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Published on: March 12, 2019
AgRP reflects glucocorticoid action: integrated experimental and clinical evidence
Natsuki Aoyama1, Mitsuru Nishiyama2,3, Yasumasa Iwasaki1,4
1Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, 1-185, Kohasu, Oko-cho, Nankoku, 783-8505, Kochi, Japan.
Purpose:
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.
Methods:
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.
Results:
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).
Conclusion:
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.
Insights
Glucocorticoids (GCs) regulate energy balance. This study shows that Agouti-related protein (AgRP) levels increase with GC action in cells, mice, and humans, suggesting AgRP as a potential biomarker for GC activity.
Area of Science:
- Endocrinology and Metabolism
- Molecular Biology
- Neuroscience
Background:
- Glucocorticoids (GCs) are critical for energy homeostasis, influencing weight in conditions like Cushing's syndrome and adrenal insufficiency.
- Currently, no established circulating biomarkers accurately reflect GC action in patients.
- Agouti-related protein (AgRP), a neuropeptide that stimulates appetite, is known to be upregulated by GCs in rodent brains.
Purpose of the Study:
- To investigate whether Agouti-related protein (AgRP) can serve as a surrogate biomarker for glucocorticoid (GC) action.
- To examine the relationship between GC levels and AgRP expression in molecular, animal, and human studies.
Main Methods:
- Reporter assays were used to assess GC-dependent transcriptional regulation of the AgRP gene promoter in neuronal cells.
- Experiments in C57BL/6J mice evaluated the impact of GCs on hypothalamic AgRP mRNA expression and correlated it with circulating GC levels.
- Circulating AgRP levels were measured in patients with adrenal Cushing's syndrome before and after surgical treatment.
Main Results:
- Two functional glucocorticoid-responsive elements (GREs) were identified in the human AgRP gene promoter, confirming GC enhances AgRP transcription.
- In mice, administration of corticosterone (CORT) led to increased food intake and elevated hypothalamic AgRP mRNA, with levels positively correlating to plasma CORT.
- Patients with adrenal Cushing's syndrome showed a significant decrease in circulating AgRP levels post-surgery, which positively correlated with preoperative serum cortisol levels.
Conclusions:
- Glucocorticoids positively regulate Agouti-related protein (AgRP) expression across molecular, animal, and clinical models.
- Circulating AgRP levels show a strong correlation with GC action, supporting its potential as a surrogate biomarker.
- Further research is needed to confirm the clinical utility of AgRP as a biomarker for GC activity.
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