Decreased expression of steroidogenic acute regulatory protein: A novel mechanism participating in the leptin-induced inhibition of glucocorticoid biosynthesis

The adipocyte-derived hormone leptin is a central modulator of food intake, metabolism and neuroendocrine functions. It is also involved in a physiolo gical loop linking the activity of the hypothalamo-pituitary-adrenal axis a nd adipose tissue. At the adrenal level, leptin has been shown to antagoniz e the effects of ACTH on glucocorticoid biosynthesis by decreasing the expr ession of various enzymes of the steroid biosynthetic pathway. The steroido genic acute regulatory protein regulates cholesterol delivery to the P450(s cc) enzyme, a process that is rate limiting in steroid hormone biosynthesis . We have demonstrated here that leptin significantly inhibits the expressi on of steroidogenic acute regulatory protein in primary cultures of rat adr enocortical cells. This inhibition was observed at both the protein and mRN A levels. In contrast, leptin was not found to interfere with the expressio n of the cytosolic enzyme cholesterol ester hydrolase or with that of the m itochondrial enzyme P450(scc). In addition, we observed the anticipated sti mulation of cAMP production by ACTH in the presence of leptin, suggesting t hat it does not interfere with intracellular ACTH signaling. In summary, ou r data provide evidence that the interplay existing between leptin and ACTH in vivo is mediated at least partially via a direct and opposite modulatio n of steroidogenic acute regulatory protein, a key factor in the adrenal st eroid biosynthetic pathway. This effect of leptin could also be relevant to other steroidogenic tissues.