A Novel Partial PPARγ Agonist Has Weaker Lipogenic Effect in Adipocytes and Stimulates GLUT4 Translocation in Skeletal Muscle Cells via AMPK-Dependent Signaling

<b><i>Introduction:</i></b> Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are highly effective in treating insulin resistance. However, associated side effects such as weight gain due to increase in adipogenesis and lipogenesis hinder their clinical use. The aim of the study was to design and synthesize novel partial PPARγ agonists with weaker lipogenic effect in adipocytes and enhanced glucose transporter 4 (GLUT4) translocation stimulatory effect in skeletal muscle cells. <b><i>Methods:</i></b> Novel partial PPARγ agonists (GS1, GS2, and GS3) were designed and screened to predict their binding interactions with PPARγ by molecular docking. The stability of the docked ligand-PPARγ complex was studied by molecular dynamics (MD) simulation. The cytotoxicity of synthesized compounds was tested in 3T3-L1 adipocytes and L6 myoblasts by MTT assay. The lipogenic effect was investigated in 3T3-L1 adipocytes using oil red O staining and GLUT4 translocation stimulatory effect in L6-GLUT4<i>myc</i> myotubes by an antibody-coupled colorimetric assay. <b><i>Results:</i></b> The molecular docking showed the binding interactions between designed agonists and PPARγ. MD simulation demonstrated good stability between the GS2-PPARγ complex. GS2 and GS3 did not show any significant effect on cell viability up to 80 or 100 μM concentration. Pioglitazone treatment significantly increased intracellular lipid accumulation in adipocytes compared to control. However, this effect was significantly less in GS2- and GS3-treated conditions compared to pioglitazone at 10 μM concentration, indicating weaker lipogenic effect. Furthermore, GS2 significantly stimulated GLUT4 translocation to the plasma membrane in a dose-dependent manner via the AMPK-dependent signaling pathway in skeletal muscle cells. <b><i>Conclusion:</i></b> GS2 may be a promising therapeutic agent for the treatment of insulin resistance and type 2 diabetes mellitus without adiposity.

Effects of peroxisome proliferator activated receptor gamma (PPARɣ) agonist on fasting model applied neuron cultures

Objectives Peroxisome proliferator activated receptor gamma (PPARγ) agonists used for the treatment of Diabetes Mellitus (DM), has important roles on the regulation of metabolism including ketogenesis in fasting and low glucose states. Recently PPARγ was proven to have anti-oxidant and anti-inflammatory effects on neuronal cells. Methods In the present study, effects of pioglitazone (PPARγ agonist) on cell survival, energy metabolism and mitochondrial functions were investigated in glucose deprived fasting model applied SH-SY5Y (ATCC/CRL 2266) cell lines. Before and after pioglitazone treatment; energy metabolites (glucose, lactate, ketone (βOHB), lactate dehydrogenase activity), mitochondrial citrate synthase activity and cell viability were investigated. Results and Conclusions PPARγ agonist addition to glucose deprived, ketone added neurons provided positive improvements in energy metabolites (p<0.01), mitochondrial functions (p<0.001) and survival rates (p<0.01). Changes in mitochondrial citrate synthase activity, lactate and LDH levels of neuronal cells treated with PPARγ agonist have not been previously shown. Our results suggest, pioglitazone as an effective alternative for the treatment of neurodegenerative diseases especially with the presence of ketone bodies. By clarifying the mechanisms of PPARγ agonists, a great contribution will be made to the treatment of neurodegenerative diseases.

Epigenetic derepression converts PPARγ into a druggable target in triple-negative and endocrine-resistant breast cancers

Clinical trials repurposing peroxisome proliferator-activated receptor-gamma (PPARγ) agonists as anticancer agents have exhibited lackluster efficacy across a variety of tumor types. Here, we report that increased PPARG expression is associated with a better prognosis but is anticorrelated with histone deacetylase (HDAC) 1 and 2 expressions. We show that HDAC overexpression blunts anti-proliferative and anti-angiogenic responses to PPARγ agonists via transcriptional and post-translational mechanisms, however, these can be neutralized with clinically approved and experimental HDAC inhibitors. Supporting this notion, concomitant treatment with HDAC inhibitors was required to license the tumor-suppressive effects of PPARγ agonists in triple-negative and endocrine-refractory breast cancer cells, and combination therapy also restrained angiogenesis in a tube formation assay. This combination was also synergistic in estrogen receptor-alpha (ERα)–positive cells because HDAC blockade abrogated ERα interference with PPARγ-regulated transcription. Following a pharmacokinetics optimization study, the combination of rosiglitazone and a potent pan-HDAC inhibitor, LBH589, stalled disease progression in a mouse model of triple-negative breast cancer greater than either of the monotherapies, while exhibiting a favorable safety profile. Our findings account for historical observations of de-novo resistance to PPARγ agonist monotherapy and propound a therapeutically cogent intervention against two aggressive breast cancer subtypes.

PPARγ-Induced Global H3K27 Acetylation Maintains Osteo/Cementogenic Abilities of Periodontal Ligament Fibroblasts

The periodontal ligament is a soft connective tissue embedded between the alveolar bone and cementum, the surface hard tissue of teeth. Periodontal ligament fibroblasts (PDLF) actively express osteo/cementogenic genes, which contribute to periodontal tissue homeostasis. However, the key factors maintaining the osteo/cementogenic abilities of PDLF remain unclear. We herein demonstrated that PPARγ was expressed by in vivo periodontal ligament tissue and its distribution pattern correlated with alkaline phosphate enzyme activity. The knockdown of PPARγ markedly reduced the osteo/cementogenic abilities of PDLF in vitro, whereas PPARγ agonists exerted the opposite effects. PPARγ was required to maintain the acetylation status of H3K9 and H3K27, active chromatin markers, and the supplementation of acetyl-CoA, a donor of histone acetylation, restored PPARγ knockdown-induced decreases in the osteo/cementogenic abilities of PDLF. An RNA-seq/ChIP-seq combined analysis identified four osteogenic transcripts, RUNX2, SULF2, RCAN2, and RGMA, in the PPARγ-dependent active chromatin region marked by H3K27ac. Furthermore, RUNX2-binding sites were selectively enriched in the PPARγ-dependent active chromatin region. Collectively, these results identified PPARγ as the key transcriptional factor maintaining the osteo/cementogenic abilities of PDLF and revealed that global H3K27ac modifications play a role in the comprehensive osteo/cementogenic transcriptional alterations mediated by PPARγ.

