Leptin-Mediated Increases in Catecholamine Signaling Reduce Adipose Tissue Inflammation via Activation of Macrophage HDAC4

Luan B, Goodarzi MO, Phillips NG, Guo X, Chen YD, Yao J, Allison M, Rotter JI, Shaw R, Montminy M. Cell Metab. (2014) 19(6): 1058-65.

Speaker: Ji-En Sie (謝季恩)                                         Time: 13:10~14:00, Oct. 1, 2014

Commentator: Dr. Yee-Shin Lin (林以行 老師)          Place: Room 601

Abstract

Obesity can promote inflammation response in macrophages and lead to the development of insulin resistance (1). According to the previous studies, the second messenger cyclic AMP (cAMP) has been shown to regulate gene expression and be an anti-inflammatory factor (2, 3). In this study, the authors used mouse bone marrow-derived macrophages (BMMs) to design the experiments. To define the role of cAMP, BMMs were exposed to bacterial lipopolysaccharide (LPS) and prostaglandin E2 (PGE2) that stimulates cAMP production, and observed that BMMs reduced proinflammatory cytokine secretion compared to LPS alone. Moreover, PGE2 blocked both the NF-κB subunit p65 and histone H4K5 acetylation over cytokine promoters and p65 recruitment to the Tnf-α and Il-12β promoters was reduced. On the other hand, the authors found that PGE2 triggered Class IIa histone deacetylase 4 (HDAC4) dephosphorylation and nuclear translocation to inhibit cytokine gene expression. In addition, the authors demonstrated that PGE2 increased HDAC4 dephosphorylation through inactivation of the salt-inducible kinases (SIKs) pathway which could phosphorylate HDACs. The authors performed the acute overnutrition animal model and the results indicated that the concentrations of norepinephrine and cAMP wereupregulated and the nuclear translocation of HDAC4 was promoted after leptin administration. Furthermore, the disruption of Hdac4 in macrophages could contribute to obesity and insulin resistance. In conclusion, cAMP-HDAC4 pathway could maintain insulin sensitivity and energy balance via its anti-inflammatory responses on the innate immune system following leptin-mediated increases in sympathetic nerve activity.

References

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3.     Mihaylova MM et al. Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell. (2011) 145(4): 607-21.