AgRP reflects glucocorticoid action: integrated experimental and clinical evidence

Glucocorticoids (GCs) are key regulators of energy homeostasis. Clinically, patients with Cushing's syndrome exhibit obesity, whereas adrenal insufficiency is associated with weight loss. However, circulating biomarkers reflecting GC action have not been established. Agouti-related protein (AgRP), an orexigenic neuropeptide, is upregulated by GC in the rodent hypothalamus. Here, we investigated whether AgRP is a surrogate marker of GC action through in vitro and in vivo experiments as well as a clinical study.

The GC-dependent transcriptional regulation of AgRP was examined using reporter assays in neuronal BE(2)C cells. In animal experiments, the effects of GC on hypothalamic AgRP mRNA expression in C57BL/6J mice were examined. Circulating AgRP levels were also analyzed in nine patients with adrenal Cushing's syndrome before and after surgery.

Two functional glucocorticoid-responsive elements (GREs) were identified in the human AgRP gene promoter, through which GC enhanced AgRP transcriptional activity. In mice, corticosterone (CORT) administration induced hyperphagia and increased hypothalamic AgRP mRNA levels, which positively correlated with plasma CORT levels. In patients with adrenal Cushing's syndrome, circulating AgRP levels significantly decreased after surgery (118.7 ± 40.3 vs. 37.7 ± 9.5 pg/mL, p < 0.01) and positively correlated with serum cortisol levels (r = 0.79, p < 0.01).

These findings demonstrate that GC positively regulates AgRP across molecular, animal, and clinical settings, supporting the hypothesis that circulating AgRP may serve as a surrogate indicator of GC action. Further studies are warranted to establish its clinical applicability.