Plasma Agouti-Related Protein and Cortisol Levels in Cushing Disease: Evidence for the Regulation of Agouti-Related Protein by Glucocorticoids in Humans

Abstract

Context Glucocorticoids regulate energy balance, in part by stimulating the orexigenic neuropeptide agouti-related protein (AgRP). AgRP neurons express glucocorticoid receptors, and glucocorticoids have been shown to stimulate AgRP gene expression in rodents. Objective We sought to determine whether there is a relationship between plasma AgRP and hypothalamic AgRP in rats and to evaluate the relationship between cortisol and plasma AgRP in humans. Methods We retrospectively evaluated plasma AgRP levels prior to transsphenoidal surgery in 31 patients with Cushing disease (CD) vs 31 sex- and body mass index–matched controls from a separate study. We then prospectively measured plasma AgRP, before and 6 to 12 months after surgery, in a subgroup of 13 patients with CD. Plasma and hypothalamic AgRP were measured in adrenalectomized rats with and without corticosterone replacement. Results Plasma AgRP was stimulated by corticosterone in rats and correlated with hypothalamic AgRP expression. Plasma AgRP levels were higher in patients with CD than in controls (139 ± 12.3 vs 54.2 ± 3.1 pg/mL; P < 0.0001). Among patients with CD, mean 24-hour urine free cortisol (UFC) levels were 257 ± 39 μg/24 hours. Strong positive correlations were observed between plasma AgRP and UFC (r = 0.76; P < 0.0001). In 11 of 13 patients demonstrating surgical cure, AgRP decreased from 126 ± 20.6 to 62.5 ± 8.0 pg/mL (P < 0.05) postoperatively, in parallel with a decline in UFC. Conclusions Plasma AgRP levels are elevated in CD, are tightly correlated with cortisol concentrations, and decline with surgical cure. These data support the regulation of AgRP by glucocorticoids in humans. AgRP’s role as a potential biomarker and as a mediator of the adverse metabolic consequences of CD deserves further study.

Ectopic ACTH Syndrome Emerging 5 Years after the Diagnosis of Neuroendocrine Tumor

“…AgRP is most well known as a hypothalamic neuropeptide that stimulates appetite and inhibits energy expenditure by inhibiting the effect of alpha-MSH at melanocortin receptors. Plasma AgRP has been shown to reflect hypothalamic AgRP; it rises with fasting, falls with refeeding, and is inversely associated with BMI [14–17]. While AgRP is regulated by leptin, it is also regulated by cortisol in both animals and humans.…”

“…While AgRP is regulated by leptin, it is also regulated by cortisol in both animals and humans. Cortisol stimulates AgRP, which may partially explain why the AgRP is high in this case despite the patient having a BMI that is not low [17]. Another likely explanation for the elevated AgRP is the production of AgRP by the metastatic lung NET.…”

The acromegaly lipodystrophy

“…AgRP and proopiomelanocortin (POMC) neurons also integrate CNS pathways that modulate glucose utilization and production ( 219 – 224 ). In healthy humans, the plasma AgRP levels relate to insulin levels and HOMA score ( 213 , 215 , 216 ), and, in mice, evidence supports an effect of AgRP neuron activation to impair glucose metabolism ( 220 , 225 – 231 ). These data suggest a possible role for GH excess, acting centrally on AgRP, in the metabolic abnormalities of acromegaly.…”