Abstract
Only three of the four thyroid hormone receptor (TR)
isoforms, α1, β1, and β2, bind thyroid hormone (TH) and are
considered to be true TRs. TRα2 binds to TH response elements on DNA,
but its role
in vivo
is still unknown. We produced mice
completely deficient in TRα (TRα
o/o
) that maintain
normal serum thyroid-stimulating hormone (TSH) concentration despite
low serum thyroxine (T
4
), suggesting increased sensitivity
to TH. We therefore examined the effects of TH
(L-3,3′,5-triiodothyronine, L-T
3
) given to TH-deprived and
to intact TRα
o/o
mice. Controls were wild-type (WT) mice
of the same strain and mice resistant to TH due to deficiency in TRβ
(TRβ
−/−
). In liver, T
3
produced
significantly greater responses in TRα
o/o
and smaller
responses in TRβ
−/−
as compared with WT mice. In
contrast, cardiac responses to L-T
3
were absent or reduced
in TRα
o/o
, whereas they were similar in WT and
TRβ
−/−
mice, supporting the notion that TRα1 is the
dominant TH-dependent TR isoform in heart. 5-Triiodothyronine
(L-T
3
) given to intact mice produced a greater suppression
of serum T
4
in TRα
o/o
than it did in WT mice
and reduced by a greater amount the TSH response to TSH-releasing
hormone. This is an
in vivo
demonstration that a TR
deficiency can enhance sensitivity to TH. This effect is likely due to
the abrogation of the constitutive “silencing” effect of TRα2
in tissues expressing the TRβ isoforms.
