Endocrine Abstracts

Purpose: Glucocorticoid is one of the key hormones that regulates energy balance. Glucocorticoid excess induce hyperphagia and obesity (e.g. Cushing syndrome), however, its mechanisms are not fully elucidated. On the other hand, Agouti-related protein (AgRP) is known as an orexigenic neuropeptide, which is expressed in the hypothalamic arcuate nucleus. To clarify the role of Agouti-related protein (AgRP) in glucocorticoid-induced obesity, we investigate here the effect of glucocorticoid on AgRP gene transcription and expression.

Methods: We examined in vitro the effect of dexamethasone on the AgRP gene transcription using the reporter assay and the electromobility shift assay (EMSA) in BE(2)C cells. We also examined in vivo the effect of corticosterone (CORT) administration on hypothalamic AgRP mRNA in C57BL6 mice using real time PCR.

Results: There are two glucocorticoid responsive elements (GRE1 and GRE2) in AgRP 5’-promoter region. Dexamethasone robust increased AgRP transcriptional activity. Deletion analysis revealed that GREs were necessary for dexamethasone responsiveness, and binding of glucocorticoid receptor to GREs was confirmed by the EMSA. CORT administration (2 weeks) increased body weight, food consumption and hypothalamic AgRP mRNA expression (AgRP/GAPDH:placebo 100.0±9.9, CORT 133.2±8.4, P<0.05).

Conclusion: These results suggest that glucocorticoid positively regulate AgRP gene transcription and expression. Glucocorticoid-induced hypothalamic AgRP could be associated with hyperphagia and obesity in Cushing syndrome.