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Cell Metab. 2014 Jun 3;19(6):1058-65. doi: 10.1016/j.cmet.2014.03.024. Epub 2014 Apr 24.

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

Author information

  • 1Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 2Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
  • 3Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502, USA.
  • 4Diabetes Research Center, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.
  • 5Molecular and Cellular Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 6Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: montminy@salk.edu.

Abstract

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.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24768298
[PubMed - indexed for MEDLINE]
PMCID:
PMC4207085
Free PMC Article

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