Green tea extract exhibits antidiabetic effects partly through regulating dipeptidyl peptidase-4 expression in adipose tissue.

The antidiabetic effects of green tea have been demonstrated in clinical trials and epidemiological studies. This study investigated the antidiabetic effects of green tea extract (GTE) and its underlying molecular mechanisms using a leptin receptor-deficient db/db mouse model (Leprdb/db). Treatment with GTE for 2 weeks improved glucose tolerance and insulin sensitivity in Leprdb/db mice. In addition, GTE treatment reduced the body weight and adiposity of Leprdb/db mice. Furthermore, GTE treatment reduced pro-inflammatory gene expression, including nuclear factor kappa B (NF-κB) in white adipose tissue (WAT), and also reduced dipeptidyl peptidase-4 (DPP4) expression levels in WAT as well as in the serum. The promoter region of Dpp4 contains the NF-κB binding site, and DPP4 was found to be a direct target of NF-κB. Consistently, in vitro treatment of cells with GTE or its main constituent epigallocatechin gallate reduced lipopolysaccharide-induced NF-κB/DPP4 expression in 3T3-L1 adipocytes and RAW264.7 cells. Overall, our data demonstrated that GTE exerts an anti-diabetic effect by regulating the expression levels of NF-κB and DPP4 in WAT.

Optimizing Artificial Neural Network-Based Models to Predict Rice Blast Epidemics in Korea.

To predict rice blast, many machine learning methods have been proposed. As the quality and quantity of input data are essential for machine learning techniques, this study develops three artificial neural network (ANN)-based rice blast prediction models by combining two ANN models, the feed-forward neural network (FFNN) and long short-term memory (LSTM), with diverse input datasets, and compares their performance. The Blast_Weather_FFNN model had the highest recall score (66.3%) for rice blast prediction. This model requires two types of input data: blast occurrence data for the last 3 years and weather data (daily maximum temperature, relative humidity, and precipitation) between January and July of the prediction year. This study showed that the performance of an ANN-based disease prediction model was improved by applying suitable machine learning techniques together with the optimization of hyperparameter tuning involving input data. Moreover, we highlight the importance of the systematic collection of long-term disease data.

Type I IFN stimulates IFI16-mediated aromatase expression in adipocytes that promotes E2-dependent growth of ER-positive breast cancer.

Although type I interferons (IFNs) play multifaceted roles during tumorigenesis and cancer treatment, the interplay between type I IFNs and estrogen signaling in breast cancer (BC) microenvironment is not well understood. Here, we report a novel function of type I IFNs in inducing aromatase expression in adipose tissues surrounding BC, which potentiates the E2-dependent growth of estrogen receptor (ER)-positive BC. First, we found that expression levels of type I IFNs correlate negatively with clinical outcome but positively with tumor grade in patients with ER-positive BC. Levels of type I IFNs were elevated in cocultured media of immune cells and BC cells, which increased aromatase expression and E2 production in Simpson-Golabi-Behmel syndrome preadipocytes. The type I IFN-induced aromatase expression was dependent on IFN-γ-inducible protein 16 (IFI16), which is encoded by an interferon-stimulated gene. At the molecular level, type I IFNs led to recruitment of HIF1α-IFI16-PRMT2 complex to the hypoxia-response element located in the aromatase PI.3/PII promoter. Next, we generated an adipocyte-specific Ifi204, which is a mouse ortholog of human IFI16, knockout mouse (Ifi204-AKO). IFNß induced E2 production in the preadipocytes isolated from the control mice, but such E2 production was far lower in the Ifi204-AKO preadipocytes. Importantly, the growth of orthotopically inoculated E0771 ER-positive mammary tumors was reduced significantly in the Ifi204-AKO mice. Taken together, our findings provide novel insights into the crosstalk between type I IFNs and estrogen signaling in the progression of ER-positive BC.

TM4SF5 Knockout Protects Mice From Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue.

Transmembrane 4 L six family member 5 (TM4SF5) functions as a sensor for lysosomal arginine levels and activates the mammalian target of rapamycin complex 1 (mTORC1). While the mTORC1 signaling pathway plays a key role in adipose tissue metabolism, the regulatory function of TM4SF5 in adipocytes remains unclear. In this study we aimed to establish a TM4SF5 knockout (KO) mouse model and investigated the effects of TM4SF5 KO on mTORC1 signaling-mediated autophagy and mitochondrial metabolism in adipose tissue. TM4SF5 expression was higher in inguinal white adipose tissue (iWAT) than in brown adipose tissue and significantly upregulated by a high-fat diet (HFD). TM4SF5 KO reduced mTORC1 activation and enhanced autophagy and lipolysis in adipocytes. RNA sequencing analysis of TM4SF5 KO mouse iWAT showed that the expression of genes involved in peroxisome proliferator-activated receptor α signaling pathways and mitochondrial oxidative metabolism was upregulated. Consequently, TM4SF5 KO reduced adiposity and increased energy expenditure and mitochondrial oxidative metabolism. TM4SF5 KO prevented HFD-induced glucose intolerance and inflammation in adipose tissue. Collectively, the results of our study demonstrate that TM4SF5 regulates autophagy and lipid catabolism in adipose tissue and suggest that TM4SF5 could be therapeutically targeted for the treatment of obesity-related metabolic diseases.

Specialized Proresolving Mediators for Therapeutic Interventions Targeting Metabolic and Inflammatory Disorders.

