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

Bing Luan; Mark O Goodarzi; Naomi G Phillips; Xiuqing Guo; Yii-Der I Chen; Jie Yao; Matthew Allison; Jerome I Rotter; Reuben Shaw; Marc Montminy

doi:10.1016/j.cmet.2014.03.024

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

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

Authors

Affiliations

¹ Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
² Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
³ 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.
⁴ Diabetes Research Center, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.
⁵ Molecular and Cellular Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
⁶ Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases
Adipose Tissue / immunology
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

Substances

Catecholamines
Leptin
Lipopolysaccharides
Rela protein, mouse
Transcription Factor RelA
Viper Venoms
edema factor
Cholera Toxin
Cyclic AMP
Pertussis Toxin
Protein Serine-Threonine Kinases
Stk11 protein, mouse
AMP-Activated Protein Kinases
Hdac5 protein, mouse
Histone Deacetylases

Abstract

Publication types

MeSH terms

Substances

Grants and funding