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

Esther Mezhibovsky; Kevin M Tveter; Jose A Villa-Rodriguez; Karen Bacalia; Dushyant Kshatriya; Nikhil Desai; Alrick Cabales; Yue Wu; Ke Sui; Rocio M Duran; Nicholas T Bello; Diana E Roopchand

doi:10.1210/jendso/bvad095

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

J Endocr Soc. 2023 Jul 24;7(9):bvad095. doi: 10.1210/jendso/bvad095. eCollection 2023 Aug 1.

Authors

Esther Mezhibovsky^{1

2}, Kevin M Tveter¹, Jose A Villa-Rodriguez¹, Karen Bacalia^{1

2}, Dushyant Kshatriya^{2

3}, Nikhil Desai¹, Alrick Cabales¹, Yue Wu¹, Ke Sui¹, Rocio M Duran¹, Nicholas T Bello³, Diana E Roopchand^{1

2}

Affiliations

¹ Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.
² Department of Nutritional Sciences Graduate Program, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.
³ Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.

Abstract

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.

Keywords: bile acids; corticosterone; diet induced obesity; farnesoid X receptor; gut microbiota; high-fat diet; hypothalamic–pituitary–adrenal axis; leptin; peptide YY; proanthocyanidins.

Abstract

Grants and funding