Transcription Factor PPARγ Research Articles

PPAR-γ Signaling and Common Protective Pathways against Obesity and Alzheimer's Disease

Transcription factor PPAR-γ is predominantly found in adipose tissue, liver, and brain. PPARs form heterodimers, interact with ligands, and regulate the expression of the genes of the PPAR-γ downstream regulatory pathways. PPAR-γ is critical in regulating many physiological processes, including adipogenesis, glucose metabolism, fatty acid metabolism, energy homeostasis, and inflammation. This review is on the functions of PPAR-γ and how dysregulation of activity or expression of PPAR-γ can lead to obesity and Alzheimer's disease (AD). The PPAR- γ agonist inhibited the downregulated pathways, such as Wnt/β-Catenin and JAK-STAT pathways, both involved in activating NF-kB. PPAR-γ has a significant role in the APOE (Apolipoprotein E) gene expression, which reduces reducing obesity, inhibits amyloid aggregation, prevents hyperphosphorylation of tau, and inhibits dysregulation of autophagy. This review provides a perspective on the intricate interplay between PPAR-γ, obesity, and AD, focusing on the molecular mechanisms and potential therapeutic implications.

FPR1 signaling aberrantly regulates S100A8/A9 production by CD14+FCN1hi macrophages and aggravates pulmonary pathology in severe COVID-19

Excessive alarmins S100A8/A9 escalate the inflammation and even exacerbate immune-driven thrombosis and multi-organ damage. However, the regulatory mechanisms of S100A8/A9 expression in infectious diseases remain unclear. In this study, high-dimensional transcriptomic data analyses revealed a high proportion of CD14+FCN1hi macrophages within the pulmonary niche post-severe SARS-CoV-2 infection. By constructing the S100-coexpression gene list and supervised module scoring, we found that CD14+FCN1hi macrophages presented the highest scores of alarmin S100, and possibly served as the trigger and amplifier of inflammation in severe COVID-19. These CD14+FCN1hi cells lacked the positive regulatory activity of transcription factor PPARγ, and lost their differentiation ability towards mature macrophages. Ex vivo experiments further validated that the epithelial cells with high ORF-3a expression promoted the expression and secretion of S100A8/A9 through ANXA1/SAA1-FPR1 signaling. S100A8/A9 heterodimers, as well as the co-localization of S100A8/A9 with microtubules, were both diminished by the FPR1 inhibitor. Phospho-kinase protein array indicated that STAT3 promoted transcription, and PLC-γ and ERK1/2 pathways were involved in the hetero-dimerization and unconventional secretion of S100A8/A9. Our study highlights the pivotal role of FPR1 signaling in the excessive production of S100A8/A9 and provides a promising target for the prevention and control of severe COVID-19 and post-acute COVID-19 sequelae.

PPARγ/ETV2 axis regulates endothelial-to-mesenchymal transition in pulmonary hypertension.

Endothelial-to-mesenchymal transition (EndoMT) plays an important role in pulmonary hypertension (PH) but the molecular mechanisms regulating EndoMT remain to be defined. We demonstrate that the axis of the transcription factors PPARγ (Peroxisome Proliferator-Activated Receptor gamma) and ETV2 (ETS variant 2) play important roles in the pathogenesis of PH. Decreased levels of the expression of PPARγ and ETV2 along with reduced endothelial and increased EndoMT markers are consistently observed in lungs and pulmonary artery endothelial cells (PAECs) of idiopathic pulmonary arterial hypertension patients, in hypoxia-exposed mouse lungs, human PAECs, and in induced-EndoMT cells. Etv2 +/- mice spontaneously developed PH and right ventricular hypertrophy (RVH), associated with increased EndoMT markers and decreased EC markers. Interestingly, chronic hypoxia exacerbated right ventricular systolic pressure and RVH in Etv2 +/- mice. PPARγ transcriptionally activates the ETV2 promoter. Consistently, while mice overexpressing endothelial PPARγ increases the expression of ETV2 and endothelial markers with reduced EndoMT markers, endothelial PPARγ KO mice show decreased ETV2 expression and enhanced EndoMT markers. Inducible overexpression of ETV2 under induced-EndoMT cell model reduces number of cells with mesenchymal morphology and decreases expression of mesenchymal markers with increased EC makers, compared to control. Therefore, our study suggests that PPARγ-ETV2 signaling regulates PH pathogenesis through EndoMT.

Targeted V-type peptide-decorated nanoparticles prevent colitis by inhibiting endosomal TLR signaling and modulating intestinal macrophage polarization

Inflammatory bowel disease (IBD) has become a serious and challenging health problem globally without curative medical treatments. Mounting evidence suggests that intestinal macrophages and their phenotypes are key players in the pathogenesis of IBD. Modulating the phenotypes and functions of intestinal macrophages through targeted interventions could be a promising approach to manage detrimental gut inflammation in IBD. In this study, we rationally design and fabricate a novel class of V-type peptide-decorated nanoparticles, VP-NP, with potent anti-inflammatory activity. Such a design allows two functional motifs FFD in a single peptide molecule to enhance the bioactivity of the nanoparticles. As expected, VP-NP exhibits a strong inhibitory activity on endosomal Toll-like receptor (TLR) signaling. Surprisingly, VP-NP can inhibit M1 polarization while facilitating M2 polarization in mouse bone marrow-derived macrophages through regulating the key transcription factors NF-κB, STAT1 and PPAR-γ. Mechanistically, VP-NP is internalized by macrophages in the endosomes, where it blocks endosomal acidification to inhibit endosomal TLR signaling; the transcriptomic analysis reveals that VP-NP potently down-regulates many genes in TLR, NF-κB, JAK-STAT, and cytokine/chemokine signaling pathways associated with inflammatory responses. In a colitis mouse model, the intraperitoneally administered VP-NP effectively alleviates the disease activities by decreasing colon inflammation and injuries, pro-inflammatory cytokine production, and myeloid cell infiltration in the gut. Furthermore, VP-NP primarily targets intestinal macrophages and alters their phenotypes from inflammatory M1-type toward the anti-inflammatory M2-type. This study provides a new nanotherapeutic strategy to specifically regulate macrophage activation and phenotypes through a dual mechanism to control gut inflammation, which may augment current clinical treatments for IBD.

Interleukin-27 signaling resists obesity by promoting the accumulation of Treg cells in visceral adipose tissue

The prevalence of obesity and its associated metabolic disorders has emerged as one of the most significant health threats worldwide. The visceral adipose tissue regulatory T cells (VAT Treg) play an essential role in maintaining homeostasis and preventing obesity mainly by secreting Interleikin-10 (IL-10) and Transforming Growth Factor β (TGF-β). However, the mechanism that regulates VAT Treg quantity and function remains unclear. Here we elucidate the pivotal role of IL-27 signaling in sustaining the accumulation of VAT Treg cells, thereby conferring protection against obesity. We found that mice with the deficiency of IL-27 receptor Wsx1 gained more body weight and VAT weight than their wild-type littermates when fed both a normal-fat diet (NFD) and a high-fat diet (HFD). Notably, the population of VAT Treg cells was reduced in Wsx1 knockout (KO) mice, regardless of whether they were fed a normal-fat diet (NFD) or a high-fat diet (HFD). Correspondingly, the expression levels of the transcription factors FOXP3 and PPAR-γ, essential for VAT Treg function, were also diminished in Wsx1 KO mice. Taken together, our findings indicate that IL-27 signaling plays a protective role in obesity by supporting the maintenance and accumulation of VAT Treg cells.

Excess Iodine Consumption Induces Oxidative Stress and Pancreatic Damage Independently of Chemical Form in Male Wistar Rats: Participation of PPAR-γ and C/EBP-β.

