Pathophysiology of sarcopenia: Genetic factors and their interplay with environmental factors.

Sarcopenia is a geriatric disorder characterized by a progressive decline in muscle mass and function. This disorder has been associated with a range of adverse health outcomes, including fractures, functional deterioration, and increased mortality. The pathophysiology of sarcopenia is highly complex and multifactorial, involving both genetic and environmental factors as key contributors. This review consolidates current knowledge on the genetic factors influencing the pathogenesis of sarcopenia, particularly focusing on the altered gene expression of structural and metabolic proteins, growth factors, hormones, and inflammatory cytokines. While the influence of environmental factors such as physical inactivity, chronic diseases, smoking, alcohol consumption, and sleep disturbances on sarcopenia is relatively well understood, there is a dearth of studies examining their mechanistic roles. Therefore, this review emphasizes the interplay between genetic and environmental factors, elucidating their cumulative role in exacerbating the progression of sarcopenia beyond their individual effects. The unique contribution of this review lies in synthesizing the latest evidence on the genetic factors and their interaction with environmental factors, aiming to inform the development of novel therapeutic or preventive interventions for sarcopenia.

Design and Synthesis of l-1'-Homologated Adenosine Derivatives as Potential Anti-inflammatory Agents.

Inflammatory responses are fundamental protective warning mechanisms. However, in certain instances, they contribute significantly to the development of several chronic diseases such as cancer. Based on previous studies of truncated 1'-homologated adenosine derivatives, l-nucleosides and their nucleobase-modified quinolone analogues were designed, synthesized, and evaluated for anti-inflammatory activities. The target molecules were synthesized via the key intramolecular cyclization of monotosylate and Mitsunobu condensation from the natural product, d-ribose. All compounds tested and showed potent anti-inflammatory activities, as indicated by their inhibition of LPS-induced IL-1ß secretion from the RAW 264.7 macrophages. Gene expressions of pro-inflammatory cytokines showed that all compounds, except 3a and 3b, significantly reduced LPS-induced IL-1ß and IL-6 mRNA expressions. The half-maximal inhibitory concentrations (IC50) of 2g and 2h against IL-1ß were 1.08 and 2.28 µM, respectively. In contrast, only 2d, 2g, and 3d effectively reversed LPS-induced TNFα mRNA expression. Our mechanistic study revealed that LPS-induced phosphorylation of NF-κB was significantly downregulated by all compounds tested, providing evidence that the NF-κB signaling pathway is involved in their anti-inflammatory activities. Among the compounds tested, 2g and 2h had the most potent anti-inflammatory effects, as shown by the extent of decrease in pro-inflammatory gene expression, protein secretion, and NF-κB phosphorylation. These findings suggest that the l-truncated 1'-homologated adenosine skeleton and its nucleobase-modified analogues have therapeutic potential as treatments for various human diseases by mediating inflammatory processes.

TNFα-induced NLRP3 inflammasome mediates adipocyte dysfunction and activates macrophages through adipocyte-derived lipocalin 2.

BACKGROUND AND AIMS: Obesity is a state of chronic low-grade systemic inflammation. Recent studies showed that NLRP3 inflammasome initiates metabolic dysregulation in adipose tissues, primarily through activation of adipose tissue infiltrated macrophages. However, the mechanism of NLRP3 activation and its role in adipocytes remains elusive. Therefore, we aimed to examine the activation of TNFα-induced NLRP3 inflammasome in adipocytes and its role on adipocyte metabolism and crosstalk with macrophages. METHODS: The effect of TNFα on adipocyte NLRP3 inflammasome activation was measured. Caspase-1 inhibitor (Ac-YVAD-cmk) and primary adipocytes from NLRP3 and caspase-1 knockout mice were utilized to block NLRP3 inflammasome activation. Biomarkers were measured by using real-time PCR, western blotting, immunofluorescence staining, and enzyme assay kits. Conditioned media from TNFα-stimulated adipocytes was used to establish the adipocyte-macrophage crosstalk. Chromatin immunoprecipitation assay was used to identify the role of NLRP3 as a transcription factor. Mouse and human adipose tissues were collected for correlation analysis. RESULTS: TNFα treatment induced NLRP3 expression and caspase-1 activity in adipocytes, partly through autophagy dysregulation. The activated adipocyte NLRP3 inflammasome participated in mitochondrial dysfunction and insulin resistance, as evidenced by the amelioration of these effects in Ac-YVAD-cmk treated 3T3-L1 cells or primary adipocytes isolated from NLRP3 and caspase-1 knockout mice. Particularly, the adipocyte NLRP3 inflammasome was involved in glucose uptake regulation. Also, TNFα induced expression and secretion of lipocalin 2 (Lcn2) in a NLRP3-dependent manner. NLRP3 could bind to the promoter and transcriptionally regulate Lcn2 in adipocytes. Treatment with adipocyte conditioned media revealed that adipocyte-derived Lcn2 was responsible for macrophage NLRP3 inflammasome activation, working as a second signal. Adipocytes isolated from high-fat diet mice and adipose tissue from obese individuals showed a positive correlation between NLRP3 and Lcn2 gene expression. CONCLUSIONS: This study highlights the importance of adipocyte NLRP3 inflammasome activation and novel role of TNFα-NLRP3-Lcn2 axis in adipose tissue. It adds rational for the current development of NLRP3 inhibitors for treating obesity-induced metabolic diseases.

