title: Wheat alkylresorcinols suppress high-fat, high-sucrose diet-induced obesity and glucose intolerance by increasing insulin sensitivity and cholesterol excretion in male mice.
abstract: BACKGROUND
  Epidemiologic studies have shown that the consumption of whole grains can reduce the risk of type 2 diabetes mellitus, cardiovascular disease, and all-cause mortality. However, the underlying mechanisms remain a matter of debate.
  
  
  OBJECTIVE
  We aimed to determine the effects of wheat bran-derived alkylresorcinols on diet-induced metabolic disorders in mice.
  
  
  METHODS
  We fed C57BL/6J mice a normal refined diet or a high-fat, high-sucrose diet [29.1% fat, 20.7% protein, 34.0% carbohydrates containing 20.0% sucrose (w/w)] alone (FS) or containing 0.4% (wt:wt) alkylresorcinols (FS-AR) for 10 wk.
  
  
  RESULTS
  The alkylresorcinols suppressed FS-induced increases in body weight by 31.0% as well as FS-induced hepatic triglyceride accumulation (means ± SEMs: 29.6 ± 3.18 and 19.8 ± 2.42 mg/g tissue in the FS and FS-AR groups, respectively), without affecting energy intake. We measured circadian changes in blood metabolic hormones and found that FS-induced hyperinsulinemia (5.1 and 2.1 μg/L at night in the FS and FS-AR groups, respectively) and hyperleptinemia (21.6 and 10.8 μg/L at night in the FS and FS-AR groups, respectively) were suppressed by alkylresorcinols. Glucose and insulin tolerance tests showed that alkylresorcinols significantly reduced fasting blood glucose concentrations (190 ± 3.62 and 160 ± 8.98 mg/dL in the FS and FS-AR groups, respectively) and suppressed glucose intolerance as well as insulin resistance induced by the FS diet. Furthermore, alkylresorcinols significantly increased insulin-stimulated hepatic serine/threonine protein kinase B phosphorylation compared to the FS diet (+81.3% and +57.4% for Ser473 and Thr308, respectively). On the other hand, pyruvate and starch tolerance tests suggested that alkylresorcinols did not affect gluconeogenesis and carbohydrate digestion, respectively. Alkylresorcinols significantly increased fecal cholesterol excretion by 39.6% and reduced blood cholesterol concentrations by 30.4%, while upregulating the expression of hepatic cholesterol synthetic genes such as sterol regulatory element binding protein 2 (Srebf2) and 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 (Hmgcs1).
  
  
  CONCLUSIONS
  These findings suggest that wheat alkylresorcinols increase glucose tolerance and insulin sensitivity by suppressing hepatic lipid accumulation and intestinal cholesterol absorption, which subsequently suppresses diet-induced obesity in mice.
authors: Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan; Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba, Japan; Department of Applied Biological Science, Graduate School of Science and Technology, Tokyo University of Science, Noda, Chiba, Japan; k-ooishi@aist.go.jp.
authors: Katsutaka
authors: K
authors: Oishi
authors: Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan;
authors: Saori
authors: S
authors: Yamamoto
authors: Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan;
authors: Nanako
authors: N
authors: Itoh
authors: Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan;
authors: Reiko
authors: R
authors: Nakao
authors: Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan; Department of Applied Biological Science, Graduate School of Science and Technology, Tokyo University of Science, Noda, Chiba, Japan;
authors: Yuki
authors: Y
authors: Yasumoto
authors: Research Center for Basic Science, Research and Development, Quality Assurance Division, Nisshin Seifun Group, Inc., Fujimino, Saitama, Japan;
authors: Keiko
authors: K
authors: Tanaka
authors: Research Center for Basic Science, Research and Development, Quality Assurance Division, Nisshin Seifun Group, Inc., Fujimino, Saitama, Japan;
authors: Yosuke
authors: Y
authors: Kikuchi
authors: Research Center for Basic Science, Research and Development, Quality Assurance Division, Nisshin Seifun Group, Inc., Fujimino, Saitama, Japan;
authors: Shin-ichi
authors: S
authors: Fukudome
authors: Yeast Function Development Unit, Oriental Yeast Co., Ltd., Itabashi, Tokyo, Japan; and.
authors: Kimiko
authors: K
authors: Okita
authors: National Food Research Institute, National Agriculture and Food Research Organization, Tsukuba, Ibaraki, Japan.
authors: Yuko
authors: Y
authors: Takano-Ishikawa
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat / Q000009:adverse effects*; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D004043:Dietary Fiber / Q000494:pharmacology; D002149:Energy Intake; D005243:Feces / Q000737:chemistry; D018149:Glucose Intolerance / Q000188:drug therapy*; D006946:Hyperinsulinism / Q000188:drug therapy; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy*; D012118:Resorcinols / Q000494:pharmacology*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D013395:Sucrose / Q000008:administration & dosage*; D014280:Triglycerides / Q000097:blood; D014908:Triticum / Q000737:chemistry*
chemical_list: D001786:Blood Glucose; D004040:Dietary Carbohydrates; D004043:Dietary Fiber; D007328:Insulin; D012118:Resorcinols; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D014280:Triglycerides; D013395:Sucrose; D002784:Cholesterol
keywords: alkylresorcinol; cholesterol absorption; circadian rhythm; glucose intolerance; insulin sensitivity; metabolic disorder; microbiota; obesity