Isoxanthohumol improves obesity and glucose metabolism via inhibiting intestinal lipid absorption with a bloom of Akkermansia muciniphila in mice
Objective: Polyphenols have health-promoting effects, such as improving insulin resistance. Isoxanthohumol (IX), a prenylated flavonoid found in beer hops, has been suggested to reduce obesity and insulin resistance; however, the mechanism remains unknown. Methods: High-fat diet-fed mice were admini...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-11-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221287782300131X |
| _version_ | 1797674131102105600 |
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| author | Yoshiyuki Watanabe Shiho Fujisaka Yoshitomo Morinaga Shiro Watanabe Allah Nawaz Hideki Hatta Tomonobu Kado Ayumi Nishimura Muhammad Bilal Muhammad Rahil Aslam Keiko Honda Yoshimi Nakagawa Samir Softic Kenichi Hirabayashi Takashi Nakagawa Yoshinori Nagai Kazuyuki Tobe |
| author_facet | Yoshiyuki Watanabe Shiho Fujisaka Yoshitomo Morinaga Shiro Watanabe Allah Nawaz Hideki Hatta Tomonobu Kado Ayumi Nishimura Muhammad Bilal Muhammad Rahil Aslam Keiko Honda Yoshimi Nakagawa Samir Softic Kenichi Hirabayashi Takashi Nakagawa Yoshinori Nagai Kazuyuki Tobe |
| author_sort | Yoshiyuki Watanabe |
| collection | DOAJ |
| description | Objective: Polyphenols have health-promoting effects, such as improving insulin resistance. Isoxanthohumol (IX), a prenylated flavonoid found in beer hops, has been suggested to reduce obesity and insulin resistance; however, the mechanism remains unknown. Methods: High-fat diet-fed mice were administered IX. We analyzed glucose metabolism, gene expression profiles and histology of liver, epididymal adipose tissue and colon. Lipase activity, fecal lipid profiles and plasma metabolomic analysis were assessed. Fecal 16s rRNA sequencing was obtained and selected bacterial species were used for in vitro studies. Fecal microbiota transplantation and monocolonization were conducted to antibiotic-treated or germ-free (GF) mice. Results: The administration of IX lowered weight gain, decreased steatohepatitis and improved glucose metabolism. Mechanistically, IX inhibited pancreatic lipase activity and lipid absorption by decreasing the expression of the fatty acid transporter CD36 in the small intestine, which was confirmed by increased lipid excretion in feces. IX administration increased markers of intestinal barrier function, including thickening the mucin layer and increasing caludin-1, a tight-junction related protein in the colon. In contrast, the effects of IX were nullified by antibiotics. As revealed using 16S rRNA sequencing, the microbial community structure changed with a significant increase in the abundance of Akkermansia muciniphila in the IX-treated group. An anaerobic chamber study showed that IX selectively promoted the growth of A. muciniphila while exhibiting antimicrobial activity against some Bacteroides and Clostridium species. To further explore the direct effect of A. muciniphila on lipid and glucose metabolism, we monocolonized either A. muciniphila or Bacteroides thetaiotaomicron to GF mice. A. muciniphila monocolonization decreased CD36 expression in the jejunum and improved glucose metabolism, with decreased levels of multiple classes of fatty acids determined using plasma metabolomic analysis. Conclusions: Our study demonstrated that IX prevents obesity and enhances glucose metabolism by inhibiting dietary fat absorption. This mechanism is linked to suppressing pancreatic lipase activity and shifts in microbial composition, notably an increase in A. muciniphila. These highlight new treatment strategies for preventing metabolic syndrome by boosting the gut microbiota with food components. |
| first_indexed | 2024-03-11T21:54:41Z |
| format | Article |
| id | doaj.art-5e617e1c998c4930b7ab219ec79db80e |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-03-11T21:54:41Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-5e617e1c998c4930b7ab219ec79db80e2023-09-26T04:12:09ZengElsevierMolecular Metabolism2212-87782023-11-0177101797Isoxanthohumol improves obesity and glucose metabolism via inhibiting intestinal lipid absorption with a bloom of Akkermansia muciniphila in miceYoshiyuki Watanabe0Shiho Fujisaka1Yoshitomo Morinaga2Shiro Watanabe3Allah Nawaz4Hideki Hatta5Tomonobu Kado6Ayumi Nishimura7Muhammad Bilal8Muhammad Rahil Aslam9Keiko Honda10Yoshimi Nakagawa11Samir Softic12Kenichi Hirabayashi13Takashi Nakagawa14Yoshinori Nagai15Kazuyuki Tobe16First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, JapanFirst Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan; Corresponding author. First Department of Internal Medicine, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.Department of Microbiology, Faculty of Medicine, University of Toyama, Toyama, JapanInstitute of Natural Medicine, University of Toyama, Toyama, JapanFirst Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan; Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Harvard Medical School, Boston, MA, USADepartment of Diagnostic Pathology, Faculty of Medicine, University of