Sympathetic Nerve Activity Maintains an Anti-Inflammatory State in Adipose Tissue in Male Mice by Inhibiting TNF-α Gene Expression in Macrophages

Adipose tissue macrophages (ATMs) play an important role in the inflammatory response in obese animals. How ATMs are regulated in lean animals has remained elusive, however. We now show that the sympathetic nervous system (SNS) is necessary to maintain the abundance of the mRNA for the proinflammatory cytokine TNF-alpha at a low level in ATMs of lean mice. Intracerebroventricular injection of agouti-related neuropeptide increased the amount of TNF-alpha mRNA in epididymal (epi) white adipose tissue (WAT), but not in interscapular brown adipose tissue (BAT), through inhibition of sympathetic nerve activity in epiWAT. The surgical denervation and beta-adrenergic antagonist propranolol up-regulated TNF-alpha mRNA in both epiWAT and BAT in vivo. Signaling by the beta(2)-adrenergic receptor (AR) and protein kinase A down-regulated TNF-alpha mRNA in epiWAT explants and suppressed lipopolysaccharide-induced up-regulation of TNF-alpha mRNA in the stromal vascular fraction of this tissue. beta-AR-deficient (beta-less) mice manifested an increased plasma TNF-alpha concentration and increased TNF-alpha mRNA abundance in epiWAT and BAT. TNF-alpha mRNA abundance was greater in ATMs (CD11b(+) cells of the stromal vascular fraction) from epiWAT or BAT of wild-type mice than in corresponding CD11b(+) cells, and beta(2)-AR mRNA abundance was greater in ATMs than in CD11b(+) cells of epiWAT. Our results show that the SNS and beta(2)-AR-protein kinase A pathway maintain an anti-inflammatory state in ATMs of lean mice in vivo, and that the brain melanocortin pathway plays a role in maintaining this state in WAT of lean mice via the SNS.