EFFECT OF HYPOTHYROIDISM ON ADENYLYL-CYCLASE ACTIVITY AND SUBTYPE GENE-EXPRESSION IN BROWN ADIPOSE-TISSUE

Brown adipose tissue (BAT) expresses several adenylyl cyclase (AC) sub types, and adrenergic stimulation selectively upregulates AC-III gene expression. Previous studies have described synergistic interactions b etween the sympathetic nervous system (SNS) and 3,5,3'-triiodothyronin e (T-3) on the regulation of gene expression in BAT. Because adrenergi c stimulation also increases the activity of BAT type II thyroxine 5'- deiodinase (DII) and local T-3 generation is important for many functi onal responses in BAT, we examined the effects of thyroid hormone stat us on the expression of various AC subtypes. Hypothyroidism selectivel y increased AC-III mRNA levels in BAT but not in white adipose tissue. Of the other subtypes examined, hypothyroidism did not alter AC-VI mR NA levels and slightly reduced AC-M mRNA levels in BAT. The increase i n AC-III expression was paralleled by an increase in forskolin-stimula ted AC activity in BAT membranes. Sympathetic denervation of BAT aboli shed the increase in both AC activity and AC-III mRNA expression produ ced by hypothyroidism, but did not affect the expression of other subt ypes. Surgical denervation also prevented the induction of AC-III in t he cold-stressed euthyroid rat, but injections of T-3 failed to alter AC-III expression in intact or denervated BAT. Our results indicate th at T-3 does not directly affect expression of AC-III. Rather, hypothyr oidism increases BAT AC-III expression indirectly via an increase in s ympathetic stimulation. Furthermore, our results strongly indicate tha t the increase in AC activity in hypothyroid BAT is due to increased e xpression of AC-III.