Mice with targeted disruption of the Dio2 gene have cold-induced overexpression of the uncoupling protein 1 gene but fail to increase brown adipose tissue lipogenesis and adaptive thermogenesis.
The Dio2 gene encodes the type 2 deiodinase (D2) that activates thyroxine (T4) to 3,3',5-triiodothyronine (T3), the disruption of which (Dio2(-/-)) results in brown adipose tissue (BAT)-specific hypothyroidism in an otherwise euthyroid animal. In the present studies, cold exposure increased Dio2(-/-) BAT sympathetic stimulation approximately 10-fold (normal approximately 4-fold); as a result, lipolysis, as well as the mRNA levels of uncoupling protein 1, guanosine monophosphate reductase, and peroxisome proliferator-activated receptor gamma coactivator 1, increased well above the levels detected in the cold-exposed wild-type animals. The sustained Dio2(-/-) BAT adrenergic hyperresponse suppressed the three- to fourfold stimulation of BAT lipogenesis normally seen after 24-48 h in the cold. Pharmacological suppression of lipogenesis with betabeta'-methyl-substituted alpha-omega-dicarboxylic acids of C14-C18 in wild-type animals also impaired adaptive thermogenesis in the BAT. These data constitute the first evidence that reduced adrenergic responsiveness does not limit cold-induced adaptive thermogenesis. Instead, the resulting compensatory hyperadrenergic stimulation prevents the otherwise normal stimulation in BAT lipogenesis during cold exposure, rapidly exhausting the availability of fatty acids. The latter is the preponderant determinant of the impaired adaptive thermogenesis and hypothermia in cold-exposed Dio2(-/-) mice.
Christoffolete
Marcelo A
MA
Department of Medicine, Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Linardi
Camila C G
CC
de Jesus
Lucia
L
Ebina
Katia Naomi
KN
Carvalho
Suzy D
SD
Ribeiro
Miriam O
MO
Rabelo
Rogerio
R
Curcio
Cyntia
C
Martins
Luciane
L
Kimura
Edna T
ET
Bianco
Antonio C
AC
D002001:Adipose Tissue, Brown / Q000473:pathology / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D001833:Body Temperature Regulation / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000235:genetics; D007037:Hypothyroidism / Q000209:etiology / Q000235:genetics / Q000473:pathology; D007453:Iodide Peroxidase / Q000172:deficiency* / Q000235:genetics*; D007473:Ion Channels; D008055:Lipids / Q000096:biosynthesis; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins; D016133:Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D000071256:Uncoupling Protein 1; D000097564:Iodothyronine Deiodinase Type II
D002352:Carrier Proteins; D017931:DNA Primers; D007453:Iodide Peroxidase; D007473:Ion Channels; D008055:Lipids; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000071256:Uncoupling Protein 1; D000097564:Iodothyronine Deiodinase Type II; C000604372:Ucp1 protein, mouse