Abstract
Adropin is a multifunctional peptide hormone encoded by the ENHO (energy homeostasis associated) gene. It plays a role in mechanisms related to increased adiposity, insulin resistance, as well as glucose, and lipid metabolism. The low adropin levels are strongly associated with obesity independent insulin resistance. On the other hand, overexpression or exogenous administration of adropin improves glucose homeostasis. The multidirectional, adropin-related effects associated with the regulation of metabolism in humans also appear to be attributable to the effects of this peptide on the activity of various elements of the endocrine system including adrenal cortex. Therefore, the main purpose of the present study was to investigate the effect of adropin on proliferation and secretory activity in the human HAC15 adrenal carcinoma cell line. In this study, we obtained several highly interesting findings. First, GPR19, the main candidate sensitizer of adrenocortical cells to adropin, was expressed in HAC15 cells. Moreover, GPR19 expression was relatively stable and not regulated by ACTH, forskolin, or adropin itself. Our findings also suggest that adropin has the capacity to decrease expression levels of steroidogenic genes such as steroidogenic acute regulatory protein (StAR) and CYP11A1, which then led to a statistically significant inhibition in cortisol and aldosterone biosynthesis and secretion. Based on whole transcriptome study and research involving transforming growth factor (TGF)-β type I receptor kinase inhibitor we demonstrated that attenuation of steroidogenesis caused by adropin is mediated by the TGF-β signaling pathway likely to act through transactivation mechanism. We found that HAC15 cells treated with adropin presented significantly higher proliferation levels than untreated cells. Using specific intracellular inhibitors, we showed that adropin stimulate proliferation via ERK1/2 and AKT dependent signaling pathways. We have also demonstrated that expression of GPR19 is elevated in adrenocortical carcinoma in relation to normal adrenal glands. High level of GPR19 expression in adrenocortical carcinoma may constitute a negative prognostic factor of disease progression.
Highlights
Adropin is a peptide hormone encoded by the expression of the adropin precursor gene (ENHO) gene, which is generally expressed in the liver, pancreas, and central nervous system [1]
We investigated the influence of exogenous adropin on proliferation and steroidogenesis in the human HAC15 adrenal carcinoma cell line
We found that exposing HAC15 cells to adropin decrease the secretion of aldosterone and cortisol by HAC15 cells
Summary
Adropin is a peptide hormone encoded by the ENHO (energy homeostasis associated) gene, which is generally expressed in the liver, pancreas, and central nervous system [1]. Hepatic ENHO expression is correlated with the expression of genes involved in glucose and lipid metabolism [4, 5]. Low adropin levels are strongly associated with pathological conditions such as insulin resistance, which is independent of the presence of obesity, dyslipidemia, hepatic steatosis, or increased fat mass [7]. Treatments involving either transgenic overexpression of adropin or systemic adropin treatment clearly attenuate insulin resistance and glucose intolerance in dieting obese mice. In parallel with these observations, adropin knockout mice have been shown to present increased hepatic steatosis, adiposity and insulin resistance [10]. Adropin deficiency correlates with the severity of obesity, dyslipidemia, and insulin resistance [3]
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