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 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.
Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Bing
B
Luan
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
Mark O
MO
Goodarzi
Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Naomi G
NG
Phillips
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502, USA.
Xiuqing
X
Guo
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502, USA.
Yii-Der I
YD
Chen
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502, USA.
Jie
J
Yao
Diabetes Research Center, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Matthew
M
Allison
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502, USA.
Jerome I
JI
Rotter
Molecular and Cellular Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Reuben
R
Shaw
Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: montminy@salk.edu.
Marc
M
Montminy
D055372:AMP-Activated Protein Kinases; D000273:Adipose Tissue / Q000276:immunology; D000818:Animals; D002395:Catecholamines / Q000378:metabolism*; D002772:Cholera Toxin / Q000276:immunology; D000242:Cyclic AMP / Q000378:metabolism*; D004734:Energy Metabolism; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D007333:Insulin Resistance / Q000276:immunology; D020738:Leptin / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000276:immunology / Q000378:metabolism; D015434:Panniculitis / Q000276:immunology*; D037342:Pertussis Toxin / Q000276:immunology; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D014757:Viper Venoms / Q000276:immunology
D002395:Catecholamines; D020738:Leptin; D008070:Lipopolysaccharides; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014757:Viper Venoms; C416405:edema factor; D002772:Cholera Toxin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases