Quantitation of brown adipose tissue perfusion in transgenic mice using near-infrared fluorescence imaging.
Brown adipose tissue (BAT; brown fat) is the principal site of adaptive thermogenesis in the human newborn and other small mammals. Of paramount importance for thermogenesis is vascular perfusion, which controls the flow of cool blood in, and warmed blood out, of BAT. We have developed an optical method for the quantitative imaging of BAT perfusion in the living, intact animal using the heptamethine indocyanine IR-786 and near-infrared (NIR) fluorescent light. We present a detailed analysis of the physical, chemical, and cellular properties of IR-786, its biodistribution and pharmacokinetics, and its uptake into BAT. Using transgenic animals with homozygous deletion of Type II iodiothyronine deiodinase, or homozygous deletion of uncoupling proteins (UCPs) 1 and 2, we demonstrate that BAT perfusion can be measured noninvasively, accurately, and reproducibly. Using these techniques, we show that UCP -1/-2 knockout animals, when compared to wild-type animals, have a higher baseline perfusion of BAT but a similar maximal response to beta 3-receptor agonist. These results suggest that compensation for UCP deletion is mediated, in part, by the control of BAT perfusion. Taken together, BAT perfusion can now be measured noninvasively using NIR fluorescent light, and pharmacological modulators of thermogenesis can be screened at relatively high throughput in living animals.
Nakayama
Akira
A
Beth Israel Deaconess Medical Center, Boston, MA, USA.
Bianco
Antonio C
AC
Zhang
Chen-Yu
CY
Lowell
Bradford B
BB
Frangioni
John V
JV
D002001:Adipose Tissue, Brown / Q000098:blood supply*; D000818:Animals; D001833:Body Temperature Regulation; D002232:Carbocyanines / Q000737:chemistry / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D005456:Fluorescent Dyes / Q000737:chemistry / Q000493:pharmacokinetics; D006439:Hemodynamics; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics; D007453:Iodide Peroxidase / Q000172:deficiency / Q000235:genetics; D007473:Ion Channels; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins; D010777:Photochemistry; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012995:Solubility; D019265:Spectroscopy, Near-Infrared / Q000379:methods*; D013347:Subcellular Fractions / Q000378:metabolism; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2
D002232:Carbocyanines; D002352:Carrier Proteins; D005456:Fluorescent Dyes; C577436:IR-786; D007211:Indoles; D007473:Ion Channels; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D007453:Iodide Peroxidase