Structure-Activity Relationships of Truncated 1'-Homologated Carbaadenosine Derivatives as New PPARγ/δ Ligands: A Study on Sugar Puckering Affecting Binding to PPARs.

Peroxisome proliferator-activated receptors (PPARs) are associated with the regulation of metabolic homeostasis. Based on a previous report that 1'-homologated 4'-thionucleoside acts as a dual PPARγ/δ modulator, carbocyclic nucleosides 2-5 with various sugar conformations were synthesized to determine whether sugar puckering affects binding to PPARs. (S)-conformer 2 was synthesized using Charette asymmetric cyclopropanation, whereas (N)-conformer 3 was synthesized using stereoselective Simmons-Smith cyclopropanation. All synthesized nucleosides did not exhibit binding affinity to PPARα but exhibited significant binding affinities to PPARγ/δ. The binding affinity of final nucleosides to PPARγ did not differ significantly based on their conformation, but their affinity to PPARδ depended greatly on their conformation, correlated with adiponectin production. (N)-conformer 3h was discovered to be the most potent PPARδ antagonist with good adiponectin production, which exhibited the most effective activity in inhibiting the mRNA levels of LPS-induced IL-1ß expression in RAW 264.7 macrophages, implicating its anti-inflammatory activity.

Licochalcone A protects against LPS-induced inflammation and acute lung injury by directly binding with myeloid differentiation factor 2 (MD2).

BACKGROUND AND PURPOSE: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a challenging clinical syndrome that leads to various respiratory sequelae and even high mortality in patients with severe disease. The novel pharmacological strategies and therapeutic drugs are urgently needed. Natural products have played a fundamental role and provided an abundant pool in drug discovery. EXPERIMENTAL APPROACH: A compound library containing 160 natural products was used to screen potential anti-inflammatory compounds. Mice with LPS-induced ALI was then used to verify the preventive and therapeutic effects of the selected compounds. KEY RESULTS: Licochalcone A was discovered from the anti-inflammatory screening of natural products in macrophages. A qPCR array validated the inflammation-regulatory effects of licochalcone A and indicated that the potential targets of licochalcone A may be the upstream proteins in LPS pro-inflammatory signalling. Further studies showed that licochalcone A directly binds to myeloid differentiation factor 2 (MD2), an assistant protein of toll-like receptor 4 (TLR4), to block both LPS-induced TRIF- and MYD88-dependent pathways. LEU61 and PHE151 in MD2 protein are the two key residues that contribute to the binding of MD2 to licochalcone A. In vivo, licochalcone A treatment alleviated ALI in LPS-challenged mice through significantly reducing immunocyte infiltration, suppressing activation of TLR4 pathway and inflammatory cytokine induction. CONCLUSION AND IMPLICATIONS: In summary, our study identified MD2 as a direct target of licochalcone A for its anti-inflammatory activity and suggested that licochalcone A might serve as a novel MD2 inhibitor and a potential drug for developing ALI/ARDS therapy.

Schisandrin B protects against LPS-induced inflammatory lung injury by targeting MyD88.

