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CST, an Herbal Formula, Exerts Anti-Obesity Effects Through Brain-Gut-Adipose Tissue Axis Modulation in High-Fat Diet Fed Mice

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CST, an Herbal Formula, Exerts Anti-Obesity Effects Through Brain-Gut-Adipose Tissue Axis Modulation in High-Fat Diet Fed Mice

AbuZar Ansari et al. Molecules.

Abstract

The brain, gut, and adipose tissue interact to control metabolic pathways, and impairment in the brain-gut-adipose axis can lead to metabolic disorders, including obesity. Chowiseungcheng-tang (CST), a herbal formulation, is frequently used to treat metabolic disorders. Here, we investigated the anti-obesity effect of CST and its link with brain-gut-adipose axis using C57BL/6J mice as a model. The animals were provided with a normal research diet (NRD) or high-fat diet (HFD) in absence or presence of CST or orlistat (ORL) for 12 weeks. CST had a significant anti-obesity effect on a number of vital metabolic and obesity-related parameters in HFD-fed mice. CST significantly decreased the expression levels of genes encoding obesity-promoting neuropeptides (agouti-related peptide, neuropeptide Y), and increased the mRNA levels of obesity-suppressing neuropeptides (proopiomelanocortin, cocaine-and amphetamine-regulated transcript) in the hypothalamus. CST also effectively decreased the expression level of gene encoding obesity-promoting adipokine (retinol-binding protein-4) and increased the mRNA level of obesity-suppressing adipokine (adiponectin) in visceral adipose tissue (VAT). Additionally, CST altered the gut microbial composition in HFD groups, a phenomenon strongly associated with key metabolic parameters, neuropeptides, and adipokines. Our findings reveal that the anti-obesity impact of CST is mediated through modulation of metabolism-related neuropeptides, adipokines, and gut microbial composition.

Keywords: adipokine; brain-gut-adipose tissue axis; chowiseungcheng-tang; gut microbiota; herb; neuropeptide; obesity.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Effect of CST on the body weight, food efficiency ratio, liver weight, and visceral adiposity in HFD-fed mice: (A) Body weight of mice during entire experimental period (0–12 weeks); (B) Body weight of animals at 0th and 12th weeks of treatments; (C) Food efficiency ratio, (D) Liver weight; (E) Visceral adipose tissue weight and (F) Adiposity index at 12th week of treatment. Data represented the mean ± SD (n = 6). Different letters above bars indicate significant difference from each other at p < 0.05 as determined by one-way ANOVA with Least Significant Difference (LSD) post hoc test. * indicates statistical significance compared with HFD group at p < 0.05.
Figure 2
Figure 2
Impact of CST on the glucose tolerance, insulin and other vital metabolic parameters: (A) Blood glucose level; (B) Insulin level; and (C) Area under the curve (AUC) in oral glucose tolerance test (OGTT); (D) Total cholesterol (TC); (E) Triglyceride (TG); (F) High-density lipoprotein (HDL); (G) Aspartate transaminase (AST); and (H) Alanine transaminase (ALT). Data represented the mean ± SD (n = 6). Different letters above bars indicate significant difference from each other at p < 0.05 as determined by one-way ANOVA with Least Significant Difference (LSD) post hoc test. * indicates statistical significance compared with HFD group at p < 0.05.
Figure 3
Figure 3
Histopathology of liver and adipose tissues: Frozen sections of the liver tissues stained with oil-O-red (AD) and counter stained with hematoxylin and eosin (H & E) (EH); Paraffin sections of fat tissues stained with H & E (IL). The histological examinations of the tissue sections were performed under light microscopy with 200× magnification (scale bar 100 μm).
Figure 4
Figure 4
Expression levels of neuropeptides and adipokines: (AD) Gene expression levels of neuropeptides in hypothalamus (n = 6); (EL) Gene expression levels of adipokines in adipose tissues (n = 3). Levels of mRNAs were measured by qRT-PCR and the fold values were normalized using the house keeping gene Gapdh. Data represented as mean ± SD (n = 3–6). Different letters above bars indicate significant difference from each other at p < 0.05 as determined by one-way ANOVA with Least Significant Difference (LSD) post hoc test.
Figure 5
Figure 5
Relative abundance of related microbes in mice fecal samples: (AC) The relative abundance of phyla; and (DJ) the relative abundance of genus of microbiota in the stool samples of mice as reflected by microbial 16sRNA gene expression. The results are expressed as normalized fold values relative to the normal group. Data represented as mean ± SD (n = 5). Different letters above bars indicate significant difference from each other at p < 0.05 as determined by one-way ANOVA with Least Significant Difference (LSD) post hoc test.
Figure 6
Figure 6
Correlation between gut microbial relative abundance and host metabolic parameters, neuropeptides and adipokines: Data of all experimental groups (except normal) were gathered and analyzed by SPSS software (17.0. version, Chicago, IL, USA) using Spearman’s rho calculated by Permut Matrix software (version 1.9.3 EN, Montpellier, France) for heatmap plots. As the colors scale shows, green color indicates a negative correlation, while red color denotes a positive correlation. The ★ symbol indicates statistically significant negative correlation (p < 0.05) and • symbol indicated statistically significant positive correlation (p < 0.05).
Figure 7
Figure 7
The possible involvement of gut microbial composition in the inter-communication among the vital components of brain-gut-adipose tissue axis associated with host metabolism. The probable interactions between and among the brain-derived neuropeptides, adipose tissue-derived adipokines and the modulated gut microbial communities resulting in the promotion or suppression of obesity are shown.

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