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Myeloid adrenergic signaling via CaMKII forms a feedforward loop of catecholamine biosynthesis Free
Yan Luo1,2,†, Bilian Liu1,†, Xin Yang2, Xiaoxiao Ma3, Xing Zhang2,4, Denis E. Bragin5, Xuexian O. Yang4, Wendong Huang3, and Meilian Liu1,2,*
1 Department of Endocrinology and Metabolism, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha 410011, China
2 Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center School of Medicine, Albuquerque, NM 87131, USA
3 Department of Diabetes Complications & Metabolism Research, City of Hope, Duarte, CA 91010, USA
4 Department of Microbiology and Molecular Genetics, University of New Mexico Health Sciences Center School of Medicine, Albuquerque, NM 87131, USA
5 Department of Neurosurgery, University of New Mexico Health Sciences Center School of Medicine, Albuquerque, NM 87131, USA † These two authors contributed equally to this study. *Correspondence to:Meilian Liu, E-mail:
J Mol Cell Biol, Volume 9, Issue 5, October 2017, Pages 422-434  
Keyword: CaMKII, adrenaline, tyrosine hydroxylase, catecholamine, UCP1

Type 2 immune response has been shown to facilitate cold-induced thermogenesis and browning of white fat. However, whether alternatively activated macrophages produce catecholamine and substantially promote adaptive thermogenesis in adipose tissue remains controversial. Here, we show that tyrosine hydroxylase (TyrH), a rate-limiting enzyme of catecholamine biosynthesis, was expressed and phosphorylated in adipose-resident macrophages. In addition, the plasma level of adrenaline was increased by cold stress in mice, and treatment of macrophages with adrenaline stimulated phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and TyrH. Genetic and pharmacological inhibition of CaMKII or PKA signaling diminished adrenaline-induced phosphorylation of TyrH in primary macrophages. Consistently, overexpression of constitutively active CaMKII upregulated basal TyrH phosphorylation, while suppressing the stimulatory effect of adrenaline on TyrH in macrophages. Myeloid-specific disruption of CaMKIIγ suppressed both the cold-induced production of norepinephrine and adipose UCP1 expression in vivo and the stimulatory effect of adrenaline on macrophage-dependent activation of brown adipocytes in vitro. Lack of CaMKII signaling attenuated catecholamine production mediated by cytokines IL-4 and IL-13, key inducers of type 2 immune response in primary macrophages. Taken together, these results suggest a feedforward mechanism of adrenaline in adipose-resident macrophages, and that myeloid CaMKII signaling plays an important role in catecholamine production and subsequent beige fat activation.