Obesity leads to multiple health problems, including diabetes, fatty liver, and even cancer. Here, we report that urolithin A (UA), a gut-microflora-derived metabolite of pomegranate ellagitannins (ETs), prevents diet-induced obesity and metabolic dysfunctions in mice without causing adverse effects. UA treatment increases energy expenditure (EE) by enhancing thermogenesis in brown adipose tissue (BAT) and inducing browning of white adipose tissue (WAT). Mechanistically, UA-mediated increased thermogenesis is caused by an elevation of triiodothyronine (T3) levels in BAT and inguinal fat depots. This is also confirmed in UA-treated white and brown adipocytes. Consistent with this mechanism, UA loses its beneficial effects on activation of BAT, browning of white fat, body weight control, and glucose homeostasis when thyroid hormone (TH) production is blocked by its inhibitor, propylthiouracil (PTU). Conversely, administration of exogenous tetraiodothyronine (T4) to PTU-treated mice restores UA-induced activation of BAT and browning of white fat and its preventive role on high-fat diet (HFD)-induced weight gain. Together, these results suggest that UA is a potent antiobesity agent with potential for human clinical applications.
Allicin, naturally present in the bulbs of the lily family, has anticancer, blood pressure lowering, blood fat lowering and diabetes improving effects. Recent studies have shown that allicin promotes the browning of white adipocytes and reduces the weight gain of mice induced by high-fat diet. While the gut microbiota has a strong relationship with obesity and energy metabolism, the effect of allicin on weight loss via gut microorganisms is still unclear. In this study, we treated obese mice induced by high-fat diet with allicin to determine its effects on fat deposition, blood metabolic parameters and intestinal morphology. Furthermore, we used high-throughput sequencing on a MiSeq Illumina platform to determine the gut microorganisms’ species. We found that allicin significantly reduced the weight gain of obese mice by promoting lipolysis and thermogenesis, as well as blood metabolism and intestinal morphology, and suppressing hepatic lipid synthesis and transport. In addition, allicin changed the composition of the intestinal microbiota and increased the proportion of beneficial bacteria. In conclusion, our study showed that allicin improves metabolism in high-fat induced obese mice by modulating the gut microbiota. Our findings provide a theoretical basis for further elucidation of the weight loss mechanism of allicin.
Fermented corn-soybean meal (fermented feed, FF) is commonly used in swine production, but the effects of FF on gut health remain unclear. In this study, serum immunity, mRNA abundances of antimicrobial peptides (AMPs) and Toll-like receptors (TLR1-9), bacterial abundance in the duodenum and colon, and colonic metabolic phenotypes were determined in crossbred barrows (Duroc × Landrace × Large White) fed FF or normal feed (unfermented feed, UF) (n = 6). When compared to the UF group, the results showed that serum levels of IgG and IgM were significantly increased in FF group pigs (P < 0.05). FF significantly decreased the abundances of Bacteroides and Verrucomicrobia in the duodenum and decreased the abundances of Bacteroides, Proteobacteria, and Verrucomicrobia in the colon while it significantly increased the abundances of Firmicutes and Actinobacteria (P < 0.05). Furthermore, a Spearman’s correlation analysis showed that serum immunity and the expression of genes related to gut immunity were associated with bacterial strains at the family level. Moreover, differentially abundant colonic microbiota were associated with colonic metabolites. LC-MS data analyses identified a total of 1,351 metabolites that markedly differed between the UF and FF groups. C5-Branched dibasic acid metabolism was significantly upregulated whereas the purine metabolism was significantly downregulated (P < 0.05) in the colonic digesta of pigs in the FF meal group compared to the UF meal group. Collectively, these results indicated that FF meal could influence serum immunity and the expression of genes related to gut immunity, correlating with the gut microbiota and bacterial metabolites in grower-finisher pigs. This study may provide an alternative strategy for improving the intestinal health of grower-finisher pigs.
The prevalence of obesity has increased dramatically worldwide in the past ~50 years. Searching for safe and effective anti-obesity strategies are urgently needed. Lactucin, a plant-derived natural small molecule, is known for anti-malaria and anti-hyperalgesia. The study is to investigate whether lactucin plays a key role in adipogenesis. To this end, in vivo male C57BL/6 mice fed a high-fat diet (HFD) were treated with 20 mg/kg/day of lactucin or vehicle by gavage for seven weeks. Compared with vehicle-treated controls, Lactucin-treated mice showed lower body mass and mass of adipose tissue. Consistently, in vitro 3T3-L1 cells were treated with 20 μM of lactucin. Compared to controls, lactucin-treated cells showed significantly less lipid accumulation during adipocyte differentiation and lower levels of lipid synthesis markers. Mechanistically, we showed the anti-adipogenic property of lactucin was largely limited to the early stage of adipogenesis. Lactucin-treated cells fail to undergo mitotic clonal expansion (MCE). Further studies demonstrate that lactucin-induced MCE arrests might result from reduced phosphorylation of JAK2 and STAT3. We then asked whether activation of JAK2/STAT3 would restore the inhibitory effect of lactucin on adipogenesis with pharmacological STAT3 activator colivelin. Our results revealed similar levels of lipid accumulation between lactucin-treated cells and controls in the presence of colivelin, indicating that inactivation of STAT3 is the limiting factor for the anti-adipogenesis of lactucin in these cells. Together, our results provide the indication that lactucin exerts an anti-adipogenesis effect, which may open new therapeutic options for obesity.
Genetic variants in the asialoglycoprotein receptor 1 (ASGR1) are associated with a reduced risk of cardiovascular disease (CVD) in humans. However, the underlying molecular mechanism remains elusive. Given the cardiovascular similarities between pigs and humans, we generated ASGR1-deficient pigs using the CRISPR/Cas9 system. These pigs show age-dependent low levels of non-HDL-C under standard diet. When received an atherogenic diet for 6 months, ASGR1-deficient pigs show lower levels of non-HDL-C and less atherosclerotic lesions than that of controls. Furthermore, by analysis of hepatic transcriptome and in vivo cholesterol metabolism, we show that ASGR1 deficiency reduces hepatic de novo cholesterol synthesis by downregulating 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and increases cholesterol clearance by upregulating the hepatic low-density lipoprotein receptor (LDLR), which together contribute to the low levels of non-HDL-C. Despite the cardioprotective effect, we unexpectedly observed mild to moderate hepatic injury in ASGR1-deficient pigs, which has not been documented in humans with ASGR1 variants. Thus, targeting ASGR1 might be an effective strategy to reduce hypercholesterolemia and atherosclerosis, whereas further clinical evidence is required to assess its hepatic impact.
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