Effect of thyroid hormones and cyclic AMP on some lipogenic enzymes of the fat cell.

Abstract

Thyroid hormones exert two types of effect on the lipogenic pathway of the fat cell of the young rat: one which is independent of cyclic AMP, and another which is under cyclic nucleotide control: Thyroidectomy leads to an enhanced conversion of glucose to glucose 6‐phosphate by the hexokinase system. The activity of hexokinase I is increased twofold in the fat cell from hypothyroid rats. The oxidation of glucose 6‐phosphate by the pentose phosphate pathway is also increased after thyroidectomy. The V of both glucose 6‐phosphate and gluconate‐6‐phosphate dehydrogenases is doubled (56 mU × min−1× mg−1 to 114 mU × min−1× mg−1) whereas the Km, is unchanged (19 μM). The activities of ATP citrate lyase and of acetyl‐CoA carboxylase are higher in the adipocytes from hypothyroid rats. The activity of fatty acid synthetase is also stimulated, but to a lesser extent. The apparent Km of acetyl‐CoA carboxylase is 0.14 mM and 0.06 mM and the V is 17.8 nmol xmin−1 xmg‐′ and 27.8 nmolxmin−1 xmg protein−1 in the adipocytes from normal and hypothyroid rats respectively. In contrast, for ATP citrate lyase the V only is doubled (62 mU × min−1× mg−1 to 111 mUxmin−1xmg−1). When fat cells from normal or hypothyroid rat were incubated in the presence of methylxanthines, dibutyryladenosine 3′,5′‐monophosphate, isoproterenol or epinephrine the activities of the hexokinase system and of glucose‐6‐phosphate and gluconate‐6‐phosphate dehydrogenases remained unchanged. In contrast, dibutyryl‐ adenosine 3′,5′‐monophosphate inhibited, by 60 ‐ 80%, the activities of ATP citrate lyase and acetyl‐CoA carboxylase in both cell types. In adipocytes prepared from normal rats, isoproterenol and epinephrine inhibited the activities of these two latter enzymes by 30 ‐ 60% while isobutylmethylxanthine potentiated their effect. In contrast, with fat cells from hypothyroid rats, isoproterenol and epinephrine had no effect upon the activities of ATP citrate lyase and acetyl‐CoA carboxylase, whereas a combination of epinephrine and ibobutylmethylxanthine was clearly inhibitory. In conclusion, thyroid hormones regulate lipogenesis in the fat cell of the young rat firstly because they control the accumulation of the substrates of this pathway, glucose 6‐phosphate and NADPH, by changing the concentrations of the hexokinase system and of the rate‐limiting enzymes of the pentose phosphate pathway. Secondly, because they have a specific effect on the amount of the enzymes (ATP citrate lyase and acetyl‐CoA carboxylase) which channel acetyl‐CoA towards long chain fatty acid synthesis; and thirdly because they allow, in response to the lipolytic hormones, the accumulation of cyclic AMP which is responsible for the inactivation of these two latter enzymes.