Deoxynivalenol Exposure Suppresses Adipogenesis by Inhibiting the Expression of Peroxisome Proliferator-Activated Receptor Gamma 2 (PPARγ2) in 3T3-L1 Cells.

Deoxynivalenol (DON)-a type B trichothecene mycotoxin, mainly produced by the secondary metabolism of Fusarium-has toxic effects on animals and humans. Although DON's toxicity in many organs including the adrenal glands, thymus, stomach, spleen, and colon has been addressed, its effects on adipocytes have not been investigated. In this study, 3T3-L1 cells were chosen as the cell model and treated with less toxic doses of DON (100 ng/mL) for 7 days. An inhibition of adipogenesis and decrease in triglycerides (TGs) were observed. DON exposure significantly downregulated the expression of PPARγ2 and C/EBPα, along with that of other adipogenic marker genes in 3T3-L1 cells and BALB/c mice. The anti-adipogenesis effect of DON and the downregulation of the expression of adipogenic marker genes were effectively reversed by PPARγ2 overexpression. The repression of PPARγ2's expression is the pivotal event during DON exposure regarding adipogenesis. DON exposure specifically decreased the di-/trimethylation levels of Histone 3 at lysine 4 in 3T3-L1 cells, therefore weakening the enrichment of H3K4me2 and H3K4me3 at the Pparγ2 promoter and suppressing its expression. Conclusively, DON exposure inhibited PPARγ2 expression via decreasing H3K4 methylation, downregulated the expression of PPARγ2-regulated adipogenic marker genes, and consequently suppressed the intermediate and late stages of adipogenesis. Our results broaden the current understanding of DON's toxic effects and provide a reference for addressing the toxicological mechanism of DON's interference with lipid homeostasis.

Cadmium modulates adipocyte functions in metallothionein-null mice.

Our previous study has demonstrated that exposure to cadmium (Cd), a toxic heavy metal, causes a reduction of adipocyte size and the modulation of adipokine expression. To further investigate the significance of the Cd action, we studied the effect of Cd on the white adipose tissue (WAT) of metallothionein null (MT(-/-)) mice, which cannot form atoxic Cd-MT complexes and are used for evaluating Cd as free ions, and wild type (MT(+/+)) mice. Cd administration more significantly reduced the adipocyte size of MT(-/-) mice than that of MT(+/+) mice. Cd exposure also induced macrophage recruitment to WAT with an increase in the expression level of Ccl2 (MCP-1) in the MT(-/-) mice. The in vitro exposure of Cd to adipocytes induce triglyceride release into culture medium, decrease in the expression levels of genes involved in fatty acid synthesis and lipid hydrolysis at 24 h, and at 48 h increase in phosphorylation of the lipid-droplet-associated protein perilipin, which facilitates the degradation of stored lipids in adipocytes. Therefore, the reduction in adipocyte size by Cd may arise from an imbalance between lipid synthesis and lipolysis. In addition, the expression levels of leptin, adiponectin and resistin decreased in adipocytes. Taken together, exposure to Cd may induce unusually small adipocytes and modulate the expression of adipokines differently from the case of physiologically small adipocytes, and may accelerate the risk of developing insulin resistance and type 2 diabetes.

Association between PRO12ALA polymorphism of the PPAR-γ2 gene and type 2 diabetes mellitus in Iranian patients.

BACKGROUND: Peroxisome proliferator-activated receptor (PPARs) have been identified as ligand-activated transcription factors that belong to the nuclear receptor superfamily. It has been shown that an association exists between Proline 12 alanine (Pro12Ala) polymorphism of PPAR-GAMMA2 (PPAR-γ2) gene and increased risk of type 2 diabetes mellitus (T2DM) in different populations. Therefore, the present study was designed to investigate the association between Pro12Ala polymorphism of PPAR-γ2 gene and T2DM in an Iranian population. MATERIALS AND METHODS: Two hundred unrelated people, including 100 healthy controls and 100 diabetic patients were recruited diagnosed based on American Diabetes Association criteria. Blood samples were used for isolation of genomic deoxyribonucleic acid (DNA). Having extracted the genomic DNA from human blood leukocytes by means of High Pure polymerase chain reaction (PCR) Template preparation kit, we carried out polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on each blood sample. Then, Genomic DNA was digested by BstU-I restriction enzyme. Thereafter, restriction products were analyzed by means of Polyacrylamide gel electrophoresis and stained by Ethidium Bromide. RESULTS: We found that the frequency of Ala allele in healthy subjects was significantly higher than in diabetic subjects (P = 0003). Moreover, the genotype frequency of Ala/Ala in healthy subjects was significantly higher than in diabetic subjects (P < 0.001). However, the genotype frequency of Ala/Pro in diabetic subjects was significantly higher than in healthy subjects (P < 0.001). CONCLUSION: The present study suggests that polymorphism of PPAR-γ2 gene is associated with T2DM. Furthermore, Ala allele is significantly found in non-diabetic individual's Iranian population.

Diabetes as a risk factor for Alzheimer's disease in the Middle East and its shared pathological mediators.

