Berberine protects against diet-induced obesity through regulating metabolic endotoxemia and gut hormone levels

Jian Hui Xu, Xing Zhen Liu, Wei Pan, Da Jin Zou, Jian Hui Xu, Xing Zhen Liu, Wei Pan, Da Jin Zou

Abstract

Systemic inflammation, which can be induced by metabolic endotoxemia, and corresponding high‑fat diet‑mediated metabolic disorders are associated with gut microbiota. In the present study reverse transcription-polymerase chain reaction, immunofluorescence, pyrosequencing, ELISA and Oil Red O staining were performed to assess whether berberine can protect against diet-induced obesity, through modulating the gut microbiota and consequently improving metabolic endotoxemia and gastrointestinal hormone levels. Alterations in the gut microbiota induced by berberine resulted in a significant reduction in bacterial lipopolysaccharide levels in portal plasma. Levels of inflammatory and oxidative stress markers, as well as the mRNA expression levels of macrophage infiltration markers in visceral adipose tissue, were also reduced by berberine. Inhibition of the inflammatory response was associated with a reduction in intestinal permeability and an increase in the expression of tight junction proteins. In addition, berberine was reported to restore aberrant levels of gut hormones in the portal plasma, such as glucagon‑like peptide‑1 and ‑2, peptide YY, glucose‑dependent insulinotropic polypeptide and pancreatic polypeptide. The present findings indicated that berberine, through modulating gut microbiota, restored the gut barrier, reduced metabolic endotoxemia and systemic inflammation, and improved gut peptide levels in high‑fat diet‑fed rats. The present study suggests that berberine may be an effective therapeutic strategy for the treatment of obesity and insulin resistance.

