Yonggong Zhai

Melatonin prevents obesity through modulation of gut microbiota in mice.

Excess weight and obesity are severe public health threats worldwide. Recent evidence demonstrates that gut microbiota dysbiosis contributes to obesity and its comorbidities. The body weight‐reducing and energy balancing effects of melatonin have been reported in several studies, but to date, no investigations toward examining whether the beneficial effects of melatonin are associated with gut microbiota have been carried out. In this study, we show that melatonin reduces body weight, liver steatosis, and low‐grade inflammation as well as improving insulin resistance in high fat diet (HFD)‐fed mice. High‐throughput pyrosequencing of the 16S rRNA demonstrated that melatonin treatment significantly changed the composition of the gut microbiota in mice fed an HFD. The richness and diversity of gut microbiota were notably decreased by melatonin. HFD feeding altered 69 operational taxonomic units (OTUs) compare with a normal chow diet (NCD) group, and melatonin supplementation reversed 14 OTUs to the same configuration than those present in the NCD group, thereby impacting various functions, in particular through its ability to decrease the Firmicutes‐to‐Bacteroidetes ratio and increase the abundance of mucin‐degrading bacteria Akkermansia, which is associated with healthy mucosa. Taken together, our results suggest that melatonin may be used as a probiotic agent to reverse HFD‐induced gut microbiota dysbiosis and help us to gain a better understanding of the mechanisms governing the various melatonin beneficial effects.

Microbiome Remodeling via the Montmorillonite Adsorption-Excretion Axis Prevents Obesity-related Metabolic Disorders

Obesity and its related metabolic disorders are closely correlated with gut dysbiosis. Montmorillonite is a common medicine used to treat diarrhea. We have previously found that dietary lipid adsorbent-montmorillonite (DLA-M) has an unexpected role in preventing obesity. The aim of this study was to further investigate whether DLA-M regulates intestinal absorption and gut microbiota to prevent obesity-related metabolic disorders. Here, we show that DLA-M absorbs free fatty acids (FFA) and endotoxins in vitro and in vivo. Moreover, the combination of fluorescent tracer technique and polarized light microscopy showed that DLA-M crystals immobilized BODIPY® FL C16 and FITC-LPS, respectively, in the digestive tract in situ. HFD-fed mice treated with DLA-M showed mild changes in the composition of the gut microbiota, particularly increases in short-chain fatty acids (SCFA)-producing Blautia bacteria and decreases in endotoxin-producing Desulfovibrio bacteria, these changes were positively correlated with obesity and inflammation. Our results indicated that DLA-M immobilizes FFA and endotoxins in the digestive tract via the adsorption-excretion axis and DLA-M may potentially be used as a prebiotic to prevent intestinal dysbiosis and obesity-associated metabolic disorders in obese individuals.

Preventive obesity agent montmorillonite adsorbs dietary lipids and enhances lipid excretion from the digestive tract.

Western diets are typically high in fat and are associated with long-term complications such as obesity and hepatic steatosis. Because of the enjoyable taste of high-fat diets (HFDs), we are interested in determining how to decrease lipid absorption and enhance lipid excretion from the digestive tract after the consumption of eating fatty foods. Montmorillonite was initially characterized as a gastrointestinal mucosal barrier protective agent for the treatment of diarrhoea. Dietary lipid adsorbent- montmorillonite (DLA-M) was isolated and purified from Xinjiang montmorillonite clay via the water extraction method. Here, we show that DLA-M has an unexpected role in preventing obesity, hyperlipidaemia and hepatic steatosis in HFD-fed rats. Interestingly, combined application of polarized light microscopy and lipid staining analyses, showed that DLA-M crystals have dietary lipid-adsorbing ability in vitro and in vivo, which enhances lipid excretion via bowel movements. In summary, our results indicate that DLA-M prevent HFD-induced obesity. This novel dietary lipid-adsorbing agent can help prevent obesity and its comorbidities.

DBZ blocks LPS-induced monocyte activation and foam cell formation via inhibiting nuclear factor-ĸB.