Human beings consume different chemical forms of iodine in their diet. These are transported by different mechanisms in the cell. The forms of iodine can be part of thyroid hormones, bind to lipids, be an antioxidant, or be an oxidant, depending on their chemical form. The excessive consumption of iodine has been associated with pancreatic damage and diabetes mellitus type 2, but the association between disease and the chemical form consumed in the diet is unknown. This research analyzes the effect of excessive iodine consumption as Lugol (molecular iodine/potassium iodide solution) and iodate on parameters of pancreatic function, thyroid and lipid profiles, antioxidant and oxidant status, the expression of IR/Akt/P-Akt/GLUT4, and transcription factors PPAR-γ and CEBP-β. Three groups of Wistar rats were treated with 300 μg/L of iodine in drinking water: (1) control, (2) KIO3, and (3) Lugol. Lugol and KIO3 consumption increased total iodine levels. Only KIO3 increased TSH levels. Both induced high serum glucose levels and increased oxidative stress and pancreatic alpha-amylase activity. Insulin levels and antioxidant status decreased significantly. PPAR-γ and C/EBP-β mRNA expression increased. The pancreatic damage, hypertriglyceridemia, and oxidative stress were independent of the chemical form of iodine consumed. These effects depended on PPAR-γ, C/EBP-β, GLUT-4, and IR.

Phyllanthus niruni (Meniran) Aqueous and Ethanol Extracts Promotes Adipogenic Differentiation in 3T3-L1 Preadipocytes

Abstract Consumers determine intramuscular fat as one of the important factors for the quality and palatability of beef meat. In a recent study, Phyllanthus niruri (meniran) has practical uses for feed additives and was screened for their ability to improve preadipocyte proliferation and differentiation. This study evaluates the effect of meniran aqueous and ethanol extracts on promoting adipogenic differentiation in 3T3-L1 preadipocytes and were investigated via CCK-8 assay, Oil red O-Staining, and RT-PCR analysis. For differentiation to adipocytes, post-confluent 3T3-L1 preadipocytes were stimulated DMEM containing 10% FBS, 5 μg/ml insulin, 0.5mM 3-isobutyl-1-methylxanthine, and 1 μM dexamethasone. 3T3-L1 were cultured with meniran aqueous and ethanol extract (25, 50, 100, and 200 ppm). Intracellular lipid accumulation was significantly increased by meniran extract until 100 ppm and decreased at 200 ppm. The expressions of adipocyte differentiation on mRNA transcription factors PPARγ and C/EBPꭤ were stimulated by 25-100 ppm of meniran both aqueous and ethanol extract but lower at 200 ppm. In the future, these findings may be applied to develop feed additives from natural plant extracts which may be used to increase intramuscular fat accumulation in beef cattle through manipulation of adipocyte differentiation.

Molecular docking, dynamics, and preclinical experimental studies identify Morin hydrate as a potent PPAR-γ and NRF-2 transcription factor agonist that mitigates colon inflammation

Introduction: Peroxisome proliferator-activated receptor gamma (PPAR-γ) plays a vital role in regulating intestine inflammation. PPAR-γ is highly expressed in the adipose tissue and the colon. The nuclear erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein1 (Keap1) system protects cells from oxidative stress and inflammation. Therefore, PPAR-γ and Nrf2 ligands offer a drug-targeting system that can be exploited to treat inflammatory bowel diseases (IBDs), especially ulcerative colitis. IBD prevalence is on the rise globally. Current mainstream therapies for IBD offer protection but with many side effects; therefore, up to 30% of IBD patients turn to alternate therapy using bioactive phytochemicals. Morin hydrate, a naturally occurring bioflavonoid in many fruits, stems, and leaves of the Moraceae family plant, possesses potent anti-inflammatory properties. The docking studies reveal that it is a potent activator of the PPAR-γ and Nrf2 transcription factors. Therefore, in this study, we investigated the role of morin hydrate modulating colon epithelial PPAR-γ transcription in colon inflammation. Aim: Therefore, this study aims to investigate morin hydrate’s anti-inflammatory properties using both in vivo and in vitro models of colon inflammation. Methodology: C57BL/6J black mice were administered 2% dextran sodium sulfate (DSS) morin hydrate administered at concentrations of 25 & 50mg/kg body for in vivo studies. The DAI, colon length, MPO, and histology changes were determined. Proinflammatory cytokines (IL-1β, IL-6, TNF-α, & IL17A) were measured using ELISA and mRNA using real-time PCR. PPAR-γ and Nrf2 expression and phosphoNF-κB/NF-κB expression were estimated. HT-29 cells were cultured in DMEM media and were stimulated using TNF-α (1ng/ml). Different concentrations of morin hydrate were treated to HT-29 cells to determine a safe dose range for further in vitro experiments by estimating cell toxicity assay. CXCL-1, IL-8, and mRNA levels were determined using real-time PCR after morin hydrate co-treatment. Morin hydrate effect on PPAR-γ and Nrf2 promoter activity was determined using full-length promoter transfection studies. Results: Morin treatment significantly ( p<0.01) decreased DAI, MPO level, and restored colon length dose-dependently in the treated group. Histological scoring for colonic inflammation was significantly ( p<0.001) improved upon morin treatment. Morin treatment also inhibited the proinflammatory cytokines (IL-1β, IL-6, TNF-α, & IL17A) significantly ( p<0.01) both at protein and mRNA levels. Morin significantly inhibited COX-2 and iNOS both at protein and mRNA levels and also decreased tissue nitrite levels. Morin also activated PPAR-γ protein expression NRF2 nuclear translocation and inhibited NF-κB expression in DSS-administered mice. Morin significantly decreased antioxidant surrogate markers superoxide dismutase (SOD) and catalase activity. Morin significantly ( p<0.01) decreased proinflammatory cytokine (CXCL-1 & IL-8) mRNA expression when HT-29 cells were challenged with TNF-α. Morin also increased PPAR-γ and Nrf2 promoter activity. Conclusion: Morin hydrate is a potent PPAR-γ and Nrf2 transcription factor activator that mitigates colon inflammation through its anti-inflammatory and antioxidant activities. This is supported from UAE University grant, fund number 12R006 and 12R169. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

