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Sulforaphane reduces obesity by reversing leptin resistance.
Authors Çakir I, Lining Pan P, Hadley CK, El-Gamal A, Fadel A, Elsayegh D, Mohamed O,
Rizk NM, Ghamari-Langroudi M
Submitted By Submitted Externally on 6/21/2022
Status Published
Journal eLife
Year 2022
Date Published 3/1/2022
Volume : Pages 11 : Not Specified
PubMed Reference 35323110
Abstract The ascending prevalence of obesity in recent decades is commonly associated
with soaring morbidity and mortality rates, resulting in increased health-care
costs and decreased quality of life. A systemic state of stress characterized by
low-grade inflammation and pathological formation of reactive oxygen species
(ROS) usually manifests in obesity. The transcription factor nuclear factor
erythroid-derived 2-like 2 (NRF2) is the master regulator of the redox
homeostasis and plays a critical role in the resolution of inflammation. Here,
we show that the natural isothiocyanate and potent NRF2 activator sulforaphane
reverses diet-induced obesity through a predominantly, but not exclusively,
NRF2-dependent mechanism that requires a functional leptin receptor signaling
and hyperleptinemia. Sulforaphane does not reduce the body weight or food intake
of lean mice but induces an anorectic response when coadministered with
exogenous leptin. Leptin-deficient Lepob/ob mice and leptin receptor mutant
Leprdb/db mice display resistance to the weight-reducing effect of sulforaphane,
supporting the conclusion that the antiobesity effect of sulforaphane requires
functional leptin receptor signaling. Furthermore, our results suggest the
skeletal muscle as the most notable site of action of sulforaphane whose
peripheral NRF2 action signals to alleviate leptin resistance. Transcriptional
profiling of six major metabolically relevant tissues highlights that
sulforaphane suppresses fatty acid synthesis while promoting ribosome
biogenesis, reducing ROS accumulation, and resolving inflammation, therefore
representing a unique transcriptional program that leads to protection from
obesity. Our findings argue for clinical evaluation of sulforaphane for weight
loss and obesity-associated metabolic disorders.


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