Targeting presynaptic norepinephrine transporter in brown adipose tissue: a novel imaging approach and potential treatment for diabetes and obesity.
Brown adipose tissue (BAT) plays a significant role in metabolism. In this study, we report the use of atomoxetine (a clinically applicable norepinephrine reuptake inhibitor) for (18)F-FDG PET imaging of BAT and its effects on heat production and blood glucose concentration. Fasted-male Sprague-Dawley rats were administered with intravenous (18)F-FDG. The same rats were treated with atomoxetine (0.1 mg/kg, i.v.) 30 min before (18)F-FDG administration. To confirm the β-adrenergic effects, propranolol (β-adrenergic inhibitor) 5 mg/kg was given intraperitoneally 30 min prior to atomoxetine administration. The effect of atomoxetine on BAT metabolism was assessed in fasted and non-fasted rats and on BAT temperature and blood glucose in fasted rats. In (18)F-FDG PET/CT images, interscapular BAT (IBAT) and other areas of BAT were clearly visualized. When rats were fasted, atomoxetine (0.1 mg/kg) increased the (18)F-FDG uptake of IBAT by factor of 24 within 30 min. Propranolol reduced the average (18)F-FDG uptake of IBAT significantly. Autoradiography of IBAT and white adipose tissue confirmed the data obtained by PET. When rats were not fasted, atomoxetine-induced increase of (18)F-FDG uptake in IBAT was delayed and occurred in 120 min. For comparison, direct stimulation of β(3)-adrenreceptors in non-fasted rats with CL-316, 243 occurred within 30 min. Atomoxetine-induced IBAT activation was associated with higher IBAT temperature and lower blood glucose. This was mediated by inhibition of norepinephrine reuptake transporters in IBAT leading to increased norepinephrine concentration in the synapse. Increased synaptic norepinephrine activates β(3)-adrenreceptors resulting in BAT hypermetabolism that is visible and quantifiable by (18)F-FDG PET/CT.
Preclinical Imaging, Department of Radiological Sciences, University of California Irvine, Irvine, California 92697-5000, USA. rezam@uci.edu
M Reza
MR
Mirbolooki
Cristian C
CC
Constantinescu
Min-Liang
ML
Pan
Jogeshwar
J
Mukherjee
D002001:Adipose Tissue, Brown / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D019788:Fluorodeoxyglucose F18 / Q000494:pharmacology; D008297:Male; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley
D018759:Adrenergic Uptake Inhibitors; D000319:Adrenergic beta-Antagonists; D001786:Blood Glucose; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011437:Propylamines; D019788:Fluorodeoxyglucose F18; D000069445:Atomoxetine Hydrochloride; D011433:Propranolol