AM-879, a PPARy non-agonist and Ser273 phosphorylation blocker, promotes insulin sensitivity without adverse effects in mice

Terra, Maiara Ferreira; García‐Arévalo, Marta; Avelino, Thayná Mendonça; Degaki, Karina Y.; Malospirito, Caíque C.; Carvalho, Murilo; Torres, Felipe Rafael; Saito, Ângela; Figueira, Ana Carolina Migliorini

doi:10.1016/j.metop.2022.100221

Cited by 3 publications

(9 citation statements)

References 86 publications

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“…The whole tissue was captured in a panoramic picture to analyze all the adipocytes. To perform shape analysis (i.e., area and perimeter) for every single cell on each treatment ( n ), we developed a Macro workflow on Fiji for image segmentation and adipocyte identification, which were posteriorly used as input for a Python optimized script, as described in [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, 100 mg of frozen liver was homogenized in a Polytron (PT1200 E), in 4:3:0.8 mixture of chloroform:methanol: PBS, and then centrifuged to obtain the organic layer [ 12 ]. The triglyceride content was measured from this layer using the Triglycerides LaborLab GODPAP Liquid Stable Kit (LaborLab—SP, Brasil), at 505 nm wavelength, in the multi-mode plate reader (Enspire-PerkinElmer, Singapore) following the manufacturer’s instructions [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

“…Gene expression was evaluated by quantitative real time PCR (qPCR) reactions using SYBR Real Time PCR master mixes (ThermoFischer Scientific) in a 7500 Real Time PCR system (Applied Biosystems). The ΔΔ-Ct evaluation method [ 26 ] was used for data normalization, with expression of reference genes 36b4 and Rpl27 [ 14 ]. The primer sequences used in this study are presented in Table S2 .…”

Section: Methodsmentioning

confidence: 99%

“…Electrophoresis gel was performed with 15 µg of protein and the following primary and secondary antibodies were used: anti-PPARγ (dilution 1:1000, Anti-PPARγ Antibody (E-8): sc-7273-Santa Cruz Biotechnology, Inc., Dallas, TX, USA), anti-S273 PPARγ (dilution 1:200, BS-4888R, Bioss, Boston, MA, USA), anti-vinculin (dilution 1:1000, ab18058-Abcam, Waltham, MA, USA), anti-rabbit IgG (dilution 1:5000, A0545, Sigma-Aldrich, St. Louis, MO, USA), and anti-mouse IgG (dilution 1:5000, 401253, Calbiochem, San Diego, CA, USA). The final result was obtained using peroxidase reaction through Amersham ECL Prime Western Blotting Detection Reagent-GE in the ImageQuant LAS 500 (GE Health Care Life Sciences, Chicago, IL, USA) equipment, as described [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

“…It was suggested that the insulin sensitization induced by many anti-diabetic drugs was due to the blockade of this phosphorylation, caused by conformational modifications induced by ligand binding [ 10 ]. Consequently, researchers have focused on molecules that can promote this blockade without activating the nuclear receptor, resulting in improved insulin sensitivity without the development of adverse effects [ 11 , 12 , 13 , 14 ]. Additionally, some ligand binding protection mechanisms against phosphorylation have been proposed [ 11 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

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Obesity-Linked PPARγ Ser273 Phosphorylation Promotes Beneficial Effects on the Liver, despite Reduced Insulin Sensitivity in Mice

et al. 2023

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Since the removal of thiazolidinediones (TZDs) from the market, researchers have been exploring alternative anti-diabetic drugs that target PPARγ without causing adverse effects while promoting insulin sensitization by blocking serine 273 phosphorylation (Ser273 or S273). Nonetheless, the underlying mechanisms of the relationship between insulin resistance and S273 phosphorylation are still largely unknown, except for the involvement of growth differentiation factor (GDF3) regulation in the process. To further investigate potential pathways, we generated a whole organism knockin mouse line with a single S273A mutation (KI) that blocks the occurrence of its phosphorylation. Our observations of KI mice on different diets and feeding schedules revealed that they were hyperglycemic, hypoinsulinemic, presented more body fat at weaning, and presented an altered plasma and hepatic lipid profile, distinctive liver morphology and gene expression. These results suggest that total blockage of S273 phosphorylation may have unforeseen effects that, in addition to promoting insulin sensitivity, could lead to metabolic disturbances, particularly in the liver. Therefore, our findings demonstrate both the beneficial and detrimental effects of PPAR S273 phosphorylation and suggest selective modulation of this post translational modification is a viable strategy to treat type 2 diabetes.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Obesity-Linked PPARγ Ser273 Phosphorylation Promotes Beneficial Effects on the Liver, despite Reduced Insulin Sensitivity in Mice

et al. 2023

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Sulfonylureas exert antidiabetic action on adipocytes by inhibition of PPARγ serine 273 phosphorylation

Haas,

Hass,

Voltz

et al. 2024

Molecular Metabolism

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Roles of protein post-translational modifications in glucose and lipid metabolism: mechanisms and perspectives

Yang

Wen

Yang

et al. 2023

Mol Med

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The metabolism of glucose and lipids is essential for energy production in the body, and dysregulation of the metabolic pathways of these molecules is implicated in various acute and chronic diseases, such as type 2 diabetes, Alzheimer’s disease, atherosclerosis (AS), obesity, tumor, and sepsis. Post-translational modifications (PTMs) of proteins, which involve the addition or removal of covalent functional groups, play a crucial role in regulating protein structure, localization function, and activity. Common PTMs include phosphorylation, acetylation, ubiquitination, methylation, and glycosylation. Emerging evidence indicates that PTMs are significant in modulating glucose and lipid metabolism by modifying key enzymes or proteins. In this review, we summarize the current understanding of the role and regulatory mechanisms of PTMs in glucose and lipid metabolism, with a focus on their involvement in disease progression associated with aberrant metabolism. Furthermore, we discuss the future prospects of PTMs, highlighting their potential for gaining deeper insights into glucose and lipid metabolism and related diseases.

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AM-879, a PPARy non-agonist and Ser273 phosphorylation blocker, promotes insulin sensitivity without adverse effects in mice

Cited by 3 publications

References 86 publications

Obesity-Linked PPARγ Ser273 Phosphorylation Promotes Beneficial Effects on the Liver, despite Reduced Insulin Sensitivity in Mice

Obesity-Linked PPARγ Ser273 Phosphorylation Promotes Beneficial Effects on the Liver, despite Reduced Insulin Sensitivity in Mice

Sulfonylureas exert antidiabetic action on adipocytes by inhibition of PPARγ serine 273 phosphorylation

Roles of protein post-translational modifications in glucose and lipid metabolism: mechanisms and perspectives

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