The incidence of Alzheimer's disease (AD) has risen exponentially worldwide over the past decade. A growing body of research indicates that AD is linked to diabetes mellitus (DM) and suggests that impaired insulin signaling acts as a crucial risk factor in determining the progression of this devastating disease. Many studies suggest people with diabetes, especially type 2 diabetes, are at higher risk of eventually developing Alzheimer's dementia or other dementias. Despite nationwide efforts to increase awareness, the prevalence of Diabetes Mellitus (DM) has risen significantly in the Middle East and North African (MENA) region which might be due to rapid urbanization, lifestyle changes, lack of physical activity and rise in obesity. Growing body of evidence indicates that DM and AD are linked because both conditions involve impaired glucose homeostasis and altered brain function. Current theories and hypothesis clearly implicate that defective insulin signaling in the brain contributes to synaptic dysfunction and cognitive deficits in AD. In the periphery, low-grade chronic inflammation leads to insulin resistance followed by tissue deterioration. Thus insulin resistance acts as a bridge between DM and AD. There is pressing need to understand on how DM increases the risk of AD as well as the underlying mechanisms, due to the projected increase in age related disorders. Here we aim to review the incidence of AD and DM in the Middle East and the possible link between insulin signaling and ApoE carrier status on Aß aggregation, tau hyperphosphorylation, inflammation, oxidative stress and mitochondrial dysfunction in AD. We also critically reviewed mutation studies in Arab population which might influence DM induced AD. In addition, recent clinical trials and animal studies conducted to evaluate the efficiency of anti-diabetic drugs have been reviewed.

Correlation of spontaneous adipocyte generation with osteogenic differentiation of porcine skin-derived stem cells.

The objective of this study was to examine effects of spontaneous adipocyte generation on osteogenic differentiation of porcine skin-derived stem cells (pSSCs). Correlation between osteogenic differentiation and adipocyte differentiation induced by osteocyte induction culture was determined using different cell lines. Osteogenic differentiation efficiency of pSSCs was then analyzed by controlling the expression of adipocyte-specific transcription factors during osteogenic induction culture. Among four cell lines, pSSCs-II had the lowest lipid droplet level but the highest calcium content (p ＜ 0.05). It also expressed significantly low levels of peroxisome proliferator-activated receptor gamma 2 (PPARγ2) and adipocyte protein 2 (aP2) mRNAs but very high levels of runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP) mRNAs as osteogenic makers (p ＜ 0.05). Oil red O extraction was increased by 0.1 µM troglitazone (TGZ) treatment but decreased by 50 µM bisphenol A diglycidyl ether (BADGE) (p ＜ 0.05). Calcium content was drastically increased after BADGE treatment compared to that in osteogenic induction control and TGZ-treated pSSCs (p ＜ 0.05). Relative expression levels of PPARγ2 and aP2 mRNAs were increased by TGZ but decreased by BADGE. Expression levels of Rucx2 and ALP mRNAs, osteoblast-specific marker genes, were significantly increased by BADGE treatment (p ＜ 0.05). The expression level of BCL2 like 1 was significantly higher in BADGE-treated pSSCs than that in TGZ-treated ones (p ＜ 0.05). The results demonstrate that spontaneous adipocyte generation does not adversely affect osteogenic differentiation. However, reducing spontaneous adipocyte generation by inhibiting PPARγ2 mRNA expression can enhance in vitro osteogenic differentiation of pSSCs.

The association of Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma2 gene with the metabolic characteristics in Chinese women with polycystic ovary syndrome.

BACKGROUND: The Pro12Ala polymorphism in the peroxisome Proliferator-activated receptor-gamma2 PPARγ2) gene that account for metabolic dysfunction in women with polycystic ovary syndrome (PCOS) remain elusive. AIM: To explore the association between PPARγ2 gene pro12ala polymorphism and the metabolic characteristics in Chinese women with PCOS. METHODS: PPARγ2 gene Pro12Ala polymorphism was assayed by PCR/RFLP methods in 120 Chinese women with PCOS and 118 normal subjects. All subjects were examined by anthropometry, lipid profile, sex hormone, oral glucose tolerance tests and insulin tolerance tests. RESULTS: In PCOS patients, women with the non-Pro/Pro genotypes of the PPARγ2 gene Pro12Ala polymorphism showed statistically significantly higher fasting triglycerides (TG) levels and WHR value than those with the Pro/Pro genotype (P=.006 for both). There was no significant difference with PPARγ2 Pro12Ala polymorphism distributions between Chinese Han women with PCOS and controls. CONCLUSION: PPARγ2 gene Pro12Ala polymorphism was not supposed to be susceptible genes in PCOS. However, in PCOS patients, the PPAR-gamma Pro12Ala polymorphism may modulate the concentrations of serum fasting TG levels and fat-deposition in abdomen, respectively.

Expression patterns of peroxisome proliferator-activated receptor gamma 1 versus gamma 2, and their association with intramuscular fat in goat tissues.

Intramuscular fat (IMF) shortage causes the lack of juiciness and tenderness of goat meat, while peroxisome proliferator-activated receptor gamma 1 (PPARγ1) and gamma 2 (PPARγ2) play key roles in lipid metabolism. Nevertheless, their expression patterns and the relationship with IMF have been poorly exposed. Using quantitative polymerase chain reaction (qPCR), classical Soxhlet extraction, and in situ hybridization, we demonstrated that among 13 goat tissues, expression of PPARγ1 was dramatically higher than that of PPARγ2 except for lung. We further demonstrated the expression patterns of PPARγ1 and PPARγ2 and their negative association with intramuscular fat content in three goat muscles with kids growing. Meanwhile, PPARγ expression was located in the connective tissues. These results suggest that PPARγ1 is rather active for most tissues of goat, and closely related with the muscular fat metabolism during early postnatal life, but a more direct proof remains to be provided.