TAT38 and TAT38 mimics potently inhibit adipogenesis by repressing C/EBPα, PPARγ, Pi-PPARγ, and SREBP1 expression

Antiretroviral therapy-naive people living with HIV possess less fat than people without HIV. Previously, we found that HIV-1 transactivator of transcription (TAT) decreases fat in ob/ob mice. The TAT38 (a.a. 20–57) is important in the inhibition of adipogenesis and contains three functional domains: Cys-ZF domain (a.a. 20–35 TACTNCYCAKCCFQVC), core-domain (a.a. 36–46, FITKALGISYG), and protein transduction domain (PTD)(a.a. 47–57, RAKRRQRRR). Interestingly, the TAT38 region interacts with the Cyclin T1 of the P-TEFb complex, of which expression increases during adipogenesis. The X-ray crystallographic structure of the complex showed that the Cys-ZF and the core domain bind to the Cyclin T1 via hydrophobic interactions. To prepare TAT38 mimics with structural and functional similarities to TAT38, we replaced the core domain with a hydrophobic aliphatic amino acid (from carbon numbers 5 to 8). The TAT38 mimics with 6-hexanoic amino acid (TAT38 Ahx (C6)) and 7-heptanoic amino acid (TAT38 Ahp (C7)) inhibited adipogenesis of 3T3-L1 potently, reduced cellular triglyceride content, and decreased body weight of diet-induced obese (DIO) mice by 10.4–11 % in two weeks. The TAT38 and the TAT38 mimics potently repressed the adipogenic transcription factors genes, C/EBPα, PPARγ, and SREBP1. Also, they inhibit the phosphorylation of PPARγ. The TAT peptides may be promising candidates for development into a drug against obesity or diabetes.

Design, synthesis, molecular dynamic simulation, DFT analysis, computational pharmacology and decoding the antidiabetic molecular mechanism of sulphonamide-thiazolidin-4-one hybrids

