Leptin-mediated increases in catecholamine signaling reduce adipose tissue inflammation via activation of macrophage HDAC4

Obesity promotes systemic insulin resistance through inflammatory changes that lead to the release of cytokines from activated macrophages. Although the mechanism is unclear, the second messenger cAMP has been found to attenuate macrophage activity in response to a variety of hormonal signals. We sh...

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Bibliographic Details
Published in:Cell metabolism Vol. 19; no. 6; p. 1058
Main Authors: Luan, Bing, Goodarzi, Mark O, Phillips, Naomi G, Guo, Xiuqing, Chen, Yii-Der I, Yao, Jie, Allison, Matthew, Rotter, Jerome I, Shaw, Reuben, Montminy, Marc
Format: Journal Article
Language:English
Published: United States 03.06.2014
Subjects:
Adipose Tissue - immunology
AMP-Activated Protein Kinases
Animals
Catecholamines - metabolism
Cholera Toxin - immunology
Cyclic AMP - metabolism
Energy Metabolism
Histone Deacetylases - biosynthesis
Histone Deacetylases - genetics
Histone Deacetylases - metabolism
Humans
Inflammation
Insulin Resistance - immunology
Leptin - metabolism
Lipopolysaccharides - immunology
Macrophages - immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Obese
Obesity - immunology
Obesity - metabolism
Panniculitis - immunology
Pertussis Toxin - immunology
Phosphorylation
Polymorphism, Single Nucleotide
Protein Serine-Threonine Kinases - antagonists & inhibitors
Protein Serine-Threonine Kinases - genetics
Signal Transduction
Transcription Factor RelA - antagonists & inhibitors
Transcription Factor RelA - biosynthesis
Transcription Factor RelA - metabolism
Viper Venoms - immunology
ISSN:1932-7420, 1932-7420
Online Access:Get more information
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Summary:Obesity promotes systemic insulin resistance through inflammatory changes that lead to the release of cytokines from activated macrophages. Although the mechanism is unclear, the second messenger cAMP has been found to attenuate macrophage activity in response to a variety of hormonal signals. We show that, in the setting of acute overnutrition, leptin triggers catecholamine-dependent increases in cAMP signaling that reduce inflammatory gene expression via the activation of the histone deacetylase HDAC4. cAMP stimulates HDAC4 activity through the PKA-dependent inhibition of the salt-inducible kinases (SIKs), which otherwise phosphorylate and sequester HDAC4 in the cytoplasm. Following its dephosphorylation, HDAC4 shuttles to the nucleus where it inhibits NF-κB activity over proinflammatory genes. As variants in the Hdac4 gene are associated with obesity in humans, our results indicate that the cAMP-HDAC4 pathway functions importantly in maintaining insulin sensitivity and energy balance via its effects on the innate immune system.
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ISSN:1932-7420
1932-7420
DOI:10.1016/j.cmet.2014.03.024