BACKGROUND: Acute lung injury (ALI) is a challenging clinical syndrome that manifests as an acute inflammatory response. Schisandrin B (Sch B), a bioactive lignan from Schisandra genus plants, has been shown to suppress inflammatory responses and oxidative stress. However, the underlying molecular mechanisms have remained elusive. HYPOTHESIS/PURPOSE: This study performed an in-depth investigation of the anti-inflammatory mechanism of Sch B in macrophages and in an animal model of ALI. METHODS: qPCR array was used to probe the differential effects and potential target of Sch B. ALI was induced by intratracheal administration of LPS in experimental mice with or without Sch B treatment. RESULTS: Our studies show that Sch B differentially modulates inflammatory factor induction by LPS in macrophages by directly binding myeloid differentiation response factor-88 (MyD88), an essential adaptor protein in the toll-like receptor-4 (TLR4) pathway. Sch B spares non-MyD88-pathways downstream of TLR4. Such inhibition suppressed key signaling mediators such as TAK1, MAPKs, and NF-κB, and pro-inflammatory factor induction. Pull down assay using biotinylated-Sch B validate the direct interaction between Sch B and MyD88 in macrophages. Treatment of mice with Sch B prior to LPS challenge reduced inflammatory cell infiltration in lungs, induction of MyD88-pathway signaling proteins, and prevented inflammatory cytokine induction. CONCLUSION: In summary, our studies have identified MyD88 as a direct target of Sch B for its anti-inflammatory activity, and suggest that Sch B may have therapeutic value for acute lung injury and other MyD88-dependent inflammatory diseases.

Inhibition of autophagy with chloroquine dysregulates mitochondrial quality control and energetics in adipocytes.

Autophagy is a complex degradation pathway through which damaged or dysfunctional proteins and organelles are removed. Its pharmacological modulators have been extensively used in a wide range of basic research and preclinical studies. However, the effects of these inhibitors on metabolism, in addition to autophagy inhibition, are not fully elucidated. Chloroquine is a clinically relevant compound that inhibits autophagy by preventing the fusion of autophagosomes with lysosomes. In this study, we aimed to examine the effect of chloroquine on mitochondrial quality control and respiratory function by utilizing 3T3-L1 mouse adipocytes treated with chloroquine at various time points. We found that chloroquine could disturb genes related to mitochondrial fission, biogenesis, and mitophagy, leading to mitochondrial DNA damage. Although the inhibition of autophagy by chloroquine resulted in an increased prohibitin expression, respiratory function was downregulated in a time-dependent manner. Moreover, chloroquine treatment induced oxidative stress, apoptosis, and metabolic dysregulation. These data demonstrated that chloroquine significantly affected mitochondrial respiratory function and metabolism, which was consistent with impaired mitochondrial quality associated with autophagy inhibition.

Gasdermin D Deficiency Does Not Protect Mice from High-Fat Diet-Induced Glucose Intolerance and Adipose Tissue Inflammation.

The adipose tissue NLRP3 inflammasome has recently emerged as a contributor to obesity-related metabolic inflammation. Recent studies have demonstrated that the activation of the NLRP3 inflammasome cleaves gasdermin D (GSDMD) and induces pyroptosis, a proinflammatory programmed cell death. However, whether GSDMD is involved in the regulation of adipose tissue function and the development of obesity-induced metabolic disease remains unknown. The aim of the present study was to investigate the role of GSDMD in adipose tissue inflammation as well as whole-body metabolism using GSDMD-deficient mice fed a high-fat diet (HFD) for 30 weeks. The effects of GSDMD deficiency on adipose tissue, liver, and isolated macrophages from wild-type (WT) and GSDMD knockout (KO) mice were examined. In addition, 3T3-L1 cells were used to examine the expression of GSDMD during adipogenesis. The results demonstrate that although HFD-induced inflammation was partly ameliorated in isolated macrophages and liver, adipose tissue remained unaffected by GSDMD deficiency. Compared with the WT HFD mice, GSDMD KO HFD mice exhibited a mild increase in HFD-induced glucose intolerance with increased systemic and adipose tissue IL-1ß levels. Interestingly, GSDMD deficiency caused accumulation of fat mass when challenged with HFD, partly by suppressing the expression of peroxisome proliferator-activated receptor gamma (PPARγ). The expression of GSDMD mRNA and protein was dramatically suppressed during adipocyte differentiation and was inversely correlated with PPARγ expression. Together, these findings indicate that GSDMD is not a prerequisite for HFD-induced adipose tissue inflammation and suggest a noncanonical function of GSDMD in regulation of fat mass through PPARγ.