In search of novel antidiabetic agents, the study was framed to hybridize and synthesize molecules based on scaffolds of benzenesulfonamide and thiazolidine-4-one, efficiently synthesized (6a-6h) and structurally characterized by FTIR, 1H NMR 13C NMR and HRMS spectroscopy. The antidiabetic activity was assessed based on α-amylase inhibition, glucose uptake assay and PPAR-γ transcription factor assay. Compound 6b (4-(2-((E)-5-((Z)-2-hydroxybenzylidene)-4-oxo-2-(phenylimino) thiazolidin-3-yl) ethyl) benzenesulfonamide) demonstrated promising activity toward α-amylase inhibition having IC50 value of 29.51±1.35 µg/ml. A glucose uptake assay was performed for compounds (6a-6h) to assess the capacity of glucose uptake. Among them, Compound 6b exhibits notable glucose uptake with 88.71% in the yeast cell line. To support the glucose uptake findings of compound 6b, expression of PPAR-γ transcription factor was measured of compound 6b as compared to pioglitazone. Furthermore, induced fit docking was carried out to predict the refined pose of synthesized compounds in the α-amylase binding pocket. MD simulation studies confirmed the stability of compound 6b in the α-amylase binding pocket. Molecules were geometrically optimized by DFT theory using B3LYP 6–31 G (d, p**) basis set, and electronic properties were studied. Network pharmacology analysis for compound 6b identified key pathways involved in T2DM and postprandial hyperglycemia like PI3K-Akt pathway, Type II diabetes mellitus pathway metabolic pathway, and digestion of dietary carbohydrates pathway. These findings provide better insights into further developing benzenesulfonamide-based thiazolidin-4-one hybrids as antidiabetic agents.

Stellera chamaejasme L. extract inhibits adipocyte differentiation through activation of the extracellular signal-regulated kinase pathway.

Stellera chamaejasme L. (SCL) is a perennial herb with demonstrated bioactivities against inflammation and metabolic dysfunction. Adipocyte differentiation is a critical regulator of metabolic homeostasis and a promising target for the treatment of metabolic diseases, so we examined the effects of SCL on adipogenesis. A methanol extract of SCL dose-dependently suppressed intracellular lipid accumulation in adipocyte precursors cultured under differentiation induction conditions and reduced expression of the adipogenic transcription factors PPARγ and C/EBPα as well as the downstream lipogenic genes fatty acid binding protein 4, adiponectin, fatty acid synthase, and stearoyl-CoA desaturase. The extract also promoted precursor cell proliferation and altered expression of the cell cycle regulators cyclin-dependent kinase 4, cyclin E, and cyclin D1. In addition, SCL extract stimulated extracellular signal-regulated kinase (ERK) phosphorylation, while pharmacological inhibition of ERK effectively blocked the inhibitory effects of SCL extract on preadipocyte differentiation. These results suggest that SCL extract contains bioactive compounds that can suppress adipogenesis through modulation of the ERK pathway.

Potential Benefits of Ethanol extract of Anredera cordifolia for Antiobesity of High Fat diet-Induced Obesity in White Male Rat Wistar

تستمر الوفيات المرتبطة بالسمنة في الارتفاع ، لذلك من الضروري إنقاص الوزن لتجنب المضاعفات ، نريديرا كورديفوليا هو نوع من النباتات النضرة من الجنس، باسيللسيا يستخدم على نطاق واسع في طب الأعشاب لتقليل وزن الجسم. تهدف الدراسة الحالية إلى تقييم الفوائد المحتملة لمستخلص الإيثانول من نريديرا كورديفوليا لنماذج الفئران السمنة لتقليل الوزن الناجم عن نظام غذائي عالي الدهون. من خلال تجريب مع اختبارات ما بعد فقد تم تصميم مجموعة ضابطة مع نموذج سمنة 36 جرذًا ، مقسمة إلى مجموعتين: ثلاث مجموعات تحكم (K1 ، K2 ، K3) وثلاث مجموعات معالجة (K1 ، K3 ، K4) (P1 ، P2 ، P3) ، أعطيت جميع مجموعات تحتوي على نسبة عالية من الدهون باستثناء K1 نظام غذائي قياسي ، K2 بدون علاج ، و K3 مع أورليستات. تلقت مجموعة العلاج من مستخلص الإيثانول نريديرا كورديفوليا بجرعات مختلفة ، P1 50 مجم / كجم من وزن الجسم ، P2 100 مجم / كجم من وزن الجسم، و P3 150 مجم / كجم من وزن الجسم. بعد 4 أسابيع من العلاج، قُتلت جميع مجموعات الفئران ، وتم قياس مستويات ERK و PPARγ في الأنسجة الدهنية الحشوية في البطن باستخدام ELISA والكيمياء المناعية. يتم قياس وزن الجسم ومحيط البطن أثناء فحص القياسات، وقد لوحظ فقدان الوزن عند تناول مستخلص الإيثانول نريديرا كورديفوليا بجرعات 100 و 150 مجم / كجم من وزن الجسم، مع انخفاض مستويات ERK و PPAR . يستخدم مستخلص الإيثانول من نريديرا كورديفوليا كمضاد للسمنة. تقلل آلية فقدان الوزن هذه من عامل نسخ PPARγ وتقلل من مستويات ERK بحيث تقل عملية تكوين الدهون.