Uncontrolled inflammation is considered the pathophysiological basis of many prevalent metabolic disorders, such as nonalcoholic fatty liver disease, diabetes, obesity, and neurodegenerative diseases. The inflammatory response is a self-limiting process that produces a superfamily of chemical mediators, called specialized proresolving mediators (SPMs). SPMs include the ω-3-derived family of molecules, such as resolvins, protectins, and maresins, as well as arachidonic acid-derived (ω-6) lipoxins that stimulate and promote resolution of inflammation, clearance of microbes, and alleviation of pain and promote tissue regeneration via novel mechanisms. SPMs function by binding and activating G protein-coupled receptors, such as FPR2/ALX, GPR32, and ERV1, and nuclear orphan receptors, such as RORα. Recently, several studies reported that SPMs have the potential to attenuate lipid metabolism disorders. However, the understanding of pharmacological aspects of SPMs, including tissue-specific biosynthesis, and specific SPM receptors and signaling pathways, is currently limited. Here, we summarize recent advances in the role of SPMs in resolution of inflammatory diseases with metabolic disorders, such as nonalcoholic fatty liver disease and obesity, obtained from preclinical animal studies. In addition, the known SPM receptors and their intracellular signaling are reviewed as targets of resolution of inflammation, and the currently available information on the therapeutic effects of major SPMs for metabolic disorders is summarized.

STK3/STK4 signalling in adipocytes regulates mitophagy and energy expenditure.

Obesity reduces adipocyte mitochondrial function, and expanding adipocyte oxidative capacity is an emerging strategy to improve systemic metabolism. Here, we report that serine/threonine-protein kinase 3 (STK3) and STK4 are key physiological suppressors of mitochondrial capacity in brown, beige and white adipose tissues. Levels of STK3 and STK4, kinases in the Hippo signalling pathway, are greater in white than brown adipose tissues, and levels in brown adipose tissue are suppressed by cold exposure and greatly elevated by surgical denervation. Genetic inactivation of Stk3 and Stk4 increases mitochondrial mass and function, stabilizes uncoupling protein 1 in beige adipose tissue and confers resistance to metabolic dysfunction induced by high-fat diet feeding. Mechanistically, STK3 and STK4 increase adipocyte mitophagy in part by regulating the phosphorylation and dimerization status of the mitophagy receptor BNIP3. STK3 and STK4 expression levels are elevated in human obesity, and pharmacological inhibition improves metabolic profiles in a mouse model of obesity, suggesting STK3 and STK4 as potential targets for treating obesity-related diseases.

Regulatory roles of G-protein coupled receptors in adipose tissue metabolism and their therapeutic potential.

The high incidence of obesity has increased the need to discover new therapeutic targets to combat obesity and obesity-related metabolic diseases. Obesity is defined as an abnormal accumulation of adipose tissue, which is one of the major metabolic organs that regulate energy homeostasis. However, there are currently no approved anti-obesity therapeutics that directly target adipose tissue metabolism. With recent advances in the understanding of adipose tissue biology, molecular mechanisms involved in brown adipose tissue expansion and metabolic activation have been investigated as potential therapeutic targets to increase energy expenditure. This review focuses on G-protein coupled receptors (GPCRs) as they are the most successful class of druggable targets in human diseases and have an important role in regulating adipose tissue metabolism. We summarize recent findings on the major GPCR classes that regulate thermogenesis and mitochondrial metabolism in adipose tissue. Improved understanding of GPCR signaling pathways that regulate these processes could facilitate the development of novel pharmacological approaches to treat obesity and related metabolic disorders.

Paenibacillus pabuli strain P7S promotes plant growth and induces anthocyanin accumulation in Arabidopsis thaliana.

In this study, a novel plant growth-promoting rhizobacteria (PGPR), the bacterial strain Paenibacillus pabuli P7S (PP7S), showed promising plant growth-promoting effects. Furthermore, it induced anthocyanin accumulation in Arabidopsis. When co-cultivated with PP7S, there was a significant increase in anthocyanin content and biomass of Arabidopsis seedlings compared with those of the control. The quantitative reverse transcription-polymerase chain reaction analysis revealed higher expression of many key genes regulating anthocyanin and flavonoid biosynthesis pathways in PP7S-treated seedlings when compared with that of the control. Furthermore, higher expression of pathogen-related genes and microbe-associated molecular pattern genes was also observed in response to PP7S, indicating that the PGPR triggered the induced systemic response (ISR) in A. thaliana. These results suggest that PP7S promotes plant growth in A. thaliana and increases anthocyanin biosynthesis by triggering specific ISRs in plant.

Evaluation of the plant growth-promoting activity of Pseudomonas nitroreducens in Arabidopsis thaliana and Lactuca sativa.

KEY MESSAGE: Pseudomonas nitroreducens: strain IHB B 13561 (PnIHB) enhances the growth of Arabidopsis thaliana and Lactuca sativa via the stimulation of cell development and nitrate absorption. Plant growth-promoting rhizobacteria (PGPR) enhance plant development through various mechanisms; they improve the uptake of soil resources by plants to greatly promote plant growth. Here, we used Arabidopsis thaliana seedlings and Lactuca sativa to screen the growth enhancement activities of a purified PGPR, Pseudomonas nitroreducens strain IHB B 13561 (PnIHB). When cocultivated with PnIHB, both species of plants exhibited notably improved growth, particularly in regard to biomass. Quantitative reverse transcription polymerase chain reaction analysis indicated high expression levels of the nitrate transporter genes, especially NRT2.1, which plays a major role in the high-affinity nitrate transport system in roots. Moreover, enhanced activity of the cyclin-B1 promoter was observed when wild-type 'Columbia-0' Arabidopsis seedlings were exposed to PnIHB, whereas upregulation of cyclin-B also occurred in the inoculated lettuce seedlings. Overall, these results suggest that PnIHB improves A. thaliana and L. sativa growth via specific pathways involved in the promotion of cell development and enhancement of nitrate uptake.