Abstract
BackgroundIn Cushing’s syndrome (CS), chronic glucocorticoid excess (GC) and disrupted circadian rhythm lead to insulin resistance (IR), diabetes mellitus, dyslipidaemia and cardiovascular comorbidities. As undifferentiated, self-renewing progenitors of adipocytes, mesenchymal stem cells (MSCs) may display the detrimental effects of excess GC, thus revealing a promising model to study the molecular mechanisms underlying the metabolic complications of CS.MethodsMSCs isolated from the abdominal skin of healthy subjects were treated thrice daily with GCs according to two different regimens: lower, circadian-decreasing (Lower, Decreasing Exposure, LDE) versus persistently higher doses (Higher, Constant Exposure, HCE), aimed at mimicking either the physiological condition or CS, respectively. Subsequently, MSCs were stimulated with insulin and glucose thrice daily, resembling food uptake and both glucose uptake/GLUT-4 translocation and the expression of LIPE, ATGL, IL-6 and TNF-α genes were analyzed at predefined timepoints over three days.ResultsLDE to GCs did not impair glucose uptake by MSCs, whereas HCE significantly decreased glucose uptake by MSCs only when prolonged. Persistent signs of IR occurred after 30 hours of HCE to GCs. Compared to LDE, MSCs experiencing HCE to GCs showed a downregulation of lipolysis-related genes in the acute period, followed by overexpression once IR was established.ConclusionsPreserving circadian GC rhythmicity is crucial to prevent the occurrence of metabolic alterations. Similar to mature adipocytes, MSCs suffer from IR and impaired lipolysis due to chronic GC excess: MSCs could represent a reliable model to track the mechanisms involved in GC-induced IR throughout cellular differentiation.
Highlights
Glucocorticoids (GCs) regulate a variety of physiological processes, such as metabolism, immune response, cardiovascular activity and brain function [1, 2]
As progenitors of specialized cellular lines that are directly implicated in the progression of chronic glucocorticoid excess (GC) excess-induced damage, mesenchymal stem cells (MSCs) are of particular interest: in a previous study, we showed that MSCs derived from the skin of patients with Cushing’s syndrome (CS) displayed dysregulated inflammatory markers and altered expression of genes related to wound healing, demonstrating how they could be a useful cellular model to study this event and their potential contribution to the development of CS manifestations [16]
MSCs derived from skin could be a good human model for studying the toxic effects of GCs
Summary
Glucocorticoids (GCs) regulate a variety of physiological processes, such as metabolism, immune response, cardiovascular activity and brain function [1, 2]. Chronic excess and dysregulation of GCs induces Cushing’s syndrome (CS), a complex clinical condition characterized by multisystem morbidities such as central obesity, hypertension, type 2 diabetes mellitus, insulin resistance (IR), dyslipidaemia, fatty liver, hypercoagulability, myopathy and osteoporosis [3–5]. Several studies have shown how chronic exposure to high levels of GCs reduces IRS-1 phosphorylation and protein expression, resulting in a lack of GLUT4 translocation and a reduction in glucose uptake in adipose tissue [11]. The chronic excess of GCs increases lipoprotein activity and expression with subsequent release of circulating fatty acids, which, in turn, induce the phosphorylation of serine in IRS-1, compromising the mechanisms that lead to glucose transport into the cell [12]. In Cushing’s syndrome (CS), chronic glucocorticoid excess (GC) and disrupted circadian rhythm lead to insulin resistance (IR), diabetes mellitus, dyslipidaemia and cardiovascular comorbidities. Self-renewing progenitors of adipocytes, mesenchymal stem cells (MSCs) may display the detrimental effects of excess GC, revealing a promising model to study the molecular mechanisms underlying the metabolic complications of CS
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