Figures

Figure 1.
Figure 1.
Berberine reduced weight gain and improved glucose homeostasis in HFD-fed rats. (A) Body weight. (B) Daily food intake per rat. (C) Fasting plasma glucose concentration. (D) Fasting plasma insulin concentration. (E) HOMA-IR index, calculated using the following equation: FBG (mmol/l) × FINS (mU/l)/22.5. (F) Oral glucose tolerance test. Data are expressed as the mean ± standard deviation. *P#P<0.05, ###P<0.001 compared with the HF group. Ctl, normal diet; HF, HFD; HB, HFD supplemented with berberine for 6 weeks; HFD, high-fat diet; HOMA-IR, homeostasis model assessment of insulin resistance; FBG, fasting blood glucose; FINS, fasting blood insulin; OGTT, oral glucose tolerance test.
Figure 2.
Figure 2.
Berberine attenuated HFD-induced hepatic injury and hepatic steatosis. (A) Hepatic triglyceride content. (B) Hepatic total cholesterol content. (C) ALT plasma concentration. (D) AST plasma concentration. (E) Fresh-frozen liver sections were stained with Oil Red O (magnification, ×100). Data are expressed as the mean ± standard deviation. *P#P<0.05, ##P<0.01 compared with the HF group. Ctl, normal diet; HF, HFD; HB, HFD supplemented with berberine for 6 weeks; HFD, high-fat diet; ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Figure 3.
Figure 3.
Berberine reduced endotoxemia and visceral adipose tissue inflammation in HFD-fed rats. (A) Portal plasma LPS concentrations. (B) TNF-α mRNA expression levels. (C) IL-1β mRNA expression levels. (D) PAI-1 mRNA expression levels. (E) NADPHox mRNA expression levels. (F) STAMP-2 mRNA expression levels. (G) MCP-1 mRNA expression levels. (H) F4/80 mRNA expression levels. Data are expressed as the mean ± standard deviation. **P##P<0.01, ###P<0.001 compared with the HF group. Ctl, normal diet; HF, HFD; HB, HFD supplemented with berberine for 6 weeks; HFD, high-fat diet; LPS, lipopolysaccharide; EU, endotoxin unit; TNF, tumor necrosis factor; IL, interleukin; PAI-1, plasminogen activator inhibitor-1; NADPHox, nicotinamide-adenine dinucleotide phosphate oxidase; STAMP-2, six transmembrane protein of prostate-2; MCP-1, monocyte chemotactic protein-1; F4/80, EGF-like module-containing mucin-like hormone receptor-like 1.
Figure 4.
Figure 4.
Metabolic endotoxemia was positively correlated with inflammation, oxidative stress and macrophage infiltration markers. Correlation between: Portal plasma LPS level and (A) TNF-α, (B) IL-1β, (C) PAI-1, (D) NADPHox, (E) STAMP-2, (F) MCP-1 and (G) F4/80 mRNA levels in visceral adipose tissue of Ctl, HF and HB rats. The inset corresponds to Pearson's correlation and corresponding P-value. Ctl, normal diet; HF, HFD; HB, HFD supplemented with berberine for 6 weeks; HFD, high-fat diet; LPS, lipopolysaccharide; TNF, tumor necrosis factor; IL, interleukin; PAI-1, plasminogen activator inhibitor-1; NADPHox, nicotinamide-adenine dinucleotide phosphate oxidase; STAMP-2, six transmembrane protein of prostate-2; MCP-1, monocyte chemotactic protein-1; F4/80, EGF-like module-containing mucin-like hormone receptor-like 1; EU, endotoxin unit.
Figure 5.
Figure 5.
Berberine reduced intestinal permeability in HFD-fed rats. (A) Plasma FITC-dextran concentration. (B) Total plasma FITC-dextran concentration. (C) Correlation between portal plasma LPS levels and plasma FITC-dextran concentration. The inset corresponds to Pearson's correlation and the corresponding P-value. Data are expressed as the mean ± standard deviation. **P##P<0.01 compared with the HF group. Ctl, normal diet; HF, HFD; HB, HFD supplemented with berberine for 6 weeks; HFD, high-fat diet; FITC, fluorescein isothiocyanate; LPS, lipopolysaccharide; EU, endotoxin unit.
Figure 6.
Figure 6.
Berberine restored the expression of tight junction proteins in HFD-fed rats. mRNA expression levels of colonic epithelial tight junction proteins (A) claudin-1, (B) claudin-2, (C) occludin and (D) ZO-1. Data are expressed as the mean ± standard deviation. *P#P<0.05, ###P<0.001 compared with the HF group. Ctl, normal diet; HF, HFD; HB, HFD supplemented with berberine for 6 weeks; HFD, high-fat diet; ZO-1, zonula occludens-1.
Figure 7.
Figure 7.
Berberine restored the expression and distribution of claudin-1 and claudin-2 in HFD-fed rats. (A) Immunofluorescent staining for claudin-1 (magnification, ×100). (B) Immunohistochemistry score for claudin-1. (C) Immunofluorescent staining for claudin-2 (magnification, ×100). (D) Immunohistochemistry score for claudin-2. Data are expressed as the mean ± standard deviation. *P##P<0.01 compared with the HF group. Ctl, normal diet; HF, HFD; HB, HFD supplemented with berberine for 6 weeks; HFD, high-fat diet.
Figure 8.
Figure 8.