PPARγ Agonists: Emergent Therapy in Endometriosis

Endometriosis is one of the major gynecological diseases of reproductive-age women. This disease is characterized by the presence of glands and stroma outside the uterine cavity. Several studies have shown the major role of inflammation, angiogenesis, adhesion and invasion, and apoptosis in endometriotic lesions. Nevertheless, the mechanisms underlying endometriotic mechanisms still remain unclear and therapies are not currently efficient. The introduction of new agents can be effective by improving the condition of patients. PPARγ ligands can directly modulate these pathways in endometriosis. However, data in humans remain low. Thus, the purpose of this review is to summarize the potential actions of PPARγ agonists in endometriosis by acting on inflammation, angiogenesis, invasion, adhesion, and apoptosis.

PPARγ transcription effect on naturally occurring O-prenyl cinnamaldehydes and cinnamyl alcohol derivatives

Background: PPARγ is known to be a key regulator of metabolism and storage of lipids and glucose and to be implicated in the pathology of severe syndromes like obesity, diabetes, atherosclerosis and cancer. Methods: As a continuation of the authors' studies on oxyprenylated secondary metabolites as effective PPARγ agonists, the authors describe herein the chemical synthesis of natural O-prenyl cinnamaldehydes and cinnamyl alcohols and preliminary data on their in vitro effects on PPARγ transcription. Results: Among the panel of eight compounds tested, three – namely, (2E)-3-(4-((E)3,7-dimethylocta-2,6-dienyloxy)-3-methoxyphenyl)acrylaldehyde, (2E)-3-(4-((E)3,7-dimethylocta-2,6-dienyloxy)-3-methoxyphenyl)prop-2-en-1-ol and boropinal A – exerted activity in a dose-dependent manner. Conclusion: O-prenyl cinnamaldehydes and cinnamyl alcohols have the potential to effectively interact with PPARγ receptor.

Interplay of Opposing Effects of the WNT/β-Catenin Pathway and PPARγ and Implications for SARS-CoV2 Treatment

The Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), has quickly reached pandemic proportions. Cytokine profiles observed in COVID-19 patients have revealed increased levels of IL-1β, IL-2, IL-6, and TNF-α and increased NF-κB pathway activity. Recent evidence has shown that the upregulation of the WNT/β-catenin pathway is associated with inflammation, resulting in a cytokine storm in ARDS (acute respire distress syndrome) and especially in COVID-19 patients. Several studies have shown that the WNT/β-catenin pathway interacts with PPARγ in an opposing interplay in numerous diseases. Furthermore, recent studies have highlighted the interesting role of PPARγ agonists as modulators of inflammatory and immunomodulatory drugs through the targeting of the cytokine storm in COVID-19 patients. SARS-CoV2 infection presents a decrease in the angiotensin-converting enzyme 2 (ACE2) associated with the upregulation of the WNT/β-catenin pathway. SARS-Cov2 may invade human organs besides the lungs through the expression of ACE2. Evidence has highlighted the fact that PPARγ agonists can increase ACE2 expression, suggesting a possible role for PPARγ agonists in the treatment of COVID-19. This review therefore focuses on the opposing interplay between the canonical WNT/β-catenin pathway and PPARγ in SARS-CoV2 infection and the potential beneficial role of PPARγ agonists in this context.

Connection between JAK/STAT and PPARγ signaling during the progression of multiple sclerosis: Insights into the modulation of T-cells and immune responses in the brain

: Multiple Sclerosis (MS) is a severe brain and spinal cord condition with a diverse autoimmune response and a wide variety of demyelination symptoms that primarily affect young adults. The primary reason for this disease is inflammation of white and grey matter caused by increased production of proinflammatory cytokines, which further damages the progenitor oligodendrocytes and appears to induce hypertrophy of the astrocytes and gliosis. Overexpression of the JAK/STAT signaling pathway contributes directly to physiological and pathological results in motor neuron diseases. Cytokines such as IL-17, IL-6, IL-12, TNF-α, and INF-ϒ use JAK/STAT signaling to trigger self-reactive CD4+ T-cells differentiate them into Th1 phenotypes that over-activate immune reactions in the brain. Similarly, PPARγ plays a critical role in regulating the immune response by providing an anti-inflammatory effect by inhibiting macrophage and cytokine production activation. PPARγ also mediates the intrinsic molecular process of the T-cell, which selectively regulates the differentiation of Th17. Various studies indicate the neuroprotective function of PPARγ agonists by attenuating the JAK/STAT mediated activation of glial cells, inhibiting interleukin, and the differentiation of Th1 cells. Therefore, to maintain the brain's immune system, both PPARγ,and JAK/STAT oppositely regulate each other. Dysregulation in JAK/STAT and PPARγ signaling contributes to several physiological changes leading to neurological disorders, including MS. Based on the above view; we summarized the combined role of JAK/STAT-PPARγsignaling in MS and explored potential therapeutic strategies for disease improvement by the use of pathway modulators.