Bacterial Toxin-Responsive Biomimetic Nanobubbles for Precision Photodynamic Therapy against Bacterial Infections.

With few options available for the effective treatment of multidrug-resistant bacteria, photodynamic therapy (PDT) has emerged as a promising therapeutic strategy that does not promote the development of antibiotic resistance. Unfortunately, the beneficial bactericidal effect of PDT is oftentimes accompanied by the uncontrollable production of reactive oxygen species. To overcome this issue, a pore-forming toxin (PFT)-responsive biomimetic nanobubble is designed, which is constructed by co-encapsulating a perfluorocarbon nanoemulsion and a photosensitizer within the red blood cell membrane. It is shown that PFTs derived from three pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), group A Streptococcus (GAS), and Listeria monocytogenes (LM), can be effectively absorbed by the nanobubble. Upon toxin absorption, the formation of pores on the nanobubble surface allows the accelerated release of oxygen dissolved inside the nanoemulsion along with the photosensitizer, thus resulting in enhanced PDT and bactericidal efficacy. In three skin infection models, treatment with the nanobubbles results in significantly decreased lesion formation and reduced inflammation. In addition to oxygen, the platform can be used to deliver nitric oxide in a bacterial toxin-dependent manner. Overall, biomimetic nanobubbles may work as a broad gas delivery system that is capable of responding to a variety of PFT-based stimuli for precision PDT.

Toxin-Enabled "On-Demand" Liposomes for Enhanced Phototherapy to Treat and Protect against Methicillin-Resistant Staphylococcus aureus Infection.

An effective therapeutic strategy against methicillin-resistant Staphylococcus aureus (MRSA) that does not promote further drug resistance is highly desirable. While phototherapies have demonstrated considerable promise, their application toward bacterial infections can be limited by negative off-target effects to healthy cells. Here, a smart targeted nanoformulation consisting of a liquid perfluorocarbon core stabilized by a lipid membrane coating is developed. Using vancomycin as a targeting agent, the platform is capable of specifically delivering an encapsulated photosensitizer along with oxygen to sites of MRSA infection, where high concentrations of pore-forming toxins trigger on-demand payload release. Upon subsequent near-infrared irradiation, local increases in temperature and reactive oxygen species effectively kill the bacteria. Additionally, the secreted toxins that are captured by the nanoformulation can be processed by resident immune cells to promote multiantigenic immunity that protects against secondary MRSA infections. Overall, the reported approach for the on-demand release of phototherapeutic agents into sites of infection could be applied against a wide range of high-priority pathogens.

Exercise-Induced Irisin Decreases Inflammation and Improves NAFLD by Competitive Binding with MD2.

Non-alcoholic fatty liver disease (NAFLD) is a global clinical problem. The MD2-TLR4 pathway exacerbates NAFLD progression by promoting inflammation. Long-term exercise is considered to improve NAFLD but the underlying mechanism is still unclear. In this study, we examined the protective effect and molecular mechanism of exercise on high-fat diet (HFD)-induced liver injury. In an HFD-induced NAFLD mouse model, exercise training significantly decreased hepatic steatosis and fibrosis. Interestingly, exercise training blocked the binding of MD2-TLR4 and decreased the downstream inflammatory response. Irisin is a myokine that is highly expressed in response to exercise and exerts anti-inflammatory effects. We found that circulating irisin levels and muscle irisin expression were significantly increased in exercised mice, suggesting that irisin could mediate the effect of exercise on NAFLD. In vitro studies showed that irisin improved lipid metabolism, fibrosis, and inflammation in palmitic acid (PA)-stimulated AML12 cells. Moreover, binding assay results showed that irisin disturbed MD2-TLR4 complex formation by directly binding with MD2 but not TLR4, and interfered with the recognition of stimuli such as PA and lipopolysaccharide with MD2. Our study provides novel evidence that exercise-induced irisin inhibits inflammation via competitive binding with MD2 to improve NAFLD. Thus, irisin could be considered a potential therapy for NAFLD.

