Grape Polyphenols May Prevent High-Fat Diet–Induced Dampening of the Hypothalamic–Pituitary–Adrenal Axis in Male Mice

CONTEXT : Chronic high-fat diet (HFD) consumption causes obesity associated with retention of bile acids (BAs) that suppress important regulatory axes, such as the hypothalamic–pituitary–adrenal axis (HPAA). HFD impairs nutrient sensing and energy balance due to a dampening of the HPAA and reduced production and peripheral metabolism of corticosterone (CORT). OBJECTIVE: We assessed whether proanthocyanidin-rich grape polyphenol (GP) extract can prevent HFD-induced energy imbalance and HPAA dysregulation. METHODS: Male C57BL6/J mice were fed HFD or HFD supplemented with 0.5% w/w GPs (HFD-GP) for 17 weeks. RESULTS: GP supplementation reduced body weight gain and liver fat while increasing circadian rhythms of energy expenditure and HPAA-regulating hormones, CORT, leptin, and PYY. GP-induced improvements were accompanied by reduced mRNA levels of Il6, Il1b, and Tnfa in ileal or hepatic tissues and lower cecal abundance of Firmicutes, including known BA metabolizers. GP-supplemented mice had lower concentrations of circulating BAs, including hydrophobic and HPAA-inhibiting BAs, but higher cecal levels of taurine-conjugated BAs antagonistic to farnesoid X receptor (FXR). Compared with HFD-fed mice, GP-supplemented mice had increased mRNA levels of hepatic Cyp7a1 and Cyp27a1, suggesting reduced FXR activation and more BA synthesis. GP-supplemented mice also had reduced hepatic Abcc3 and ileal Ibabp and Ostβ, indicative of less BA transfer into enterocytes and circulation. Relative to HFD-fed mice, CORT and BA metabolizing enzymes (Akr1d1 and Srd5a1) were increased, and Hsd11b1 was decreased in GP supplemented mice. CONCLUSION: GPs may attenuate HFD-induced weight gain by improving hormonal control of the HPAA and inducing a BA profile with less cytotoxicity and HPAA inhibition, but greater FXR antagonism.