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 ofwhole 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: Weaimed to determine the effects of wheat bran-derived alkylresorcinols on diet-inducedmetabolic disorders inmice. 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 bodyweight by 31.0% aswell as FS-induced hepatic triglyceride accumulation(means±SEMs:29.6±3.18and 19.8±2.42mg/g tissue in theFSandFS-ARgroups, respectively), without affecting energy intake.Wemeasured circadian changes in bloodmetabolic 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)weresuppressedbyalkylresorcinols. Glucoseandinsulintolerancetestsshowedthat 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 suppressedglucose intoleranceaswellasinsulin resistanceinducedbytheFSdiet.Furthermore,alkylresorcinolssignificantly increased insulin-stimulated hepatic serine/threonine protein kinaseBphosphorylation 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 carbohydratedigestion, respectively. Alkylresorcinols significantly increasedfecal cholesterol excretionby 39.6% andreduced bloodcholesterol concentrationsby 30.4%,while upregulating theexpressionof hepatic cholesterol syntheticgenes 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.