Toyama, Toyama, JapanFirst Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, JapanFirst Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, JapanFirst Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, JapanFirst Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, JapanFirst Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, JapanDivision of Complex Biosystem Research, Department of Research and Development, Institute of Natural Medicine, University of Toyama, Toyama, JapanDepartment of Pediatrics, Division of Pediatric Gastroenterology, University of Kentucky College of Medicine, Lexington, KY, USADepartment of Diagnostic Pathology, Faculty of Medicine, University of Toyama, Toyama, JapanDepartment of Molecular and Medical Pharmacology, Faculty of Medicine, University of Toyama, Toyama, JapanDepartment of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, JapanFirst Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan; Corresponding author. First Department of Internal Medicine, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.Objective: Polyphenols have health-promoting effects, such as improving insulin resistance. Isoxanthohumol (IX), a prenylated flavonoid found in beer hops, has been suggested to reduce obesity and insulin resistance; however, the mechanism remains unknown. Methods: High-fat diet-fed mice were administered IX. We analyzed glucose metabolism, gene expression profiles and histology of liver, epididymal adipose tissue and colon. Lipase activity, fecal lipid profiles and plasma metabolomic analysis were assessed. Fecal 16s rRNA sequencing was obtained and selected bacterial species were used for in vitro studies. Fecal microbiota transplantation and monocolonization were conducted to antibiotic-treated or germ-free (GF) mice. Results: The administration of IX lowered weight gain, decreased steatohepatitis and improved glucose metabolism. Mechanistically, IX inhibited pancreatic lipase activity and lipid absorption by decreasing the expression of the fatty acid transporter CD36 in the small intestine, which was confirmed by increased lipid excretion in feces. IX administration increased markers of intestinal barrier function, including thickening the mucin layer and increasing caludin-1, a tight-junction related protein in the colon. In contrast, the effects of IX were nullified by antibiotics. As revealed using 16S rRNA sequencing, the microbial community structure changed with a significant increase in the abundance of Akkermansia muciniphila in the IX-treated group. An anaerobic chamber study showed that IX selectively promoted the growth of A. muciniphila while exhibiting antimicrobial activity against some Bacteroides and Clostridium species. To further explore the direct effect of A. muciniphila on lipid and glucose metabolism, we monocolonized either A. muciniphila or Bacteroides thetaiotaomicron to GF mice. A. muciniphila monocolonization decreased CD36 expression in the jejunum and improved glucose metabolism, with decreased levels of multiple classes of fatty acids determined using plasma metabolomic analysis. Conclusions: Our study demonstrated that IX prevents obesity and enhances glucose metabolism by inhibiting dietary fat absorption. This mechanism is linked to suppressing pancreatic lipase activity and shifts in microbial composition, notably an increase in A. muciniphila. These highlight new treatment strategies for preventing metabolic syndrome by boosting the gut microbiota with food components.http://www.sciencedirect.com/science/article/pii/S221287782300131XAkkermansia muciniphilaInsulin resistanceIsoxanthohumolLipid absorptionMicrobiotaObesity |
| spellingShingle | Yoshiyuki Watanabe Shiho Fujisaka Yoshitomo Morinaga Shiro Watanabe Allah Nawaz Hideki Hatta Tomonobu Kado Ayumi Nishimura Muhammad Bilal Muhammad Rahil Aslam Keiko Honda Yoshimi Nakagawa Samir Softic Kenichi Hirabayashi Takashi Nakagawa Yoshinori Nagai Kazuyuki Tobe Isoxanthohumol improves obesity and glucose metabolism via inhibiting intestinal lipid absorption with a bloom of Akkermansia muciniphila in mice Molecular Metabolism Akkermansia muciniphila Insulin resistance Isoxanthohumol Lipid absorption Microbiota Obesity |
| title | Isoxanthohumol improves obesity and glucose metabolism via inhibiting intestinal lipid absorption with a bloom of Akkermansia muciniphila in mice |
| title_full | Isoxanthohumol improves obesity and glucose metabolism via inhibiting intestinal lipid absorption with a bloom of Akkermansia muciniphila in mice |
| title_fullStr | Isoxanthohumol improves obesity and glucose metabolism via inhibiting intestinal lipid absorption with a bloom of Akkermansia muciniphila in mice |
| title_full_unstemmed | Isoxanthohumol improves obesity and glucose metabolism via inhibiting intestinal lipid absorption with a bloom of Akkermansia muciniphila in mice |
| title_short | Isoxanthohumol improves obesity and glucose metabolism via inhibiting intestinal lipid absorption with a bloom of Akkermansia muciniphila in mice |
| title_sort | isoxanthohumol improves obesity and glucose metabolism via inhibiting intestinal lipid absorption with a bloom of akkermansia muciniphila in mice |
| topic | Akkermansia muciniphila Insulin resistance Isoxanthohumol Lipid absorption Microbiota Obesity |
| url | http://www.sciencedirect.com/science/article/pii/S221287782300131X |
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