Thyroxine 5'-deiodination mediates norepinephrine-induced lipogenesis in dispersed brown adipocytes.
In euthyroid rats, maximal sympathetic nervous system stimulation (e.g. during cold exposure) results in a 3- to 4-fold increase in brown adipose tissue lipogenesis, a response that is blunted in hypothyroid rats. To further investigate this phenomenon, the role of local type II 5'-deiodinase (5'-DII) was studied in freshly isolated brown adipocytes. In a typical experiment, 1.5 x 10(6) cells were incubated for up to 48 h in a water-saturated 5% CO2-95% O2 atmosphere. After incubation with medium alone or with different concentrations of T4, T3, and/or norepinephrine (NE), lipogenesis was studied by measuring 1) the rate of fatty acid synthesis as reflected by 3H2O incorporation into lipids and 2) the activity of key rate-limiting enzymes, i.e. acetyl coenzyme A carboxylase and malic enzyme, and the results are reported in terms of DNA content per tube. Lipogenesis decreased progressively over time (approximately 40%) when no additions were made to the incubation medium. T4 or T3 partially prevented that inhibition at physiological concentrations (65 x 10[-9] and 0.77 x 10[-9] M, respectively), whereas a receptor-saturating concentration of T3, (154 x 10[-9] M) doubled the lipogenesis rate. The addition of 10(-6) M NE inhibited lipogenesis acutely (approximately 50% by 12 h) and was followed by a progressive stimulation that reached approximately 2-fold by 48 h, but only in the presence of T4. Furthermore, NE did not attenuate T3 (154 x 10[-9] M)-induced lipogenesis. Both the inhibition and the stimulation of lipogenesis caused by NE showed a strong dose-response relationship within the range of 10(-11)-10(-5) M. The role of local 5'-DII was further tested by incubating brown adipocytes with 10(-6) M NE and T4 (65 x 10[-9] M) in the presence of 100 microM iopanoic acid, a potent inhibitor of 5'-DII. Although iopanoic acid did not affect the T3 stimulation of lipogenesis, it did block the approximately 2-fold stimulation of lipogenesis triggered by NE in the presence of T4, confirming the mediation of 5'-DII in this process. In conclusion, lipogenesis in brown adipose tissue is under complex hormonal control, with key roles played by NE, thyroid hormones, and local 5'-DII. As in other tissues, NE-generated signals acutely (12 h) inhibited lipogenesis. However, the presence of the 5'-DII generated enough T3 to stimulate lipogenesis and gradually reverse the short-lived NE-induced inhibition, leading to the 2- to 3-fold response observed at later time points.
Bianco
A C
AC
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Brazil. acbianco@usp.br
Carvalho
S D
SD
Carvalho
C R
CR
Rabelo
R
R
Moriscot
A S
AS
D017667:Adipocytes / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D003584:Cytological Techniques; D004305:Dose-Response Relationship, Drug; D004798:Enzymes / Q000378:metabolism; D007453:Iodide Peroxidase / Q000502:physiology*; D007480:Iopanoic Acid / Q000494:pharmacology; D008055:Lipids / Q000096:biosynthesis*; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D004798:Enzymes; D008055:Lipids; D007453:Iodide Peroxidase; D007480:Iopanoic Acid; D009638:Norepinephrine