Inhibitory Effects of Sesquiterpenoids Isolated from Artemisia scoparia on Adipogenic Differentiation of 3T3-L1 Preadipocytes.

Obesity and related complications are significant health issues in modern society, largely attributed to a sedentary lifestyle and a carbohydrate-rich diet. Since anti-obesity drugs often come with severe side effects, preventative measures are being sought globally, including dietary changes and functional foods that can counteract weight gain. In this context, plant-based metabolites are extensively studied for their advantageous biological effects against obesity. Several plants within the Artemisia genus have been reported to possess anti-adipogenic properties, preventing adipocytes from maturing and accumulating lipids. The present study investigated the anti-adipogenic potential of two sesquiterpenoids, reynosin and santamarine, isolated from A. scoparia in adipose-induced 3T3-L1 preadipocytes. Differentiating 3T3-L1 adipocytes treated with these isolated compounds displayed fewer adipogenic characteristics compared to untreated mature adipocytes. The results indicated that cells treated with reynosin and santamarine accumulated 55.0% and 52.5% fewer intracellular lipids compared to untreated control adipocytes, respectively. Additionally, the mRNA expression of the key adipogenic marker, transcription factor PPARγ, was suppressed by 87.2% and 91.7% following 60 μM reynosin and santamarine treatment, respectively, in differentiated adipocytes. Protein expression was also suppressed in a similar manner, at 92.7% and 82.5% by 60 μM reynosin and santamarine treatment, respectively. Likewise, SERBP1c and C/EBPα were also downregulated at both gene and protein levels in adipocytes treated with samples during differentiation. Further analysis suggested that the anti-adipogenic effect of the compounds might be a result of AMPK activation and the subsequent suppression of MAPK phosphorylation. Overall, the present study suggested that sesquiterpenoids, reynosin, and santamarine were two potential bioactive compounds with anti-adipogenic properties. Further research is needed to explore other bioactive agents within A. scoparia and elucidate the in vivo action mechanisms of reynosin and santamarine.

Enhancer-mediated FOXO3 expression promotes MSC adipogenic differentiation by activating autophagy

BackgroundMesenchymal stem cells (MSCs) are pluripotent stem cells capable of differentiating into osteocytes, adipocytes and chondrocytes. However, in osteoporosis, the balance of differentiation is tipped toward adipogenesis and the key mechanism is controversial. Researches have shown that, as upstream regulatory elements of gene expression, enhancers ar involved in the expression of identity genes. In this study, we identified enhancers-mediated gene FOXO3 promoting MSC adipogenic differentiation by activating autophagy. MethodsWe integrated data of RNA sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq) and ATAC-sequencing (ATAC-seq) to find the identity gene FOXO3. The expression of FOXO3 protein, adipogenic transcription factors and the substrate of autophagy were measured by western blotting. The Oil Red O (ORO) staining was used to visualize the adipogenesis of MSCs. Immunohistochemistry was used to visualize the FOXO3 expression in adipocytes in bone marrow. Immunofluorescence was used to detect the expression of PPARγ and LC3B. ResultsDuring adipogenesis, enhancers redistribute to genes associated with adipogenic differentiation, among which we identified the pivotal identity gene FOXO3. FOXO3 could promote the expression of the adipogenic transcription factors PPARγ, CEBPα, and CEBPβ during adipogenic differentiation, while PPARγ, CEBPα, and CEBPβ could in turn bind to FOXO3 and continue to promote FOXO3 expression to form a positive feedback loop. Consistently elevated FOXO3 expression promotes autophagy by activating the PI3K-AKT pathway which mediates adipogenic differentiation. ConclusionsPivotal identity gene FOXO3 promotes autophagy by activating PI3K-AKT pathway, which provokes adipogenic differentiation of MSCs. Enhancer-regulated adipogenic identity gene FOXO3 could be an attractive treatment for osteoporosis.

