Re-highlighting the action of PPARγ in treating metabolic diseases

Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor family and plays an important role in adipocyte differentiation, glucose homeostasis, and insulin sensitivity. Thiazolidinediones (TZDs), synthetic ligands of PPARγ, have been used for the treatment of diabetes mellitus for two decades. TZDs were expected to be amazing drugs not only for type 2 diabetes but also for metabolic syndrome and atherosclerotic vascular disease because they can reduce both insulin resistance and inflammation in experimental studies. However, serious unwanted effects pushed TZDs back to an optional second-tier drug for type 2 diabetes. Nevertheless, PPARγ is still one of the most important targets for the treatment of insulin resistance and diabetes mellitus, and novel strategies to modulate PPARγ activity to enhance its beneficial effects and reduce unwanted adverse effects are anticipated. Recent studies showed that post-translational modification (PTM) of PPARγ regulates PPARγ activity or stability and may be a novel way to optimize PPARγ activity with reduced adverse effects. In this review, we will focus on recent advances in PTM of PPARγ and the mechanisms regulating PPARγ function as well as in the development of PPARγ modulators or agonists.

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Gene therapy of type 2 diabetes mellitus: state of art

Terapevticheskii arkhiv ◽

10.26442/00403660.2019.02.000042 ◽

2019 ◽

Vol 91 (2) ◽

pp. 149-152 ◽

Cited By ~ 2

Author(s):

Yu S Stafeev ◽

M Yu Menshikov ◽

Ye V Parfyonova

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Gene Therapy ◽

Type 2 Diabetes Mellitus ◽

Metabolic Diseases ◽

Modern World ◽

Viral Gene

Type 2 diabetes mellitus (T2DM) and other metabolic diseases are essential links in the structure of morbidity and mortality in the modern world. The accepted strategy for the correction of T2DM and insulin resistance is drug therapy aimed at delivering insulin from the outside, stimulating the secretion of own insulin and reducing the concentration of blood glucose. However, modern studies demonstrate a great potential for the use of gene therapy approaches for the correction of T2DM and insulin resistance. In the present review, the main variants of plasmid gene therapy of T2DM using the genes of adiponectin and type 1 glucagon-like peptide, as well as the main variants of viral gene therapy of T2DM using the genes of type 1 and leptin are considered. T2DM gene therapy is currently not ready to enter into routine clinical practice, but, subject to improvements in delivery systems, it can be a powerful link in combination therapy for diabetes.

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Chiglitazar Preferentially Regulates Gene Expression via Configuration-Restricted Binding and Phosphorylation Inhibition of PPARγ

PPAR Research ◽

10.1155/2017/4313561 ◽

2017 ◽

Vol 2017 ◽

pp. 1-16 ◽

Cited By ~ 9

Author(s):

De-Si Pan ◽

Wei Wang ◽

Nan-Song Liu ◽

Qian-Jiao Yang ◽

Kun Zhang ◽

...

Keyword(s):

Gene Expression ◽

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Glucose And Lipid Metabolism ◽

Effective Part

Type 2 diabetes mellitus is often treated with insulin-sensitizing drugs called thiazolidinediones (TZD), which improve insulin resistance and glycemic control. Despite their effectiveness in treating diabetes, these drugs provide little protection from eminent cardiovascular disease associated with diabetes. Here we demonstrate how chiglitazar, a configuration-restricted non-TZD peroxisome proliferator-activated receptor (PPAR) pan agonist with moderate transcription activity, preferentially regulates ANGPTL4 and PDK4, which are involved in glucose and lipid metabolism. CDK5-mediated phosphorylation at serine 273 (S273) is a unique regulatory mechanism reserved for PPARγ, and this event is linked to insulin resistance in type 2 diabetes mellitus. Our data demonstrates that chiglitazar modulates gene expression differently from two TZDs, rosiglitazone and pioglitazone, via its configuration-restricted binding and phosphorylation inhibition of PPARγ. Chiglitazar induced significantly greater expression of ANGPTL4 and PDK4 than rosiglitazone and pioglitazone in different cell models. These increased expressions were dependent on the phosphorylation status of PPARγ at S273. Furthermore, ChIP and AlphaScreen assays showed that phosphorylation at S273 inhibited promoter binding and cofactor recruitment by PPARγ. Based on these results, activities from pan agonist chiglitazar can be an effective part of a long-term therapeutic strategy for treating type 2 diabetes in a more balanced action among its targeted organs.

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The PPARβ/δ-AMPK Connection in the Treatment of Insulin Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms22168555 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8555

Author(s):

David Aguilar-Recarte ◽

Xavier Palomer ◽

Walter Wahli ◽

Manuel Vázquez-Carrera

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

New Drugs ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Ampk Pathway ◽

Antidiabetic Effects

The current treatment options for type 2 diabetes mellitus do not adequately control the disease in many patients. Consequently, there is a need for new drugs to prevent and treat type 2 diabetes mellitus. Among the new potential pharmacological strategies, activators of peroxisome proliferator-activated receptor (PPAR)β/δ show promise. Remarkably, most of the antidiabetic effects of PPARβ/δ agonists involve AMP-activated protein kinase (AMPK) activation. This review summarizes the recent mechanistic insights into the antidiabetic effects of the PPARβ/δ-AMPK pathway, including the upregulation of glucose uptake, muscle remodeling, enhanced fatty acid oxidation, and autophagy, as well as the inhibition of endoplasmic reticulum stress and inflammation. A better understanding of the mechanisms underlying the effects resulting from the PPARβ/δ-AMPK pathway may provide the basis for the development of new therapies in the prevention and treatment of insulin resistance and type 2 diabetes mellitus.

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Effect of sitagliptin on expression of skeletal muscle peroxisome proliferator-activated receptor γ coactivator-1α and irisin in a rat model of type 2 diabetes mellitus

Journal of International Medical Research ◽

10.1177/0300060519885569 ◽

2020 ◽

Vol 48 (5) ◽

pp. 030006051988556

Author(s):

Yuntao Liu ◽

Feng Xu ◽

Pan Jiang

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Type 2 Diabetes Mellitus ◽

Rat Model ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Tnf Α

Objective To evaluate the effect of sitagliptin on skeletal muscle expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), irisin, and phosphoadenylated adenylate activated protein kinase (p-AMPK) in a rat model of type 2 diabetes mellitus (T2DM). Methods A high-fat diet/streptozotocin T2DM rat model was established. Rats were divided into T2DM, low-dose sitagliptin (ST1), high-dose sitagliptin (ST2), and normal control groups (NC). PGC-1α, irisin, and p-AMPK protein levels in skeletal muscle were measured by western blot, and PCG-1α and Fndc5 mRNA levels were assessed by reverse transcription-polymerase chain reaction. Results Fasting plasma glucose (FPG), fasting insulin (FIns), homeostatic model assessment-insulin resistance (HOMA-IR), and tumor necrosis factor-α (TNF-α) were significantly up-regulated in the T2DM compared with the other groups, and FPG, FIns, total cholesterol, triglycerides, TNF-α, and HOMA-IR were significantly down-regulated in the ST2 compared with the ST1 group. PGC-1α, irisin, and p-AMPK expression levels decreased successively in the ST2, ST1, and DM groups compared with the NC, and were all significantly up-regulated in the ST2 compared with the ST1 group. Conclusion Down-regulation of PGC-1α and irisin in skeletal muscle may be involved in T2DM. Sitagliptin can dose-dependently up-regulate PCG-1α and irisin, potentially improving insulin resistance and glycolipid metabolism and inhibiting inflammation.

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