Exercise Inhibits NLRP3 Inflammasome Activation in Obese Mice via the Anti-Inflammatory Effect of Meteorin-like.

Obesity is associated with chronic low-grade inflammation. The benefits of exercise are partly attributed to its anti-inflammatory effect, but whether exercise can regulate NLRP3 inflammasome activation in obese adipose tissue remains unknown. Meteorin-like (METRNL), a recently discovered myokine, has been implicated in mediating the effect of exercise on metabolism. Herein, we examined the effect of exercise and METRNL on NLRP3 inflammasome activation. High-fat diet (HFD)-induced obese mice were subjected to treadmill exercise for 8 weeks. A subgroup of HFD mice was switched to normal chow with the exercise intervention. Exercise and diet attenuated weight gain, fat accumulation, and insulin resistance in obese mice. In addition, exercise downregulated gene and protein levels of inflammasome markers, including NLRP3 and caspase-1, in adipose tissue. In isolated bone marrow-derived macrophages, activation of NLRP3 inflammasome was suppressed in the exercise group, as confirmed by the downregulation of IL-1ß and IL-18. Exercise significantly enhanced the expression of METRNL in various muscle depots, and further in vitro analysis revealed that recombinant METRNL treatment inhibited IL-1ß secretion in macrophages. In conclusion, exercise exerts its anti-inflammatory action by suppressing adipose tissue NLRP3 inflammasome, and this is, in part, associated with METRNL induction in muscle and its anti-inflammatory effects in macrophages.

Associations of Circulating Irisin with FNDC5 Expression in Fat and Muscle in Type 1 and Type 2 Diabetic Mice.

Irisin is an exercise-induced myokine, suggested to exert beneficial effects on metabolism. However, the studies on the regulation of irisin secretion and the expression of its precursor FNDC5 have shown conflicting data. The discrepancies among previous correlation studies in humans are related to the heterogeneity of the study population. The fact that irisin is not only a myokine but also an adipokine leads to the further complexity of the role of irisin in metabolic regulation. In this study, we examined the regulation of FNDC5 expression and irisin in circulation in both type 1 and type 2 diabetic mice, and their potential relationships with metabolic parameters. In streptozotocin (STZ)-induced type 1 diabetic mice, high-fat diet (HFD)-induced obese mice and db/db mice, the circulating irisin as well as FNDC5 gene expression in subcutaneous fat was downregulated. Muscle FNDC5 expression was only significantly lower in STZ mice, and epididymal fat FNDC5 expression was unaltered. It is interesting to note that plasma irisin levels correlated positively with subcutaneous fat FNDC5 expression, but not epididymal fat or muscle. Moreover, both irisin levels and subcutaneous fat FNDC5 correlated negatively with markers of insulin resistance. These results suggest a regulatory role for subcutaneous fat-derived FNDC5/irisin in metabolic disease.

Fibroblast growth factor 2 exacerbates inflammation in adipocytes through NLRP3 inflammasome activation.

Chronic inflammation in adipose tissue is the hallmark of obesity and a major risk factor for the development of obesity-induced insulin resistance. NLRP3 inflammasome regulates the maturation and secretion of pro-inflammatory cytokines, such as IL-1ß and IL-18, and was recently discovered to be involved in obesity-related metabolic diseases. Fibroblast growth factors (FGFs) such as FGF1, FGF10, and FGF21 are adipokines that regulate adipocyte development and metabolism, but reports on the effect of other FGFs on adipocytes are lacking. In the present study, the novel role of FGF2 in NLRP3 inflammasome activation was elucidated. Our results showed that FGF2 levels were increased during adipocyte differentiation and in the adipose tissue of high-fat diet (HFD)-induced obese mice. Recombinant FGF2 treatment upregulated inflammasome markers such as NLRP3, which was further exaggerated by TNF-ɑ treatment. Interestingly, ß-Klotho, a co-receptor of FGF21, was significantly decreased by FGF2 treatment. Results from mice confirmed the positive correlation between FGF2 and NLRP3 expression in epididymal and subcutaneous adipose tissue, while exercise training effectively reversed HFD-induced NLRP3 expression as well as FGF2 levels in both adipose depots. Our results suggest that FGF2 is an adipokine that may exacerbate the inflammatory response in adipocytes through NLRP3 inflammasome activation.

