P311, a novel intrinsically disordered protein, regulates adipocyte development.

Adipocyte development and adipose tissue expansion have many implications for human diseases, including obesity. Obesity is a debilitating disorder and a risk factor for metabolic disorders including insulin resistance and diabetes mellitus, due in part to an overabundance of adipocytes and adipocyte dysfunction. In recent years, obesity has become a global pandemic with approximately one-third of US adults classified as obese. Adipose tissue has recently been identified as a major metabolic organ, classified into white adipose tissue (WAT) and brown adipose tissue (BAT). Other than lifestyle modifications and invasive surgeries, only a very limited number of drugs are available to treat obesity and overweight. P311 has been shown to play a key role in blood pressure regulation, vascular contractility and tissue remodeling. Here we present a role for P311 in adipogenesis using a 3T3-L1 cell culture model. P311 expression is initiated with the induction of adipogenesis and increased during adipogenesis. This increase correlates with an increase in the expression of the key adipogenic transcriptional factors PPARγ2 and C/EBPα. In addition, siRNA-mediated P311 knockdown inhibits adipogenic differentiation in 3T3-L1 cells. Finally, P311 binds to the PPARγ2 promoter, implicating P311 mediates adipogenesis partly through PPARγ activation.

Adipokine CTRP6 improves PPARγ activation to alleviate angiotensin II-induced hypertension and vascular endothelial dysfunction in spontaneously hypertensive rats.

Angiotensin II (AngII) is the most important component of angiotensin, which has been regarded as a major contributor to the incidence of hypertension and vascular endothelial dysfunction. The adipocytokine C1q/TNF-related protein 6 (CTRP6) was recently reported to have multiple protective effects on cardiac and cardiovascular function. However, the exact role of CTRP6 in the progression of AngII induced hypertension and vascular endothelial function remains unclear. Here, we showed that serum CTRP6 content was significantly downregulated in SHRs, accompanied by a marked increase in arterial systolic pressure and serum AngII, CRP and ET-1 content. Then, pcDNA3.1-mediated CTRP6 delivery or CTRP6 siRNA was injected into SHRs. CTRP6 overexpression caused a significant decrease in AngII expression and AngII-mediated hypertension and vascular endothelial inflammation. In contrast, CTRP6 knockdown had the opposite effect to CTRP6 overexpression. Moreover, we found that CTRP6 positively regulated the activation of the ERK1/2 signaling pathway and the expression of peroxisome proliferator-activated receptor γ (PPARγ), a recently proven negative regulator of AngII, in the brain and vascular endothelium of SHRs. Finally, CTRP6 was overexpressed in endothelial cells, and caused a significant increase in PPARγ activation and suppression in AngII-mediated vascular endothelial dysfunction and apoptosis. The effect of that could be rescued by the ERK inhibitor PD98059. In contrast, silencing CTRP6 suppressed PPARγ activation and exacerbated AngII-mediated vascular endothelial dysfunction and apoptosis. In conclusion, CTRP6 improves PPARγ activation and alleviates AngII-induced hypertension and vascular endothelial dysfunction.

Natural products, PGC-1 α , and Duchenne muscular dystrophy.

Peroxisome proliferator-activated receptor γ (PPARγ) is a transcriptional coactivator that binds to a diverse range of transcription factors. PPARγ coactivator 1 (PGC-1) coactivators possess an extensive range of biological effects in different tissues, and play a key part in the regulation of the oxidative metabolism, consequently modulating the production of reactive oxygen species, autophagy, and mitochondrial biogenesis. Owing to these findings, a large body of studies, aiming to establish the role of PGC-1 in the neuromuscular system, has shown that PGC-1 could be a promising target for therapies targeting neuromuscular diseases. Among these, some evidence has shown that various signaling pathways linked to PGC-1α are deregulated in muscular dystrophy, leading to a reduced capacity for mitochondrial oxidative phosphorylation and increased reactive oxygen species (ROS) production. In the light of these results, any intervention aimed at activating PGC-1 could contribute towards ameliorating the progression of muscular dystrophies. PGC-1α is influenced by different patho-physiological/pharmacological stimuli. Natural products have been reported to display modulatory effects on PPARγ activation with fewer side effects in comparison to synthetic drugs. Taken together, this review summarizes the current knowledge on Duchenne muscular dystrophy, focusing on the potential effects of natural compounds, acting as regulators of PGC-1α.

Design and synthesis of novel Y-shaped barbituric acid derivatives as PPARγ activators.

Novel Y-shaped barbituric acid (BA) derivatives have been designed using rational methods including molecular docking. Fourteen novel compounds were synthesized using hydroxyl group protection-deprotection strategies for PPARγ activation. Competitive binding analysis of the synthesized molecules using time-resolved fluorescence resonance energy transfer (FRET) method was carried out, and the IC50 values were determined. The symmetrically substituted derivatives have shown greater binding affinity than unsymmetrically substituted derivatives. Nitrobenzyl and cyanophenyl substituted derivatives have shown reasonable binding affinities (10.1 and 6.5 µM, respectively), while mono and diacetate derivatives were found inactive. Molecular dynamics simulations show that the designed compounds have interaction profiles similar to partial agonists. The most significant finding of our study is that BA derivatives with symmetrically substituted weakly polar side chains result in the desired moderate level of PPARγ binding affinities.