DEPP Deficiency Contributes to Browning of White Adipose Tissue.

Decidual protein induced by progesterone (DEPP) was originally identified as a modulator in the process of decidualization in the endometrium. Here, we define that DEPP is involved in adipose tissue thermogenesis, which contributes to metabolic regulation. Knockdown of DEPP suppressed adipocyte differentiation and lipid accumulation in 3T3-L1 cells, induced expression of brown adipose tissue (BAT) markers in primary brown adipocyte and induced mouse embryonic fibroblasts (MEFs) differentiation to brown adipocytes. Moreover, DEPP deficiency in mice induced white adipocyte browning and enhanced BAT activity. Cold exposure stimulated more browning of white adipose tissue (WAT) and maintained higher body temperature in DEPP knockout mice compared to that in wild-type control mice. DEPP deficiency also protected mice against high-fat-diet-induced insulin resistance. Mechanistic studies demonstrated that DEPP competitively binds SIRT1, inhibiting the interaction between peroxisome proliferator-activated receptor gamma (PPARγ) and Sirtuin 1 (SIRT1). Collectively, these findings suggest that DEPP plays a crucial role in orchestrating thermogenesis through regulating adipocyte programs and thus might be a potential target for the treatment of metabolic disorders.

Knowledge-Induced Multiple Kernel Fuzzy Clustering.

The introduction of domain knowledge opens new horizons to fuzzy clustering. Then knowledge-driven and data-driven fuzzy clustering methods come into being. To address the challenges of inadequate extraction mechanism and imperfect fusion mode in such class of methods, we propose the Knowledge-induced Multiple Kernel Fuzzy Clustering (KMKFC) algorithm. First, to extract knowledge points better, the Relative Density-based Knowledge Extraction (RDKE) method is proposed to extract high-density knowledge points close to cluster centers of real data structure, and provide initialized cluster centers. Moreover, the multiple kernel mechanism is introduced to improve the adaptability of clustering algorithm and map data to high-dimensional space, so as to better discover the differences between the data and obtain superior clustering results. Second, knowledge points generated by RDKE are integrated into KMKFC through a knowledge-influence matrix to guide the iterative process of KMKFC. Third, we also provide a strategy of automatically obtaining knowledge points, and thus propose the RDKE with Automatic knowledge acquisition (RDKE-A) method and the corresponding KMKFC-A algorithm. Then we prove the convergence of KMKFC and KMKFC-A. Finally, experimental studies demonstrate that the KMKFC and KMKFC-A algorithms perform better than thirteen comparison algorithms with regard to four evaluation indexes and the convergence speed.

Effects of polysaccharides from Morchella conica on nitric oxide production in lipopolysaccharide-treated macrophages.

Morchella conica is a species of rare edible mushroom whose multiple medicinal functions have been proven. However, reports barely mention the mechanisms of these functions. In this study, the effects of two polysaccharides from M. conica (PMCs) on nitric oxide (NO) production in lipopolysaccharide (LPS)-treated macrophages were investigated. The results showed that 50-200 µg/ml of the extracellular polysaccharide (EPMC) and 25-200 µg/ml of the intracellular polysaccharide (IPMC) significantly inhibited NO production. Accordingly, the signal mechanisms were also explored. It was found that 100 µg/ml of EPMC and 25 µg/ml of IPMC could efficiently down-regulate the inducible nitric oxide synthase (iNOS) expression and nuclear factor-κB (NF-κB) DNA-binding activity and up-regulate heme oxygenase 1 (HO-1) expression. Moreover, by using a HO-1 inhibitor NaPP to treat the cells, the PMC-inhibited NO production and iNOS expression, rather than NF-κB activation, were released partially, indicating that HO-1 probably medicates the inhibition of PMCs on iNOS and NO. Besides, EPMC also significantly suppressed the phosphorylation of p38 mitogen-activated protein kinase (p38), c-jun N-terminal kinase, mitogen-activated protein kinase kinase 4, and expression of NF-κB inducing kinase, while IPMC seemed to show no regular effect on p38. In conclusion, PMCs inhibited NO production in LPS-induced macrophages through regulating a series of signal pathways, suggesting that PMCs play a potential role on immunomodulation and treating related diseases.

The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism.

Farnesoid X receptor (FXR) has important roles in maintaining bile acid and cholesterol homeostasis. Here we report that the antiparasitic drug ivermectin is a ligand for nuclear FXR. We identify ivermectin using a high-throughput compound library screening and show that it induces the transcriptional activity of the FXR with distinctive properties in modulating coregulator recruitment. The crystal structure of ivermectin complexed with the ligand-binding domain of FXR reveals a unique binding mode of ivermectin in the FXR ligand-binding pocket, including the highly dynamic AF-2 helix and an expanded ligand-binding pocket. Treatment of wild-type mice, but not of FXR-null mice, with ivermectin decreases serum glucose and cholesterol levels, suggesting that ivermectin regulates metabolism through FXR. Our results establish FXR as the first mammalian protein targeted by ivermectin with high selectivity. Considering that ivermectin is a widely used clinical drug, our findings reveal a safe template for the design of novel FXR ligands.