The Effects of Triterpenoid Saponins from the Seeds of Momordica cochinchinensis on Adipocyte Differentiation and Mature Adipocyte Inflammation.

Obesity is a medical condition in which abnormal or excessive fat accumulates to an extent that is associated with various diseases. In our ongoing research to figure out natural products with anti-obesity effects, a phytochemical investigation of the EtOH extract of the seeds of Momordica cochinchinensis was carried out, which resulted in the isolation of two major triterpenoid saponins: gypsogenin 3-O-ß-d-galactopyranosyl(1→2)-[α-l-rhamnopyranosyl (1→3)]-ß-d-glucuronopyranoside (1) and quillaic acid 3-O-ß-d-galactopyranosyl(1→2)-[α-l-rhamnopyranosyl(1→3)]-ß-d-glucuronopyranoside (2). Then, the effects of the isolated triterpenoid saponins (1 and 2) on adipocyte differentiation were evaluated, and it was demonstrated that the isolated saponin (1) showed inhibitory effects on adipogenesis. In mature adipocytes, the isolated saponin (1) reversed tumor necrosis factor α (TNFα)-induced proinflammatory cytokine gene expression. Additionally, the isolated saponin (1) reduced lipolytic gene expression leading to decreased basal lipolysis activity. Collectively, these findings suggest that saponin (1) of M. cochinchinensis exerts beneficial effects in the regulation of adipogenesis and adipocyte inflammation and could be a potential therapeutic alternative in the treatment of obesity-induced metabolic diseases.

Bio-transformation of green tea infusion with tannase and its improvement on adipocyte metabolism.

Catechins in green tea possess various health benefits. Enzymatic treatment improves physiological activities by inducing bioconversion of catechins. Here, we investigated the effect of green tea infusion (GT) after tannase treatment, which transforms (-)-epigallocatechin gallate (EGCG) to gallic acid (GA) and (-)-epigallocatechin (EGC), on adipocyte differentiation and mature adipocyte metabolism. The optimal conditions for tannase-mediated improvement in GA and EGC yields in GT were investigated using response surface methodology. Yields of GA and EGC were 43-fold (0.43 mg/mL) and 1.66-fold higher (1.11 mg/mL), respectively, compared to GT without tannase treatment. The optimal reaction conditions for tannase-mediated biotransformation were observed on 0.54 mg mL-1 of tannase, reaction time (86.79 min), and reaction temperature at 22.59 °C. GT and tannase-treated GT (TANs) upregulated adiponectin, uncoupling protein 1, adipose triglyceride lipase, and hormone-sensitive lipase gene expression in differentiated 3T3-L1 adipocytes, with TAN inducing better effects than GT, which implies that tannase treatment improved the beneficial effect of GT on adipocyte metabolism. Thus, tannase-mediated bio-transformation is an attractive candidate for preparing GT with enhanced anti-obesity properties.

Irisin Exerts Inhibitory Effect on Adipogenesis Through Regulation of Wnt Signaling.

Irisin is an exercise-induced myokine known to induce adipocyte browning through induction of uncoupling protein 1. Recent studies have reported that irisin is also an adipokine. However, there is limiting evidence on the role of endogenous irisin from adipocytes. In this study we aim to elucidate the expression and secretion pattern of irisin during adipocyte differentiation and the role of endogenous and exogenous irisin on the adipogenic process. As such, recombinant irisin, plasmid expressing FNDC5 and small interfering RNA were utilized. Our results show that the gene expression of irisin precursor FNDC5 and irisin secretion increases at the early stage of adipogenesis. Both recombinant irisin treated cells and FNDC5-overexpressed cells resulted in inhibition of adipogenesis evidenced by downregulated C/EBPα, PPARγ, and FABP4 expression and reduced lipid accumulation. Further data showed that the inhibitory effect of irisin on adipogenesis is mediated though potentiation of Wnt expression, which is known to determine the fate of mesenchymal stem cells and regulate adipogenesis. Conversely, FNDC5 knockdown cells showed downregulated Wnt expression, but failed to further induce adipogenesis. This study suggests that both exogenous and endogenous irisin is able to inhibit adipogenesis and that activation of Wnt and subsequent repression of transcription factors is partly involved in this process. This provides a novel insight on the local effect of irisin on adipocytes and additional benefit to protect against obesity-related metabolic disorders.