Modeling elucidates context dependence in adipose regulation

Single-cell data and computational simulations reveal the dynamics of the transcription factors HIF1α and PPARγ during adipocyte differentiation and maturation. Modeling feedback within this network predicts a HIF1α-mediated choice between lipid accumulation and incomplete differentiation. Invitro experiments support this model, with implications for adipose dynamics in metabolic disorders involving hypoxia.

Testicular ACE regulates sperm metabolism and fertilization through the transcription factor PPARγ

Testis angiotensin-converting enzyme (tACE) plays a critical role in male fertility, but the mechanism is unknown. By using ACE C-domain KO (CKO) mice which lack tACE activity, we found that ATP in CKO sperm was 9.4-fold lower than WT sperm. Similarly, an ACE inhibitor (ACEi) reduced ATP production in mouse sperm by 72%. Metabolic profiling showed that tACE inactivation severely affects oxidative metabolism with decreases in several Krebs cycle intermediates including citric acid, cis-aconitic acid, NAD, α-ketoglutaric acid, succinate, and L-malic acid. We found that sperms lacking tACE activity displayed lower levels of oxidative enzymes (CISY, ODO1, MDHM, QCR2, SDHA, FUMH, CPT2, and ATPA) leading to a decreased mitochondrial respiration rate. The reduced energy production in CKO sperms leads to defects in their physiological functions including motility, acrosine activity, and fertilization in vitro and in vivo. Male mice treated with ACEi show severe impairment in reproductive capacity when mated with female mice. In contrast, an angiotensin II receptor blocker (ARB) had no effect. CKO sperms express significantly less peroxisome proliferators-activated receptor gamma (PPARγ) transcription factor, and its blockade eliminates the functional differences between CKO and WT sperms, indicating PPARγ might mediate the effects of tACE on sperm metabolism. Finally, in a cohort of human volunteers, in vitro treatment with the ramipril or a PPARγ inhibitor reduced ATP production in human sperm and hence its motility and acrosine activity. These findings may have clinical significance since millions of people take ACEi daily, including men who are reproductively active.

A gut microbial metabolite of linoleic acid ameliorates liver fibrosis by inhibiting TGF-β signaling in hepatic stellate cells

The antidiabetic drug pioglitazone ameliorates insulin resistance by activating the transcription factor PPARγ. In addition to its blood glucose–lowering action, pioglitazone exerts pleiotropic effects including amelioration of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). The mechanism by which pioglitazone achieves this latter effect has remained unclear, however. We here show that pioglitazone administration increases the amount of linoleic acid (LA) metabolites in adipose tissue of KK-Ay mice. These metabolites are produced by lactic acid bacteria in the gut, and pioglitazone also increased the fraction of Lactobacillus in the gut microbiota. Administration of the LA metabolite HYA (10-hydroxy-cis-12-octadecenoic acid) to C57BL/6 J mice fed a high-fat diet improved liver histology including steatosis, inflammatory cell infiltration, and fibrosis. Gene ontology analysis of RNA-sequencing data for the liver revealed that the top category for genes downregulated by HYA treatment was related to extracellular matrix, and the expression of individual genes related to fibrosis was confirmed to be attenuated by HYA treatment. Mechanistically, HYA suppressed TGF-β–induced Smad3 phosphorylation and fibrosis-related gene expression in human hepatic stellate cells (LX-2). Our results implicate LA metabolites in the mechanism by which pioglitazone ameliorates liver fibrosis, and they suggest that HYA is a potential therapeutic for NAFLD/NASH.

