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Histone deacetylase 6 inhibition restores leptin sensitivity and reduces
Authors Çakir I, Hadley CK, Pan PL, Bagchi RA, Ghamari-Langroudi M, Porter DT, Wang Q,
Litt MJ, Jana S, Hagen S, Lee P, White A, Lin JD, McKinsey TA, Cone RD
Submitted By Submitted Externally on 3/9/2022
Status Published
Journal Nature metabolism
Year 2022
Date Published 1/1/2022
Volume : Pages 4 : 44 - 59
PubMed Reference 35039672
Abstract The adipose tissue-derived hormone leptin can drive decreases in food intake
while increasing energy expenditure. In diet-induced obesity, circulating leptin
levels rise proportionally to adiposity. Despite this hyperleptinemia, rodents
and humans with obesity maintain increased adiposity and are resistant to
leptin's actions. Here we show that inhibitors of the cytosolic enzyme histone
deacetylase 6 (HDAC6) act as potent leptin sensitizers and anti-obesity agents
in diet-induced obese mice. Specifically, HDAC6 inhibitors, such as tubastatin
A, reduce food intake, fat mass, hepatic steatosis and improve systemic glucose
homeostasis in an HDAC6-dependent manner. Mechanistically, peripheral, but not
central, inhibition of HDAC6 confers central leptin sensitivity. Additionally,
the anti-obesity effect of tubastatin A is attenuated in animals with a
defective central leptin-melanocortin circuitry, including db/db and MC4R
knockout mice. Our results suggest the existence of an HDAC6-regulated adipokine
that serves as a leptin-sensitizing agent and reveals HDAC6 as a potential
target for the treatment of obesity.


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