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Inducible Nitric Oxide Synthase in Rat Brown Adipocytes: Implications for Blood Flow to Brown Adipose Tissue¹

Department of Pharmacology, Chemotherapy, and Medical Toxicology, LITA Ospedale L. Sacco, Milan University, School of Medicine, Milan, Italy

Address all correspondence and requests for reprints to: Dr. Enzo Nisoli, Dipartimento di Farmacologia, Chemioterapia e Tossicologia Medica, Università degli Studi, Via Vanvitelli 32, 20129 Milan, Italy.

Exposure of rat brown adipocytes differentiated in culture to norepinephrine (NE) results in the production of nitrites (NO₂^-), the breakdown product of nitric oxide (NO). This production, which is blocked by actinomycin D, is directly related to the duration of exposure to and dose of NE. Cytosol from NE-treated brown fat cells, but not from untreated cultures, catalyzed the Ca²⁺-independent conversion of L-arginine to L-citrulline, which could be significantly blocked by the specific nitric oxide synthase (NOS) inhibitor N^G-nitro-L-arginine methyl ester. Reverse transcriptase-PCR demonstrates that the addition of NE; selective ß₁-, ß₂-, or ß₃-adrenergic receptor agonists; or agents increasing cAMP production, such as forskolin, to brown adipocytes stimulates inducible NOS (iNOS) messenger RNA, which is present within 4 h after exposure. That iNOS is synthesized in brown fat cells is confirmed by immunoblotting using an antibody to the iNOS of mouse macrophages. Finally, in both brown adipose tissue (BAT) and brown adipocyte preparations from animals exposed to low temperature, iNOS messenger RNA and protein were expressed, and NOS activity was detectable; these findings were unlikely for room temperature-acclimated rats. We conclude that brown fat cells can express an inducible form of NOS similar to the iNOS of macrophages, and that its production is directly dependent on sympathetic activity in physiological conditions. NO generated by stimulation of iNOS in brown adipocytes may represent an important mechanism to modulate different BAT functions, among which is vasodilation of the BAT microcirculation.

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