Absence of thyroid hormone activation during development underlies a permanent defect in adaptive thermogenesis.
Type 2 deiodinase (D2), which is highly expressed in brown adipose tissue (BAT), is an enzyme that amplifies thyroid hormone signaling in individual cells. Mice with inactivation of the D2 pathway (D2KO) exhibit dramatically impaired thermogenesis in BAT, leading to hypothermia during cold exposure and a greater susceptibility to diet-induced obesity. This was interpreted as a result of defective acute activation of BAT D2. Here we report that the adult D2KO BAT has a permanent thermogenic defect that stems from impaired embryonic BAT development. D2KO embryos have normal serum T3 but due to lack of D2-generated T3 in BAT, this tissue exhibits decreased expression of genes defining BAT identity [i.e. UCP1, PGC-1alpha and Dio2 (nonfunctional)], which results in impaired differentiation and oxidative capacity. Coinciding with a reduction of these T3-responsive genes, there is oxidative stress that in a cell model of brown adipogenesis can be linked to decreased insulin signaling and decreased adipogenesis. This discovery highlights the importance of deiodinase-controlled thyroid hormone signaling in BAT development, where it has important metabolic repercussions for energy homeostasis in adulthood.
Hall
Jessica A
JA
Biological and Biomedical Sciences Program, Harvard Medical School, Boston, Massachusetts 02115, USA.
Ribich
Scott
S
Christoffolete
Marcelo A
MA
Simovic
Gordana
G
Correa-Medina
Mayrin
M
Patti
Mary Elizabeth
ME
Bianco
Antonio C
AC
D000064:Acclimatization / Q000235:genetics / Q000502:physiology; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics / Q000502:physiology; D002001:Adipose Tissue, Brown / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010101:Oxygen Consumption / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013696:Temperature; D022722:Thermogenesis / Q000235:genetics / Q000502:physiology*; D013963:Thyroid Hormones / Q000097:blood / Q000378:metabolism*; D013997:Time Factors; D000097564:Iodothyronine Deiodinase Type II
D007453:Iodide Peroxidase; D013963:Thyroid Hormones; D000097564:Iodothyronine Deiodinase Type II