| ObjectiveIn accompany with the improved nutritional standards and altered life styles of humans, overweight and obese populations throughout the world are gradually overwhelming, and obesity-originated health and societal issues become more and more severe. How to reduce body weight and prevent the obesity-related diseases remains the most concerned topics and hot-spots under investigations. The present study intends to validate our suggested "chronic low-grade inflammation is originated from trace bacterial endotoxin" hypothesis by comparing the noninflammatory and inflammatory mouse obese models induced by high-fat (HF)+high-dose lipopolysaccharide (LPS) and HF +low-dose LPS. Furthermore, the therapeutic effects of monomer and compound medicines with weight-reducing potentials will be evaluated, and their mechanisms of action will be also elucidated in order to access a possibility of dieting-mimic calorie non-restriction anti-inflammatory weight reduction, which should be beneficial to the future development of more effective weight loss regimens.MethodsUpon constructing HF-induced simply nutritional, HF+high-/low-dose LPS-induced simulatively infectious, and HF+chlorpromazine (CPZ)-induced sedatively conservative mouse obese models, based on the morphological indices (body weight curve, body/adipose ratio, body/liver index), the serological indices (triglycerides, cholesterol, transaminases, insulin, and leptin levels), and the genomic indices (proinflammatory cytokine gene chips and protein chips), and using the classic weight-reducing medicine 2,4- dinitrophenol (DNP) (discarded long ago due to serious side effects) as a positive control, we conducted the comparative investigations on the weight-reducing effects of the clinically used antimalarial artesunate (ART), the angina-relieving drug nitroglycerin (NIT) and the popularly used but not yet proved weight-reducing traditional Chinese medicinal compound Luhui Chongcao Tablet (LCT). According to lactic acid (LA), nitric oxide (NO), 3-nitrotyrosine (3NT), signaling molecules, inflammatory cytokine profiling, fatty liver-relevant gene expression microarray, and gut microbiota classification phenotyping, we explored the plausible causes of obesity and accessible ways towards weight reduction.ResultsHF-based LPS modeling or CPZ modeling can effectively induced mouse obesity within weeks (body weight increases for above 20%). In the HF+LPS model, the body/adipose ratio (P<0.01), serum cholesterol content (P<0.05), and serum insulin level (P<0.001) were significantly elevated. In the HF+ CPZ model, alanine aminotransferase (ALT) activity was remarkably increased (P<0.05). The evaluation of drug effects using the HF+low-dose LPS model showed that DNP (16mg/kg), ART (0.25mg/kg), and NIT (6mg/kg) led to the substantial decrease of the body adipose ratio (P<0.05), and also allowed the recovery of serum insulin levels to those seen in the control, suggesting an impressive weight-reducing role.The inflammation-activated markers NF-κ B mRNA in the HF+low-dose LPS model were upregulated (P<0.001). In contrast, three monomers extremely downregulated NF-κ B mRNA to the control levels. Furthermore, proinflammatory cytokine mRNAs were upregulated in the modeling group, whereas they were downregulated in treatment group. Thus, anti-inflammation might be the important mechanism underlying weight loss by DNP, ART, and NIT. Additionally, H0-1 mRNA and VEGF mRNA was declined in the modeling group, whereas it was elevated by ART in the treatment group, suggesting a pro-angiogenic role.To investigate the inductive role of HT+LPS on non-alcoholic fat liver disease (NAFLD), we analyzed the expression levels of 40 inflammatory cytokines in the serum and 84 fat liver-related genes in the liver of HT+ high-dose LPS (1.2mg/kg)-or low-dose LPS (0.25mg/kg)-induced obese mice using the microarray chip data. Consequently, HT+high-dose LPS only slightly upregulated inflammatory cytokines and partially activated fat liver-related genes, and injection with high-dose LPS allowed the synchronous alterations of NO and 3NT from high levels to low levels within days. It was suggested that high-dose LPS seemingly induced anti-LPS antibodies for LPS clearing, thereby alleviating inflammation-induced liver lesions. In contrast, HT+ low-dose LPS considerably upregulated proinflammatory cytokines and totally activated fatty liver-related genes, but their expression levels were recovered to normal after drug administrations.The body/adipose ratio and body/liver index in the HF-induced obese mouse model were higher than those in the control with very significant difference (P<0.001), and the difference of serum cholesterol content was also reached a significant level ((P<0.05). After a daily enema by LCT, the body/adipose ratio and body/liver index in the treatment group were much lower than those in the model group, in which the decrease of pre-modeling drug administration exhibited very significant difference (P<0.01), and the decrease of post-modeling drug administration also showed significant difference (P<0.05). These results indicated that this compound medicine was not only phylactic, but also therapeutic for obesity. The species-classified culture of mouse gut microbiota indicated that LCT accelerated Escherichia coll proliferation and benefited microbe-carrying defecation, and also promote in vitro cultured E. coli propagation, implying that this compound likely played a weight-reducing role by expelling microbial strains, in particular, depriving those with the capacity of effective nutrition uptake.ConelusionsThis study have discovered, for the first time, that low-dose LPS might induce a systemic chronic low-grade inflammation, confirmed that the antimalarial ART and the angina-relieving drug NIT possess a potential weight-reducing role, elucidated that ART and NIT reduce weight by anti-inflammatory and fat-lowering mechanisms, and validated that LCT exhibits the effects of microbe expelling and weight reduction. Because weight reduction without calorie restriction (dieting) is much more acceptable, those types of weight-reducing medicines should be warmly welcomed and prospectively developed. |
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