IL-33 promotes pancreatic β-cell survival and insulin secretion under diabetogenic conditions through PPARγ

Pancreatic β-cell dysfunction plays a vital role in the development of diabetes. IL-33 exerts anti-diabetic effects via its anti-inflammatory properties and has been demonstrated to increase insulin secretion in animal models. However, IL-33, as a pleiotropic cytokine, may also exert a deleterious effect on β-cells, which has not been rigorously studied. In the present study, we found that IL-33 promoted cell survival and insulin secretion in MIN6 (a mouse pancreatic β-cell line) cells under diabetogenic conditions. IL-33 increased the expression of its receptor ST2 and the transcription factor PPARγ, whereas PPARγ inhibition impaired IL-33-mediated β-cell survival and insulin release. IL-33 did not repress the expression of pro-inflammatory mediators, including Tf, Icam1, Cxcl10, and Il1b, whereas it significantly reduced the expression of Ccl2. IL-33 decreased TNF-α secretion and increased IL-10 secretion; these effects were completely reversed by PPARγ inhibition. IL-33 increased glucose uptake and expression of Glut2. It upregulated the expression of glycolytic enzyme genes, namely, Pkm2, Hk2, Gpi1, and Tpi, and downregulated the expression of Gck, Ldha, and Mct4. However, it did not alter hexokinase activity. Moreover, IL-33 increased the number and activity of mitochondria, accompanied by increased ATP production and reduced accumulation of ROS. IL-33 upregulated the expression of PGC-1α and cytochrome c, and mitochondrial fission- and fusion-associated genes, including Mfn1, Mfn2, and Dnm1l. IL-33-mediated mitochondrial homeostasis was partially reversed by PPARγ inhibition. Altogether, IL-33 protects β-cell survival and insulin secretion that could be partially driven via PPARγ, which regulates glucose uptake and promotes mitochondrial function and anti-inflammatory responses.

Regulation of low-density lipoprotein on lipid metabolism in macrophages of large yellow croaker (Larimichthys crocea)

Low-density lipoprotein (LDL) is the main carrier of cholesterol transport in plasma, which participates in regulating lipid homeostasis. Studies in mammals have shown that high levels of LDL in plasma absorbed by macrophages trigger the formation of lipid-rich foam cells, leading to the development of atherosclerotic plaques. Although lipid-rich atherosclerosis-like lesions have been discovered in the aorta of several fish species, the physiological function of LDL in fish macrophages remains poorly understood. In the present study, LDL was isolated from the plasma of large yellow croaker (Larimichthys crocea), and mass spectrometry analysis identified two truncated forms of apolipoprotein B100 in the LDL protein profile. Transcriptomic analysis of LDL-stimulated macrophages revealed that differentially expressed genes (DEGs) were enriched in various pathways related to lipid metabolism, as confirmed by the fact that LDL increased total cholesterol and cholesteryl esters content. Meanwhile, the gene and protein expression levels of perilipin2 (PLIN2), a DEG enriched in the PPAR signaling pathway, were upregulated in response to LDL stimulation. Importantly, knocking down plin2 significantly attenuates LDL-induced cholesterol accumulation and promotes cholesterol efflux. Furthermore, the transcription factor PPARγ, which is upregulated in response to LDL stimulation, can enhance the promoter activity of plin2. In conclusion, this study suggests that LDL may upregulate plin2 expression through PPARγ, resulting in cholesterol accumulation in fish macrophages. This study will facilitate the investigation of the function of LDL in regulating lipid homeostasis in macrophages and shed light on the evolutionary origin of LDL metabolism in vertebrates.

Chrysin inhibits adipogenesis by modulating PPARγ: in silico and in vitro studies

Adipose tissue is the major storage site of lipids and plays a vital role in energy homeostasis. Adipogenesis is a well-regulated process wherein preadipocytes differentiate into adipocytes. It requires the sequential activation of numerous transcription factors, including peroxisome proliferator activated receptor-γ (PPAR-γ). Phytochemicals have been reported to regulate adipogenesis and flavonoids represent the most researched groups of phytochemicals with regard to their effect on adipogenesis. Chrysin is a naturally occurring flavone and is reported to have anti-inflammatory effects in obese conditions. The present study was aimed to examine the effect of chrysin on adipogenesis. In silico Molecular docking, dynamic simulation studies and in vitro cell-based assays showed that chrysin inhibited adipogenesis by modulating key adipogenic transcription factor PPARγ. Enhanced adipogenesis leads to obesity and targeting adipogenesis is potential in regulating adipose tissue development. So, these investigations may provide important information for designing therapeutic interventions to control adiposity. Communicated by Ramaswamy H. Sarma