Epigallocatechin Exerts Anti-Obesity Effect in Brown Adipose Tissue.

Catechins in green tea are well-known to be effective in reducing the risk of obesity. The purpose of this study was to elucidate the effects of catechins present in green tea on adipocyte differentiation and mature adipocyte metabolism. Treatment of 3T3-L1 mouse adipocyte during differentiation adipocytes with (-)-epigallocatechin (EGC) and gallic acid (GA) resulted in dose-dependent inhibition of adipogenesis. Specifically, EGC increased adiponectin and uncoupling protein 1 (UCP1) transcription in mature adipocytes. Transcription levels of adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) were not significantly impacted by either of the compounds. These results suggest that the EGC is the most effective catechin having anti-obesity activity. Finally, EGC is an attractive candidate component for remodeling obesity.

Network-based integrated analysis of omics data reveal novel players of TGF-ß1-induced EMT in human peritoneal mesothelial cells.

Long-term peritoneal dialysis is associated with progressive fibrosis of the peritoneum. Epithelial-mesenchymal transition (EMT) of mesothelial cells is an important mechanism involved in peritoneal fibrosis, and TGF-ß1 is considered central in this process. However, targeting currently known TGF-ß1-associated pathways has not proven effective to date. Therefore, there are still gaps in understanding the mechanisms underlying TGF-ß1-associated EMT and peritoneal fibrosis. We conducted network-based integrated analysis of transcriptomic and proteomic data to systemically characterize the molecular signature of TGF-ß1-stimulated human peritoneal mesothelial cells (HPMCs). To increase the power of the data, multiple expression datasets of TGF-ß1-stimulated human cells were employed, and extended based on a human functional gene network. Dense network sub-modules enriched with differentially expressed genes by TGF-ß1 stimulation were prioritized and genes of interest were selected for functional analysis in HPMCs. Through integrated analysis, ECM constituents and oxidative stress-related genes were shown to be the top-ranked genes as expected. Among top-ranked sub-modules, TNFAIP6, ZC3H12A, and NNT were validated in HPMCs to be involved in regulation of E-cadherin, ZO-1, fibronectin, and αSMA expression. The present data shows the validity of network-based integrated analysis in discovery of novel players in TGF-ß1-induced EMT in peritoneal mesothelial cells, which may serve as new prognostic markers and therapeutic targets for peritoneal dialysis patients.

Integrative Omics Reveals Metabolic and Transcriptomic Alteration of Nonalcoholic Fatty Liver Disease in Catalase Knockout Mice.

The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased with the incidence of obesity; however, the underlying mechanisms are unknown. In this study, high-resolution metabolomics (HRM) along with transcriptomics were applied on animal models to draw a mechanistic insight of NAFLD. Wild type (WT) and catalase knockout (CKO) mice were fed with normal fat diet (NFD) or high fat diet (HFD) to identify the changes in metabolic and transcriptomic profiles caused by catalase gene deletion in correspondence with HFD. Integrated omics analysis revealed that cholic acid and 3ß, 7α-dihydroxy-5-cholestenoate along with cyp7b1 gene involved in primary bile acid biosynthesis were strongly affected by HFD. The analysis also showed that CKO significantly changed all-trans-5,6-epoxy-retinoic acid or all-trans-4-hydroxy-retinoic acid and all-trans-4-oxo-retinoic acid along with cyp3a41b gene in retinol metabolism, and α/γ-linolenic acid, eicosapentaenoic acid and thromboxane A2 along with ptgs1 and tbxas1 genes in linolenic acid metabolism. Our results suggest that dysregulated primary bile acid biosynthesis may contribute to liver steatohepatitis, while up-regulated retinol metabolism and linolenic acid metabolism may have contributed to oxidative stress and inflammatory phenomena in our NAFLD model created using CKO mice fed with HFD.