title: Sympathetic Nerve Activity Maintains an Anti-Inflammatory State in Adipose Tissue in Male Mice by Inhibiting TNF-α Gene Expression in Macrophages.
abstract: 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-α at a low level in ATMs of lean mice. Intracerebroventricular injection of agouti-related neuropeptide increased the amount of TNF-α 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 β-adrenergic antagonist propranolol up-regulated TNF-α mRNA in both epiWAT and BAT in vivo. Signaling by the β2-adrenergic receptor (AR) and protein kinase A down-regulated TNF-α mRNA in epiWAT explants and suppressed lipopolysaccharide-induced up-regulation of TNF-α mRNA in the stromal vascular fraction of this tissue. β-AR-deficient (β-less) mice manifested an increased plasma TNF-α concentration and increased TNF-α mRNA abundance in epiWAT and BAT. TNF-α 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 β2-AR mRNA abundance was greater in ATMs than in CD11b(-) cells of epiWAT. Our results show that the SNS and β2-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.
authors.affiliation: Division of Endocrinology and Metabolism (L.T., S.O., K.T., T.Sa., K.S., S.Y., Y.M.), Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Aichi 444-8585, Japan; Department of Physiological Sciences (S.O., T.Sa., Y.M.), Sokendai (The Graduate University for Advanced Studies), Hayama, Kanagawa 240-0193, Japan; Department of Integrative Physiology (T.Sh.), Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima City, Tokushima 770-8503, Japan; and Section of Comparative Medicine (C.T.), Yale University School of Medicine, New Haven, Connecticut 06520-8016.
authors.forename: Lijun
authors.initials: L
authors.lastname: Tang
authors.affiliation: Division of Endocrinology and Metabolism (L.T., S.O., K.T., T.Sa., K.S., S.Y., Y.M.), Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Aichi 444-8585, Japan; Department of Physiological Sciences (S.O., T.Sa., Y.M.), Sokendai (The Graduate University for Advanced Studies), Hayama, Kanagawa 240-0193, Japan; Department of Integrative Physiology (T.Sh.), Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima City, Tokushima 770-8503, Japan; and Section of Comparative Medicine (C.T.), Yale University School of Medicine, New Haven, Connecticut 06520-8016.
authors.forename: Shiki
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Division of Endocrinology and Metabolism (L.T., S.O., K.T., T.Sa., K.S., S.Y., Y.M.), Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Aichi 444-8585, Japan; Department of Physiological Sciences (S.O., T.Sa., Y.M.), Sokendai (The Graduate University for Advanced Studies), Hayama, Kanagawa 240-0193, Japan; Department of Integrative Physiology (T.Sh.), Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima City, Tokushima 770-8503, Japan; and Section of Comparative Medicine (C.T.), Yale University School of Medicine, New Haven, Connecticut 06520-8016.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Shiuchi
authors.affiliation: Division of Endocrinology and Metabolism (L.T., S.O., K.T., T.Sa., K.S., S.Y., Y.M.), Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Aichi 444-8585, Japan; Department of Physiological Sciences (S.O., T.Sa., Y.M.), Sokendai (The Graduate University for Advanced Studies), Hayama, Kanagawa 240-0193, Japan; Department of Integrative Physiology (T.Sh.), Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima City, Tokushima 770-8503, Japan; and Section of Comparative Medicine (C.T.), Yale University School of Medicine, New Haven, Connecticut 06520-8016.
authors.forename: Chitoku
authors.initials: C
authors.lastname: Toda
authors.affiliation: Division of Endocrinology and Metabolism (L.T., S.O., K.T., T.Sa., K.S., S.Y., Y.M.), Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Aichi 444-8585, Japan; Department of Physiological Sciences (S.O., T.Sa., Y.M.), Sokendai (The Graduate University for Advanced Studies), Hayama, Kanagawa 240-0193, Japan; Department of Integrative Physiology (T.Sh.), Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima City, Tokushima 770-8503, Japan; and Section of Comparative Medicine (C.T.), Yale University School of Medicine, New Haven, Connecticut 06520-8016.
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Takagi
authors.affiliation: Division of Endocrinology and Metabolism (L.T., S.O., K.T., T.Sa., K.S., S.Y., Y.M.), Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Aichi 444-8585, Japan; Department of Physiological Sciences (S.O., T.Sa., Y.M.), Sokendai (The Graduate University for Advanced Studies), Hayama, Kanagawa 240-0193, Japan; Department of Integrative Physiology (T.Sh.), Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima City, Tokushima 770-8503, Japan; and Section of Comparative Medicine (C.T.), Yale University School of Medicine, New Haven, Connecticut 06520-8016.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sato
authors.affiliation: Division of Endocrinology and Metabolism (L.T., S.O., K.T., T.Sa., K.S., S.Y., Y.M.), Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Aichi 444-8585, Japan; Department of Physiological Sciences (S.O., T.Sa., Y.M.), Sokendai (The Graduate University for Advanced Studies), Hayama, Kanagawa 240-0193, Japan; Department of Integrative Physiology (T.Sh.), Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima City, Tokushima 770-8503, Japan; and Section of Comparative Medicine (C.T.), Yale University School of Medicine, New Haven, Connecticut 06520-8016.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Saito
authors.affiliation: Division of Endocrinology and Metabolism (L.T., S.O., K.T., T.Sa., K.S., S.Y., Y.M.), Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Aichi 444-8585, Japan; Department of Physiological Sciences (S.O., T.Sa., Y.M.), Sokendai (The Graduate University for Advanced Studies), Hayama, Kanagawa 240-0193, Japan; Department of Integrative Physiology (T.Sh.), Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima City, Tokushima 770-8503, Japan; and Section of Comparative Medicine (C.T.), Yale University School of Medicine, New Haven, Connecticut 06520-8016.
authors.forename: Shigefumi
authors.initials: S
authors.lastname: Yokota
authors.affiliation: Division of Endocrinology and Metabolism (L.T., S.O., K.T., T.Sa., K.S., S.Y., Y.M.), Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Aichi 444-8585, Japan; Department of Physiological Sciences (S.O., T.Sa., Y.M.), Sokendai (The Graduate University for Advanced Studies), Hayama, Kanagawa 240-0193, Japan; Department of Integrative Physiology (T.Sh.), Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima City, Tokushima 770-8503, Japan; and Section of Comparative Medicine (C.T.), Yale University School of Medicine, New Haven, Connecticut 06520-8016.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Minokoshi
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D054369:Agouti-Related Protein / Q000008:administration & dosage; D000818:Animals; D002460:Cell Line; D004822:Epididymis / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D015151:Immunoblotting; D018836:Inflammation Mediators / Q000378:metabolism*; D007276:Injections, Intraventricular; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000008:administration & dosage; D011433:Propranolol / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013562:Sympathectomy; D013564:Sympathetic Nervous System / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D000319:Adrenergic beta-Antagonists; D054369:Agouti-Related Protein; D018836:Inflammation Mediators; D010446:Peptide Fragments; D011943:Receptors, Adrenergic, beta; D014409:Tumor Necrosis Factor-alpha; C412618:agouti-related peptide, (Yc(CRFFNAFC)Y); D011433:Propranolol