The interactions among effects of thyroid status, glucagon, and dibutyryl cAMP (DBcAMP) on the regulation of hepatic metabolism of FFA were studied in perfused livers isolated from euthyroid, hypothyroid, and hyperthyroid male rats. The animals were made hypothyroid by treatment with propylthiouracil or hyperthyroid by treatment with T 3 . Uptake of oleic acid by perfused livers was not altered by treatment of the animal with T3 or propylthiouracil, or by addition to the medium of glucagon (10~9 M), DBCAMP (2 X 10~5 M), or methylisobutylxanthine (MIX; 2 HIM). In agreement with previous data, hepatic formation and secretion of triglyceride were diminished and ketogenesis was stimulated by hyperthyroidism, glucagon, and DBcAMP. These effects of diminished triglyceride output and enhanced ketogenesis observed in hyperthyroidism were exacerbated by glucagon, while livers from hypothyroid rats were insensitive to the effects of glucagon. MIX, a phosphodiesterase inhibitor, reversed the insensitivity of the livers from hypothyroid rats to the effects of glucagon. DBcAMP stimulated ketogenesis and inhibited triglyceride output by livers in the three treatment groups. The effects of DBcAMP were not modulated by thyroid status under the conditions of these experiments. The effects of glucagon on hepatic triglyceride concentration were qualitatively similar to those effects on perfusate triglyceride. DBcAMP did not affect hepatic triglyceride concentration in any of the treatment groups. Glucagon stimulated glucose output by livers from all treatment groups but was less effective with livers from hypothyroid rats than from euthyroid animals. DBcAMP stimulated glucose output from all treatment groups. It may be concluded from these data that thyroid status modulates the sensitivity of the liver to glucagon, as evaluated by metabolism of FFA. Because 2 mM MIX reversed the insensitivity of hypothyroid livers to 10~9 M glucagon, it is possible that the mechanism (s) through which thyroid hormones and glucagon interact to affect hepatic fatty acid metabolism may, in part, be mediated through pathways of cAMP metabolism, perhaps by altering the activity of hepatic cyclic nucleotide phosphodiesterase. (Endocrinology 110: 1740(Endocrinology 110: , 1982 I T WAS REPORTED in previous studies from this laboratory that although uptake of FFA by the isolated perfused rat liver was not altered by thyroid status (2, 3), glucagon (4, 5), or dibutyryl cAMP (DBcAMP; 6, 7), the subsequent metabolism of FFA was profoundly affected. Output of triglyceride was diminished, whereas ketogenesis was stimulated by T3, glucagon, and