Indole-3-carbinol ameliorates ER stress-mediated hyperleptinemia in western diet-fed apoE-/- mice

Abstract

Background: Endoplasmic reticulum (ER) stress during overnutrition causes leptin resistance in obese animals and humans. ER stress induces the activation of the unfolded protein response, which disrupts the leptin signaling pathway, accelerating atherosclerosis development and its complications.

Objective: Indole-3-carbinol (I3C) improves metabolic dysfunction in diet-induced obesity; however, its role in protecting against ER stress-induced hyperleptinemia remains unclear. Herein, we explored whether dietary I3C alleviates ER stress in apolipoprotein E-deficient (apoE^-/-) mice fed a western diet (WD).

Design: ApoE^-/- mice were fed either WD (60 kcal from fat, n = 10) or WD supplemented with 0.05% I3C (w/w, n = 10) for 12 weeks.

Results: I3C supplementation (0.05%) resulted in reduced adipose tissue weight and plasma leptin levels compared with those in WD-fed apoE^-/- mice after 12 weeks. I3C also significantly decreased the protein expression of ER stress markers, whereas increased the mRNA expression of genes related to cholesterol efflux and fatty acid β-oxidation in the liver, despite no changes in plasma cholesterol and triglyceride levels. Immunohistochemistry revealed reduced aortic localization of glucose-related protein 78 compared with the WD group, suggesting that I3C partially alleviated ER stress in atherosclerotic lesions of WD-fed apoE^-/- mice.

Conclusion: I3C may serve as a feasible compound for preventing atherosclerosis and its associated complications.