Thyroid hormone (TH) responsive genes can be both positively and negatively 
regulated by TH through receptors (TR) alpha and beta expressed in most body 
tissues. However, their relative roles in the regulation of specific gene 
expression remain unknown. The TR beta knockout mouse, which lacks both TR beta1 
and TR beta2 isoforms, provides a model to examine the role of these receptors 
in mediating TH action. TR beta deficient (TR beta-/-) mice that show no 
compensatory increase in TR alpha, and wild-type (TR beta+/+) 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 
(0.5, 5.5, and 25 microg/day/mouse). TH deprivation alone increased the serum 
cholesterol concentration by 25% in TR beta+/+ mice and reduced it paradoxically 
by 23% in TR beta-/- mice. TH deprivation reduced the serum alkaline phosphatase 
(AP) concentration by 31% in TR beta+/+ mice but showed no change in the TR 
beta-/- mice. Treatment with L-T3 (0.5 to 25 microg/mouse/day) caused a 57% 
decrease in serum cholesterol and a 231% increase in serum AP in the TR beta+/+ 
mice. The TR beta-/- 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 TR beta-/- mice was higher than that of TR beta+/+ mice by 
11%. HR and energy expenditure (EE) in both TR beta+/+ and TR beta-/- 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 TR beta+/+ and TR beta-/- mice. In contrast 
treatment with L-T3 produced an increase in S14 and ME but no change in TR 
beta-/- mice. From these results, it can be concluded that regulation of HR and 
EE are independent of TR beta. 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 TR beta. Thus, as previously shown for serum TSH, TR beta 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 TR beta.