Phenethyl isothiocyanate activates leptin signaling and decreases food intake.

Miho Yagi,Hiroki Ota,Noriyuki Miyoshi,Ayumi Maeda,Mitsugu Akagawa,Yukiko Nakatsuji,Yoshimasa Nakamura,Ryosuke Kamikubo,Clarissa Menezes Maya-Monteiro

doi:10.1371/journal.pone.0206748

Miho Yagi, Hiroki Ota + Show 7 more

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https://doi.org/10.1371/journal.pone.0206748

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Abstract

Obesity, a principal risk factor for the development of diabetes mellitus, heart disease, and hypertension, is a growing and serious health problem all over the world. Leptin is a weight-reducing hormone produced by adipose tissue, which decreases food intake via hypothalamic leptin receptors (Ob-Rb) and the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway. Protein tyrosine phosphatase 1B (PTP1B) negatively regulates leptin signaling by dephosphorylating JAK2, and the increased activity of PTP1B is implicated in the pathogenesis of obesity. Hence, inhibition of PTP1B may help prevent and reduce obesity. In this study, we revealed that phenethyl isothiocyanate (PEITC), a naturally occurring isothiocyanate in certain cruciferous vegetables, potently inhibits recombinant PTP1B by binding to the reactive cysteinyl thiol. Moreover, we found that PEITC causes the ligand-independent phosphorylation of Ob-Rb, JAK2, and STAT3 by inhibiting cellular PTP1B in differentiated human SH-SY5Y neuronal cells. PEITC treatment also induced nuclear accumulation of phosphorylated STAT3, resulting in enhanced anorexigenic POMC expression and suppressed orexigenic NPY/AGRP expression. We demonstrated that oral administration of PEITC to mice significantly reduces food intake, and stimulates hypothalamic leptin signaling. Our results suggest that PEITC might help prevent and improve obesity.

Highlights

The prevalence of obesity has been increasing explosively over the past decades, resulting today in over 600 million adults worldwide with a body mass index (BMI) of 30 kg/m2 or greater [1,2]
Accumulating evidence from animal models, clinical and cellular studies suggest that protein tyrosine phosphatase 1B (PTP1B) could be involved in the pathways leading to leptin resistance as a major negative regulator of leptin signaling
A recent study revealed that hypothalamic PTP1B levels in rats increase coincident with the initial development of leptin resistance, and that intracerebroventricular administration of a pharmacological competitive PTP1B inhibitor restores leptin sensitivity, resulting in a dose-dependent inhibition of food intake [15]

Summary

Introduction

The prevalence of obesity has been increasing explosively over the past decades, resulting today in over 600 million adults worldwide with a body mass index (BMI) of 30 kg/m2 or greater [1,2]. The phosphorylated Tyr-1141 binds the signal transducer and activator of transcription 3 (STAT3) from the cytosol, which becomes phosphorylated on a C-terminal tyrosine, either directly by the receptor or by JAK2. Recent studies have indicated that hypothalamic PTP1B is increased during high-fat (HF) diet-induced leptin resistance [14,15]. Based on these facts, PTP1B is a highly plausible candidate for a leptin resistance factor [16] and inhibiting its activity has emerged as a potential therapeutic strategy to treat obesity by restoring leptin sensitivity [17,18]

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