Phenethyl isothiocyanate ameliorates high-fat diet-induced obesity by antagonizing hypothalamic leptin resistance.

BACKGROUND

Phenethyl isothiocyanate (PEITC) is an isothiocyanate produced from the glucosinolate gluconasturtiin in cruciferous plants and has been shown to reduce fat accumulation. Hypothalamic leptin resistance is a key contributor to obesity.

PURPOSE: This study aimed to determine whether PEITC affects hypothalamic leptin signaling and obesity in mice fed a high-fat diet (HFD).

METHODS

Male C57BL/6 J mice were randomly divided into four groups. Mice in the control, HFD, low-dose PEITC, and high-dose PEITC groups received a standard diet (10 kcal% fat), HFD (60 kcal% fat), or PEITC-enriched HFD (60 kcal% fat with 0.5‰ or 1‰ PEITC, w/w) for 12 weeks, respectively. Obesity was evaluated by body weight and visceral fat. Leptin signaling, neuroinflammation, endoplasmic reticulum (ER) stress, neuronal activity in hypothalamus, as well as leptin sensitivity were tested.

RESULTS

PEITC dose-dependently decreased body weight gain and visceral fat in HFD-fed mice. It restored leptin sensitivity and hypothalamic leptin signaling by increasing Ob-Rb expression and JAK2 and STAT3 phosphorylation, while rebalancing leptin signaling regulators. PEITC suppressed hypothalamic neuroinflammation and attenuated ER stress across all three unfolded protein response branches. As a result, PEITC reactivated POMC neurons and inhibited AgRP neurons, enhancing energy metabolism.

CONCLUSION

PEITC protects against high-fat diet-induced obesity by improving hypothalamic leptin sensitivity.