Mechanistic study of anti-obesity effect of polymethoxyflavones through their bioavailability, biotransformation and interaction with gut microbiota in vivo
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Zhang, Man.
Mechanistic study of anti-obesity effect of polymethoxyflavones through their bioavailability, biotransformation and interaction with gut microbiota in vivo. Retrieved from
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TitleMechanistic study of anti-obesity effect of polymethoxyflavones through their bioavailability, biotransformation and interaction with gut microbiota in vivo
Date Created2020
Other Date2020-10 (degree)
Extent1 online resource (xxi, 191 pages) : illustrations
DescriptionPolymethoxyflavones (PMFs) are a unique class of flavonoids that have at least two methoxy groups on the flavone skeleton. About 80 PMFs have been identified from the citrus so far. Among them, tangeretin and nobiletin are the two most prevalent PMFs and widely studied for their biological activities. PMFs have demonstrated a broad spectrum of bioactivities, including neuroprotection, anti-inflammatory, anti-cancer, anti-obesity, anti-atherosclerosis activities. In particular, emerging studies find that PMFs have beneficial effect to maintain the metabolic homeostasis by regulating signals coordinating multiple organs, including the brain, pancreas, liver, adipose tissues, muscles and gastrointestinal (GI) track. However, the underlying mechanisms of their anti-obesity effect still remain unclear. This study aims to explore the anti-obesity activity and biological fate of PMFs in in vivo by investigating their bioavailability, biotransformation and interaction with gut microbiota. Besides, we also have developed delivery systems with the aim of improving PMFs bioavailability. The delivery systems are found to play important roles on the biological fate of PMFs, and thus may influence their bioefficacy in vivo.
In the first part of this work, we have studied the interplay of PMFs and gut microbiota and its implication for obesity control. Using the high fat diet (HFD) induced obese mice, we investigate the modulation effect on gut microbiota by PMFs extracted from the aged citrus peels. PMFs are found to have prebiotic effect by reducing biomarkers of microbial dysbiosis caused by HFD and promoting beneficial bacteria, such as Bifidobacteria and Lactobacillius. PMFs treatment increases the fecal short chain fatty acids (SCFA) production. The metagenomic analysis of the feces shows that the xenobiotics metabolism of the gut microbiota is enhanced by PMFs treatment. Besides, we also study the biotransformation of nobiletin by gut microbiota and in the host organs (in the liver and brain) after 8-week feeding of nobiletin for the HFD-fed mice. The concentration ratio of demethylated metabolites in feces increases dramatically in the feces during the 8 weeks. Both the metagenomics and biotransformation analysis suggest that the long-term metabolic input of PMFs would enable gut microbiota with enhanced biotransformation activity for metabolizing PMFs.
PMFs have shown good anti-obesity activity from recent studies. However, the biological fate of PMFs in vivo remains unclear. The second part of this study is to compare the bioavailability and biotransformation of a typical PMF--nobiletin in the lean- and obese rats. From the excretion study, gut microbiota demonstrates higher extent of demethylation activity than the host, since more di-demethylated nobiletin is found in the feces than the urine. The bioavailability of nobiletin in the lean- and obese- rats is similar, which is about 20%. Higher ratio of demethylated metabolites to nobiletin was found in the feces and plasma in the obese rats than the lean rats after oral administration of 100mg/kg nobiletin. The metabolites profile in the plasma after intravenous injection does not show significant difference for lean- and obese rats. Comparing the results for the oral and injected administration, it suggests that gut microbiota (the microbiome from the lean- and obese rats) plays important role on the biotransformation of PMFs in vivo.
Due to the multiple methoxy groups, PMFs have poor water solubility. We have developed two emulsion systems to enhance the bioavailability of PMFs: the conventional emulsion and organogel-based emulsion. The lecithin-based conventional emulsion with 1% nobiletin has an average droplet size of around 330 nm; has the viscoelastic and gel-like behavior; but could not completely prevent the crystallization of PMFs. According to the pharmacokinetic study using rat model, the conventional emulsion can increase the bioavailable nobiletin and its major metabolite in the blood by about 2 times, as compared to the oil suspension. To further optimize the emulsion formulation, we develop the organogel-based emulsion, which increases the solubility of PMFs by about 3.5 times in the oil phase without crystallization in the room temperature. Furthermore, from the in vitro lipolysis results, the organogel-based emulsion shows better efficiency to improve the bioaccessibility of PMFs, compared to the conventional emulsion.
NotePh.D.
NoteIncludes bibliographical references
Genretheses, ETD doctoral
LanguageEnglish
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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