Background/Aims: It has been widely accepted that chronic inflammation plays important roles in the atherogenesis. Danshensu Bingpian Zhi (DBZ) is a novel synthetic compound derived from the traditional Chinese medicine (TCM) formula Fu Fang Dan Shen (FFDS), which is effective on atherosclerosis clinically. We hypothesized that DBZ possessed the anti-atherosclerosis potentials. Here, we examined the inhibitory effects of DBZ on LPS-induced monocyte activation and foam cell formation. Methods: The effects of DBZ were assessed on LPS-induced inflammatory factors expression in monocyte/macrophage. Activation of NF-ĸB and AP-1 was analyzed by luciferase reporter assay and signaling pathway of NF-ĸB was investigated to elucidate mechanisms underlying DBZ mediated anti-inflammatory activity. Effects of DBZ on macrophage lipid accumulation were evaluated in native LDL and LPS co-incubated macrophages. Results: DBZ inhibited LPS-induced inflammatory factors expression dose dependently in monocytes. DBZ inhibited NF-ĸB activation strongly and AP-1 slightly. DBZ suppressed the LPS-induced degradation of IĸBα, thereby decreasing the translocation of p65 to nucleus. Furthermore, DBZ suppressed LPS-activated macrophages lipid accumulation, partly due to inhibiting the expression of LPS-induced aP2 and ADRP in macrophges. Conclusion: These results demonstrate that DBZ has potentials on anti-atherosclerosis by suppressing monocyte activation and foam cell formation.

RORα inhibits adipocyte-conditioned medium-induced colorectal cancer cell proliferation and migration and chick embryo chorioallantoic membrane angiopoiesis

Lipid metabolic disturbances are related to many diseases, such as obesity, diabetes, and certain cancers. Notably, lipid metabolic disturbances have been reported to be a risk factor for colorectal cancer. Nuclear receptors act as ligand-dependent transcription regulators and play key roles in the regulation of body lipid metabolism and the development of many cancers. Retinoic acid receptor-related orphan receptor α (RORα) is a nuclear receptor and can regulate several lipid metabolism genes in certain cancers. Herein, we demonstrate that the conditioned medium from adipocytes has a proproliferative and promigratory effect on colorectal cancer cells and enhances angiogenesis in chicken embryonic chorioallantoic membranes. In addition, the conditioned medium leads to a decrease in the expression of RORα and its target genes. Meanwhile, RORα and its target gene expressions are lower in human colorectal tumor tissue compared with control colorectal tissue. Activation of RORα inhibits the effect of conditioned medium on the proliferation and migration of colorectal cancer cells as well as the angiogenesis in chicken embryonic allantoic membranes. In colorectal cancer cells, the putative ligand of RORα, cholesterol sulfate (CS), prevents cell cycle progression at the G1/S boundary and concurrently modulates the expression of cell cycle-regulatory genes in colorectal cancer cell. CS inhibits angiogenesis in chicken embryonic chorioallantoic membranes and concurrently decreases the mRNA expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α as well as the secretion of VEGF. In addition, lipogenic gene expression is higher in human colorectal tumor tissue compared with control colorectal tissue. CS inhibits the expression of lipogenic genes in colorectal cancer cells. These results suggest that RORα could represent a direct link between local lipid metabolism of colorectal tissue and colorectal cancer. Therefore, the reduction of the expression of RORα could represent a potential warning sign of colorectal cancer.

DBZ is a putative PPARγ agonist that prevents high fat diet-induced obesity, insulin resistance and gut dysbiosis

BACKGROUNDnThe nuclear receptor PPARγ is an effective pharmacological target for some types of metabolic syndrome, including obesity, diabetes, nonalcoholic fatty liver disease, and cardiovascular disease. However, the current PPARγ-targeting thiazolidinedione drugs have undesirable side effects. Danshensu Bingpian Zhi (DBZ), also known as tanshinol borneol ester derived from Salvia miltiorrhiza, is a synthetic derivative of natural compounds used in traditional Chinese medicine for its anti-inflammatory activity.nnnMETHODSnIn vitro, investigations of DBZ using a luciferase reporter assay and molecular docking identified this compound as a novel promising PPARγ agonist. Ten-week-old C57BL/6J mice were fed either a normal chow diet (NCD) or a high-fat diet (HFD). The HFD-fed mice were gavaged daily with either vehicle or DBZ (50mg/kg or 100mg/kg) for 10weeks. The gut microbiota composition was assessed by analyzing the 16S rRNA gene V3+V4 regions via pyrosequencing.nnnRESULTSnDBZ is an efficient natural PPARγ agonist that shows lower PPARγ-responsive luciferase reporter activity than thiazolidinediones, has excellent effects on the metabolic phenotype and exhibits no unwanted adverse effects in a HFD-induced obese mouse model. DBZ protects against HFD-induced body weight gain, insulin resistance, hepatic steatosis and inflammation in mice. DBZ not only stimulates brown adipose tissue (BAT) browning and maintains intestinal barrier integrity but also reverses HFD-induced intestinal microbiota dysbiosis.nnnCONCLUSIONSnDBZ is a putative PPARγ agonist that prevents HFD-induced obesity-related metabolic syndrome and reverse gut dysbiosis.nnnGENERAL SIGNIFICANCEnDBZ may be used as a beneficial probiotic agent to improve HFD-induced obesity-related metabolic syndrome in obese individuals.

