Effects of hypothyroidism on brown adipose tissue adenylyl cyclase activity.

Hypothyroidism profoundly reduces the capacity of brown adipose tissue (BAT) to generate cAMP in response to adrenergic stimulation. Evidence obtained with isolated brown adipocytes suggests a postreceptor defect that offsets the hypothyroidism-induced increase in beta3-adrenergic receptors. The goal of the present studies was to identify the defect in the cAMP generation pathway for which we studied cAMP generation in isolated cells and purified BAT membranes from normal and hypothyroid rats. Studies with adenosine deaminase and the adenosine receptor-1 agonist r-phenyl isopropyl adenosine (R-PIA) show that hypothyroid cells are not more sensitive to adenosine (same EC50) but more inhibited by high concentrations of R-PIA. Pretreatment with pertussis toxin reduced the gap in cAMP generation between eu- and hypothyroid cells and the inhibition mediated by R-PIA, but did not normalize the cAMP response to forskolin in hypothyroid cells. Although purified euthyroid BAT membranes increased cAMP production wi...