Berberine modulated intestinal hormone levels in portal plasma of HFD-fed rats. (A) Portal plasma GLP-1 levels. (B) Portal plasma GLP-2 levels. (C) Portal plasma GIP, PP and PYY levels. (D) Colonic proglucagon mRNA expression levels. (E) Colonic L-cell numbers. Data are expressed as the mean ± standard deviation. *P#P<0.05, ###P<0.001 compared with the HF group. Ctl, normal diet; HF, HFD; HB, HFD supplemented with berberine for 6 weeks; HFD, high-fat diet; GLP, glucagon-like peptide; GIP, gastric inhibitory polypeptide; PP, pancreatic polypeptide; PYY, peptide YY.
Figure 9.
Figure 9.
Berberine altered the gut microbiota composition in HFD-fed rats. (A) Rarefaction curves. (B) Weighted UniFrac PCoA. Each point represents the microbiota of each rat in the Ctl, HF and HB groups. (C) PCA. P-values were calculated by MCPP. (D) RDA between the Ctl and HF groups. Berberine altered the gut microbiota composition in HFD-fed rats. (E) RDA between the Ctl and HB groups. (F) RDA between the HB and HF groups. P-values were calculated by MCPP. Ctl, normal diet; HF, HFD; HB, HFD supplemented with berberine for 6 weeks; HFD, high-fat diet; PCoA, principal coordinates analysis; PCA, principal components analysis; RDA, redundancy analysis; MCPP, Monte Carlo permutation tests.
Figure 9.
Figure 9.
Berberine altered the gut microbiota composition in HFD-fed rats. (A) Rarefaction curves. (B) Weighted UniFrac PCoA. Each point represents the microbiota of each rat in the Ctl, HF and HB groups. (C) PCA. P-values were calculated by MCPP. (D) RDA between the Ctl and HF groups. Berberine altered the gut microbiota composition in HFD-fed rats. (E) RDA between the Ctl and HB groups. (F) RDA between the HB and HF groups. P-values were calculated by MCPP. Ctl, normal diet; HF, HFD; HB, HFD supplemented with berberine for 6 weeks; HFD, high-fat diet; PCoA, principal coordinates analysis; PCA, principal components analysis; RDA, redundancy analysis; MCPP, Monte Carlo permutation tests.
Figure 9.
Figure 9.
Berberine altered the gut microbiota composition in HFD-fed rats. (A) Rarefaction curves. (B) Weighted UniFrac PCoA. Each point represents the microbiota of each rat in the Ctl, HF and HB groups. (C) PCA. P-values were calculated by MCPP. (D) RDA between the Ctl and HF groups. Berberine altered the gut microbiota composition in HFD-fed rats. (E) RDA between the Ctl and HB groups. (F) RDA between the HB and HF groups. P-values were calculated by MCPP. Ctl, normal diet; HF, HFD; HB, HFD supplemented with berberine for 6 weeks; HFD, high-fat diet; PCoA, principal coordinates analysis; PCA, principal components analysis; RDA, redundancy analysis; MCPP, Monte Carlo permutation tests.
Figure 9.
Figure 9.
Berberine altered the gut microbiota composition in HFD-fed rats. (A) Rarefaction curves. (B) Weighted UniFrac PCoA. Each point represents the microbiota of each rat in the Ctl, HF and HB groups. (C) PCA. P-values were calculated by MCPP. (D) RDA between the Ctl and HF groups. Berberine altered the gut microbiota composition in HFD-fed rats. (E) RDA between the Ctl and HB groups. (F) RDA between the HB and HF groups. P-values were calculated by MCPP. Ctl, normal diet; HF, HFD; HB, HFD supplemented with berberine for 6 weeks; HFD, high-fat diet; PCoA, principal coordinates analysis; PCA, principal components analysis; RDA, redundancy analysis; MCPP, Monte Carlo permutation tests.
Figure 9.
Figure 9.
Berberine altered the gut microbiota composition in HFD-fed rats. (A) Rarefaction curves. (B) Weighted UniFrac PCoA. Each point represents the microbiota of each rat in the Ctl, HF and HB groups. (C) PCA. P-values were calculated by MCPP. (D) RDA between the Ctl and HF groups. Berberine altered the gut microbiota composition in HFD-fed rats. (E) RDA between the Ctl and HB groups. (F) RDA between the HB and HF groups. P-values were calculated by MCPP. Ctl, normal diet; HF, HFD; HB, HFD supplemented with berberine for 6 weeks; HFD, high-fat diet; PCoA, principal coordinates analysis; PCA, principal components analysis; RDA, redundancy analysis; MCPP, Monte Carlo permutation tests.
Figure 9.
Figure 9.
Berberine altered the gut microbiota composition in HFD-fed rats. (A) Rarefaction curves. (B) Weighted UniFrac PCoA. Each point represents the microbiota of each rat in the Ctl, HF and HB groups. (C) PCA. P-values were calculated by MCPP. (D) RDA between the Ctl and HF groups. Berberine altered the gut microbiota composition in HFD-fed rats. (E) RDA between the Ctl and HB groups. (F) RDA between the HB and HF groups. P-values were calculated by MCPP. Ctl, normal diet; HF, HFD; HB, HFD supplemented with berberine for 6 weeks; HFD, high-fat diet; PCoA, principal coordinates analysis; PCA, principal components analysis; RDA, redundancy analysis; MCPP, Monte Carlo permutation tests.

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