DBZ (Danshensu Bingpian Zhi), a Novel Natural Compound Derivative, Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice

Background DBZ (Danshensu Bingpian Zhi), a synthetic derivative of a natural compound found in traditional Chinese medicine, has been reported to suppress lipopolysaccharide‐induced macrophage activation and lipid accumulation in vitro. The aim of this study was to assess whether DBZ could attenuate atherosclerosis at early and advanced stages. Methods and Results The effects of DBZ on the development of atherosclerosis were studied using apolipoprotein E–deficient (apoE−/−) mice. For early treatment, 5‐week‐old apoE−/− mice were fed a Western diet and treated daily by oral gavage with or without DBZ or atorvastatin for 10 weeks. For advanced treatment, 5‐week‐old apoE−/− mice were fed a Western diet for 10 weeks to induce atherosclerosis, and then they were randomly divided into 4 groups and subjected to the treatment of vehicle, 20 mg/kg per day DBZ, 40 mg/kg per day DBZ, or 10 mg/kg per day atorvastatin for the subsequent 10 weeks. We showed that early treatment of apoE−/− mice with DBZ markedly reduced atherosclerotic lesion formation by inhibiting inflammation and decreasing macrophage infiltration into the vessel wall. Treatment with DBZ also attenuated the progression of preestablished diet‐induced atherosclerotic plaques in apoE−/− mice. In addition, we showed that DBZ may affect LXR (liver X receptor) function and that treatment of macrophages with DBZ suppressed lipopolysaccharide‐stimulated cell migration and oxidized low‐density lipoprotein–induced foam cell formation. Conclusions DBZ potentially has antiatherosclerotic effects that involve the inhibition of inflammation, macrophage migration, leukocyte adhesion, and foam cell formation. These results suggest that DBZ may be used as a therapeutic agent for the prevention and treatment of atherosclerosis.

Mature adipocytes observed to undergo reproliferation and polyploidy

Lipid‐filled mature adipocytes are important for the study of lipid metabolism and in the development of obesity, but whether they are capable of reproliferation is still controversial. Here, we monitored lipid droplet dynamics and adipocyte reproliferation in live, differentiated 3T3‐L1 cells using a phase‐contrast microscope in real time. Phase‐contrast microscopy achieves a similar visual effect in situ to that obtained using traditional dyes such as Oil Red O and BODIPY in vitro. Using this method, we captured the process that lipid droplets use for dynamic fusion in living cells. Unexpectedly, we acquired images of the moment that differentiated 3T3‐L1 cells containing lipid droplets entered mitosis. In addition, we observed some binucleated mature adipocytes. This information provides a better understanding of the adipocyte differentiation process.

The CAR agonist TCPOBOP inhibits lipogenesis and promotes fibrosis in the mammary gland of adolescent female mice

Constitutive androstane receptor (CAR) is a nuclear receptor that not only regulates drug-metabolizing enzymes but also influences energy metabolism. TC, 1, 4-bis [2-(3, 5-dichloropyridyloxy)] benzene (TCPOBOP) has been shown to inhibit lipogenesis in the liver and adipose tissues. The mammary gland is mainly composed of fat pads and duct systems in adolescent female mice. Here, activation of CAR by TC reduces the mammary gland weight, blocks lipid accumulation by inhibiting lipogenesis and gluconeogenesis, and accelerates collagen formation and fibrosis in the mammary fat pad of adolescent female mice. This information provides a reference for CAR activation, which may affect mammary gland development in adolescent females.

The Role of PPAR and Its Cross-Talk with CAR and LXR in Obesity and Atherosclerosis

The prevalence of obesity and atherosclerosis has substantially increased worldwide over the past several decades. Peroxisome proliferator-activated receptors (PPARs), as fatty acids sensors, have been therapeutic targets in several human lipid metabolic diseases, such as obesity, atherosclerosis, diabetes, hyperlipidaemia, and non-alcoholic fatty liver disease. Constitutive androstane receptor (CAR) and liver X receptors (LXRs) were also reported as potential therapeutic targets for the treatment of obesity and atherosclerosis, respectively. Further clarification of the internal relationships between these three lipid metabolic nuclear receptors is necessary to enable drug discovery. In this review, we mainly summarized the cross-talk of PPARs-CAR in obesity and PPARs-LXRs in atherosclerosis.