CPT1A and sterol o‐acyltransferase1 (SOAT1) were enhanced and contributed to the development of hepatocellular carcinoma by disruption of lipid homoeostasis (Ren et al, 2021). PPARA is a transcription factor that plays an important regulatory role in glucolipid metabolism (Li et al, 2021). PPARα has been found to suppress the ERR transcriptional pathway, resulting in the progression of various cardiovascular diseases (e.g., cardiac hypertrophy, heart failure, and diabetic cardiomyopathy) (Oka et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

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Fat deposition, fatty acid profiles, antioxidant capacity and differentially expressed genes in subcutaneous fat of Tibetan sheep fed wheat‐based diets with and without xylanase supplementation

Zhou,

Raza,

Gao

et al. 2023

Animal Physiology Nutrition

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Xylanase, an exogenous enzyme that plays an essential role in energy metabolism by hydrolysing xylan into xylose, has been shown to positively influence nutrient digestion and utilisation in ruminants. The objective of this study was to evaluate the effects of xylanase supplementation on the back‐fat thickness, fatty acid profiles, antioxidant capacity, and differentially expressed genes (DEGs) in the subcutaneous fat of Tibetan sheep. Sixty three‐month‐old rams with an average weight of 19.35 ± 2.18 kg were randomly assigned to control (no enzyme added, WH group) and xylanase (0.2% of diet on a dry matter basis, WE group) treatments. The experiment was conducted over 97 d, including 7 d of adaption to the diets. The results showed that xylanase supplementation in the diet increased adipocyte volume of subcutaneous fat (p < 0.05), shown by hematoxylin and eosin (H&E) staining. Gas chromatography showed greater concentrations of C14:0 and C16:0 in the subcutaneous fat of controls compared with the enzyme‐treated group (p < 0.05), while opposite trend was seen for the absolute contents of C18:1n9t, C20:1, C18:2n6c, C18:3, and C18:3n3 (p < 0.05). Compared with controls, supplementation with xylanase increased the activity of T‐AOC significantly (p < 0.05). Transcriptomic analysis showed the presence of 1630 DEGs between the two groups, of which 1023 were up‐regulated and 607 were down‐regulated, with enrichment in 4833 Gene Ontology terms, and significant enrichment in 31 terms (p < 0.05). The common DEGs were enriched in 295 pathways and significantly enriched in 26 pathways. Additionally, the expression of lipid‐related genes, including fatty acid synthase, superoxide dismutase, fatty acid binding protein 5, carnitine palmytoyltransferase 1 A, and peroxisome proliferator‐activated receptor A were verified via quantitative reverse‐transcription polymerase chain reaction. In conclusion, dietary xylanase supplementation was found to reduce subcutaneous fat deposition in Tibetan sheep, likely through modulating the expression of lipid‐related genes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fat deposition, fatty acid profiles, antioxidant capacity and differentially expressed genes in subcutaneous fat of Tibetan sheep fed wheat‐based diets with and without xylanase supplementation

Zhou,

Raza,

Gao

et al. 2023

Animal Physiology Nutrition

View full text Add to dashboard Cite

show abstract

“…The pharmacological evaluation of ZLY06 revealed a significant reduction in glucose levels in HF/STZ and ob/ob mice. It also promoted glucolipid metabolism without gaining weight, fatty acid oxidation, and inhibition of hepatic lipid accumulation [ 127 ].…”

Section: Recent Developments In the Medicinal Chemistry Of Pparsmentioning

confidence: 99%

Development of Heterocyclic PPAR Ligands for Potential Therapeutic Applications

et al. 2022

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The family of nuclear peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, and PPARγ) is a set of ligand-activated transcription factors that regulate different functions in the body. Whereas activation of PPARα is known to reduce the levels of circulating triglycerides and regulate energy homeostasis, the activation of PPARγ brings about insulin sensitization and increases the metabolism of glucose. On the other hand, PPARβ when activated increases the metabolism of fatty acids. Further, these PPARs have been claimed to be utilized in various metabolic, neurological, and inflammatory diseases, neurodegenerative disorders, fertility or reproduction, pain, and obesity. A series of different heterocyclic scaffolds have been synthesized and evaluated for their ability to act as PPAR agonists. This review is a compilation of efforts on the part of medicinal chemists around the world to find novel compounds that may act as PPAR ligands along with patents in regards to PPAR ligands. The structure–activity relationship, as well as docking studies, have been documented to better understand the mechanistic investigations of various compounds, which will eventually aid in the design and development of new PPAR ligands. From the results of the structural activity relationship through the pharmacological and in silico evaluation the potency of heterocycles as PPAR ligands can be described in terms of their hydrogen bonding, hydrophobic interactions, and other interactions with PPAR.

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“…Hence, over the years, various strategies have been attempted to obtain compounds with good therapeutic potential and fewer side effects. Among the possible candidates are PPARα-δ/γ dual agonists [ 16 , 17 ] or PPARα/γ/δ pan-agonists [ 18 ], which beneficially alter carbohydrate and lipid metabolism in a coordinated manner, and selective PPARγ modulators (SPPARγMs). The latter showed an improved therapeutic profile compared to PPARγ full agonists, due to the different conformational changes induced by the ligands, giving rise to different PPARγ transcriptional signatures [ 19 , 20 , 21 , 22 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Biological Screening and Crystallographic Studies of Hydroxy γ-Lactone Derivatives to Investigate PPARγ Phosphorylation Inhibition

et al. 2023

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PPARγ represents a key target for the treatment of type 2 diabetes and metabolic syndrome. To avoid serious adverse effects related to the PPARγ agonism profile of traditional antidiabetic drugs, a new opportunity is represented by the development of molecules acting as inhibitors of PPARγ phosphorylation by the cyclin-dependent kinase 5 (CDK5). Their mechanism of action is mediated by the stabilization of the PPARγ β-sheet containing Ser273 (Ser245 in PPARγ isoform 1 nomenclature). In this paper, we report the identification of new γ-hydroxy-lactone-based PPARγ binders from the screening of an in-house library. These compounds exhibit a non-agonist profile towards PPARγ, and one of them prevents Ser245 PPARγ phosphorylation by acting mainly on PPARγ stabilization and exerting a weak CDK5 inhibitory effect.

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Discovery of the first-in-class dual PPARδ/γ partial agonist for the treatment of metabolic syndrome

Cited by 10 publications

References 27 publications

Fat deposition, fatty acid profiles, antioxidant capacity and differentially expressed genes in subcutaneous fat of Tibetan sheep fed wheat‐based diets with and without xylanase supplementation

Fat deposition, fatty acid profiles, antioxidant capacity and differentially expressed genes in subcutaneous fat of Tibetan sheep fed wheat‐based diets with and without xylanase supplementation

Development of Heterocyclic PPAR Ligands for Potential Therapeutic Applications

Biological Screening and Crystallographic Studies of Hydroxy γ-Lactone Derivatives to Investigate PPARγ Phosphorylation Inhibition

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