3-(4-Hydroxy-3-methoxyphenyl)propionic Acid Produced from 4-Hydroxy-3-methoxycinnamic Acid by Gut Microbiota Improves Host Metabolic Condition in Diet-Induced Obese Mice

4-Hydroxy-3-methoxycinnamic acid (HMCA), a hydroxycinnamic acid derivative, is abundant in fruits and vegetables, including oranges, carrots, rice bran, and coffee beans. Several beneficial effects of HMCA have been reported, including improvement of metabolic abnormalities in animal models and human studies. However, its mitigating effects on high-fat diet (HFD)-induced obesity, and the mechanism underlying these effects, remain to be elucidated. In this study, we demonstrated that dietary HMCA was efficacious against HFD-induced weight gain and hepatic steatosis, and that it improved insulin sensitivity. These metabolic benefits of HMCA were ascribable to 3-(4-hydroxy-3-methoxyphenyl)propionic acid (HMPA) produced by gut microbiota. Moreover, conversion of HMCA into HMPA was attributable to a wide variety of microbes belonging to the phylum Bacteroidetes. We further showed that HMPA modulated gut microbes associated with host metabolic homeostasis by increasing the abundance of organisms belonging to the phylum Bacteroidetes and reducing the abundance of the phylum Firmicutes. Collectively, these results suggest that HMPA derived from HMCA is metabolically beneficial, and regulates hepatic lipid metabolism, insulin sensitivity, and the gut microbial community. Our results provide insights for the development of functional foods and preventive medicines, based on the microbiota of the intestinal environment, for the prevention of metabolic disorders

Barley β-glucan improves metabolic condition via short-chain fatty acids produced by gut microbial fermentation in high fat diet fed mice

<div><p>Dietary intake of barley β-glucan (BG) is known to affect energy metabolism. However, its underlying mechanism remains poorly understood because studies have presented inconsistent results, with both positive and negative effects reported in terms of satiety, energy intake, weight loss, and glycemic control. The objective of this study was to clarify the physiological role underlying the metabolic benefits of barley BG using a mouse model of high fat diet (HFD)-induced obesity. Male 4-wk-old C57BL/6J mice were fed an HFD with 20% barley flour containing either high BG (HBG; 2% BG) or low BG (LBG; 0.6% BG) levels under conventional and germ-free (GF) conditions for 12 wks. In addition, mice were fed either an HFD with 5% cellulose (HFC; high fiber cellulose) or 5% barley BG (HFB; high fiber β-glucan) for 12 wks. Then, metabolic parameters, gut microbial compositions, and the production of fecal short-chain fatty acids (SCFAs) were analyzed. The weight gain and fat mass of HBG-fed mice were lower than those of control mice at 16-wk-old. Moreover, the secretion of the gut hormones PYY and GLP-1 increased in HBG-fed mice, thereby reducing food intake and improving insulin sensitivity by changing the gut microbiota and increasing SCFAs (especially, butyrate) under conventional condition. These effects in HBG-fed mice were abolished under GF conditions. Moreover, the HFB diets also increased PYY and GLP-1 secretion, and decreased food intake compared with that in HFC-fed mice. These results suggest that the beneficial metabolic effects of barley BG are primary due to the suppression of appetite and improvement of insulin sensitivity, which are induced by gut hormone secretion promoted via gut microbiota-produced SCFAs.</p></div

HBG barley flour suppresses appetite and improves insulin sensitivity.

<p>Plasma insulin (A), leptin (B), PYY (C), and GLP-1 levels (D) were measured in male mice fed Co, HBG, or LBG diets for 12 weeks (n = 8–10). Daily food intakes were measured at 10 weeks of age (E), and glucose tolerance test was investigated at 14 (ipGTT; F) and 15 (OGTT; G) weeks of age in male mice fed Co, HBG or LBG diet. Values are means ± S.E.M. n = 4–6. *, <i>P</i> < 0.05, and ** <i>P</i> <0.01, compared with Co (Tukey-Kramer test for A-D, and F) (student’s t-test for E and G). Co, control; HBG, β-glucan rich barley; LBG, general barley; GLP-1, glucagon-like peptide 1; PYY, peptide YY.</p

HFB suppresses HFD-induced obesity.

<p>Plasma PYY (A) and GLP-1 levels (B) were measured in male mice fed HFC or HFB for 12 weeks. Daily food intakes were measured at 9 to11 weeks of age (C). Fecal short chain fatty acids were measured by GC/MS (D). <i>Firmicutes</i> / <i>Bacteroidetes</i> ratio (E) and <i>Actinobacteria</i> (F) in feces were measured by quantitative real-time PCR. Values are means ± S.E.M. n = 7–9. *, <i>P</i> < 0.05, and **, <i>P</i> < 0.01, compared with HFC (student’s t-test). Epi, epididymal; GLP-1, glucagon-like peptide 1; HFB, high fat diet + 5% barley β-glucan; HFC, high fat diet + 5% cellulose; Peri, perirenal; PYY, peptide YY; Sub, subcutaneous; WAT, white adipose tissue.</p

HBG barley flour suppresses HFD-induced obesity.

<p>Body weight changes (A), fat mass (B), blood glucose (C), and plasma triglyceride (D) were measured in male mice fed Co, HBG, or LBG diets for 12 weeks. Values are means ± S.E.M. n = 8–13. *, <i>P</i> < 0.05, compared with Co (Tukey-Kramer test). Co, control; Epi, epididymal; HBG, β-glucan rich barley; LBG, general barley; Peri, perirenal; Sub, subcutaneous; WAT, white adipose tissue.</p

HBG barley flour produces SCFAs and changes the gut microbial composition.

<p>Fecal short chain fatty acids were measured in male mice fed Co, HBG, or LBG diets for 12 weeks (A). <i>Firmicutes</i> / <i>Bacteroidetes</i> ratio (B), and <i>Actinobacteria</i> (C) in feces were measured by quantitative real-time PCR for Co, HBG, or LBG diets for 2 weeks. Values are means ± S.E.M. n = 4–8. *, <i>P</i> < 0.05, **, <i>P</i> < 0.01, and ***, <i>P</i> < 0.001, compared with Co. Co (Tukey-Kramer test), control; HBG, β-glucan rich barley; LBG, general barley.</p

Metabolic benefits of HBG barley flour are abolished under GF conditions.

<p>Fecal short chain fatty acids in germ-free and conventional mice were measured by GC/MS (A). Body weight changes (B), fat mass (C), plasma PYY (D), and GLP-1 levels (E) were measured in male germ-free mice fed a Co or HBG diets for 12 weeks. Daily food intakes were measured at 8 to 10 weeks of age (F). Values are means ± S.E.M. n = 5. **, <i>P</i> < 0.01, compared with Co (Tukey-Kramer test for A) (student’s t-test for B-F). Co, Control; Conv-Co, Conventional mice fed a Co diet; Epi, epididymal; GF-Co, Germ-Free mice fed a Co; GF-HBG, Germ-Free mice fed a HBG; GLP-1, glucagon-like peptide 1; HBG, β-glucan rich barley; Peri, perirenal; PYY, peptide YY; Sub, subcutaneous; WAT, white adipose tissue.</p