Thyroid hormone (TH) responsive genes can be both positively and negatively regulated by TH through receptors (TR) α and γ expressed in most body tissues. However, their relative roles in the regulation of specific gene expression remain unknown. The TRβ knockout mouse, which lacks both TRβ1 and TRβ2 isoforms, provides a model to examine the role of these receptors in mediating TH action. TRβ deficient (TRβ-/-) mice that show no compensatory increase in TRα, and wild-type (TRβ+/+) mice of the same strain were deprived of TH by feeding them a low iodine diet containing propylthiouracil, and were then treated with supraphysiological doses of L- T3 (0.51 5.5, and 25 μg/day/mouse). TH deprivation alone increased the serum cholesterol concentration by 25% in TRβ+/+ mice and reduced it paradoxically by 23% in TRβ-/- mice. TH deprivation reduced the serum alkaline phosphatase (AP) concentration by 31% in TRβ+/+ mice but showed no change in the TRβ-/- mice. Treatment with L-T3 (0.5 to 25 μg/mouse/day) caused a 57% decrease in serum cholesterol and a 231% increase in serum AP in the TRβ+/+ mice. The TRβ-/- mice were resistant to the L-T3 induced changes in serum cholesterol and showed increase in AP only with the highest L-T3 dose. Basal heart rate (HR) in TRβ-/- mice was higher than that of TRβ+/+ mice by 11%. HR and energy expenditure (EE) in both TRβ+/+ and TRβ- /mice showed similar decreases (49 and 46%)and increases (49 and 41%) in response to TH deprivation and L-T3 treatment, respectively. The effect of TH on the accumulation of messenger RNA (mRNA) of TH regulated liver genes was also examined. TH deprivation down regulated spot 14 (S14) mRNA and showed no change in malic enzyme (ME) mRNA in both TRβ+/+ and TRβ-/- mice. In contrast treatment with L-T3 produced an increase in S14 and ME but no change in TRβ-/- mice. From these results, it can be concluded that regulation of HR and EE are independent of TRβ. With the exception of serum cholesterol concentration and liver ME mRNA accumulation, all other markers of TH action examined during TH deprivation exhibited the expected responses in the absence of TRβ. Thus, as previously shown for serum TSH, TRβ is not absolutely necessary for some changes typical of hypothyroidism to occur. In contrast, except for HR and EE, the full manifestation of TH-mediated action required the presence of TRβ.
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