Thyroid hormone and norepinephrine signaling in brown adipose tissue. II: Differential effects of thyroid hormone on beta 3-adrenergic receptors in brown and white adipose tissue.

Abstract

beta 3-adrenergic receptors (AR) are predominantly expressed in brown (BAT) and white adipose tissue (WAT), being more abundant in the former. There is growing interest in these receptors because of their potential to be pharmacologically targeted to control energy expenditure and lipid accretion. We have examined, in BAT and WAT of rats, the effect of thyroid hormone on the expression of beta 3-AR and their contribution to cAMP generation. Receptor density was assessed with the nonselective beta 3-AR ligand [125I]-cyanopindolol ([125I]-CYP) and the highly selective beta 3-AR agonist CL3216,243. beta 3-AR messenger RNA (mRNA) was analyzed by Northern blotting of total BAT and WAT RNA. Generation of cAMP by brown adipocytes in response to norepinephrine (NE) and CL316,243 was measured by RIA. In BAT, beta 3-AR can account for as much as 50% of the maximal cAMP response to NE, whereas in WAT these receptors probably account for all the effect of NE. In hypothyroidism. BAT beta 3-AR number is increased, as are beta 3-AR mRNA (4- to 6-fold) and the relative contribution of these receptors to the maximal cAMP production. In contrast, both beta 3-AR number and mRNA levels are reduced in WAT of hypothyroid rats. The injection of T3 to hypothyroid rats reverts the changes in beta 3-AR within 24 h, and T3 excess causes a greater than 90% reduction in beta 3-AR mRNA in BAT but a 5-fold increase in WAT. In both tissues, hypothyroidism is associated with a marked reduction in the capacity to generate cAMP, but this is not completely restored even after 2 days of a receptor-saturating dose of T3. 1) thyroid hormone differentially affects the expression of beta 3-AR in BAT and WAT; 2) these effects of T3 are both rapid and marked and seem to take place at a pretranslational level; 3) in both tissues there is a postreceptor defect in the generation of cAMP that is corrected by T3 much later after the changes in beta 3-AR are reversed; and 4) thyroid hormone is among the known factors that most vigorously affect the expression of beta 3-AR.