Wnt/β-catenin signaling pathway and lipolysis enzymes participate in methylprednisolone induced fat differential distribution between subcutaneous and visceral adipose tissue
Graphical abstract
Introduction
Glucocorticoids (GCs) have broad effects on anti-inflammation and carbohydrate, lipid, and protein metabolism. One of the most distressing side effects for patients receiving long-term GCs treatment is weight gain, often with disfiguring fat deposition. There are several important differences between synthetic and natural GCs. Many synthetic GCs also have some amount of mineralocorticoid properties. Other key differences between synthetic and natural GCs include the degree of absorption through lipid barriers and the half-life. The pharmacological effects of natural and synthetic GCs are mediated by the same genomic and non-genomic pathways. Methylprednisolone (MPL) is a synthetic glucocorticoid that binds to both glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) [1]. Methylprednisolone is widely used in the therapy of severe inflammation, autoimmune conditions, hypersensitivity reactions and organ rejection.
For humans treated with GCs, the accumulation of adipocytes occurs primarily in the visceral fat and interscapular depots, leading to a characteristic “buffalo hump” and truncal obesity. However, the mechanisms of GCs induced fat distribution are not fully explicable. GCs exert major effects on adipose tissue metabolism, both on lipid accumulation and mobilization. These GCs effects are mediated via a specific GR, with a variable density in different regions of adipose tissue, in a ranking order of visceral > abdominal subcutaneous > femoral subcutaneous fat [2]. However, GCs have been proposed to be both adipogenic and lipolytic in action within adipose tissue. Regional differences of GR density between visceral and subcutaneous adipose depots can not fully explain GCs-induced fat distribution. Therefore, new insights on the mechanisms underlying GCs induced fat differential distribution between SAT and VAT is of importance.
As a molecular switch, the canonical Wnt/β-catenin signaling pathway should be suppressed during the adipogenesis. Wnt10b, DKK-1 and β-catenin as key proteins of Wnt/β-catenin signaling pathway have been described as major molecules in adipogenesis. The transgenic mice expressing Wnt10b show a 50% decline in total body fat and resist high-fat-diet-induced white adipose tissue (WAT) accumulation [3]. Adipose-specific expression of Wnt10b also protects against genetic obesity owing to leptin deficiency [4]. Wnt/β-catenin signaling pathway has also been implicated in the regulation of body fat distribution in humans and mice [5]. In humans, mutations in Wnt10b are associated with obesity [6]. Recent studies have found that a functional promoter polymorphism of Wnt10b was associated with abdominal fat [7]. In recent years, many studies have proved that Wnt/β-catenin signaling pathway is involved in the formation of fat in vitro [8], [9], [10]. Inhibition of Wnt/β-catenin signaling by dexamethasone promotes adipocyte differentiation in vitro [11].
An increase in adipogenesis is a likely effect of GCs. however, evaluation of adipose morphology in Cushing patients shows that they have enlarged, hypertrophic adipocytes [12]; the same occurs in rodents treated with exogenous GCs [13]. Therefore, GCs must also stimulate hypertrophy, through either increased synthesis or decreased breakdown, in addition to hyperplasia. Evidences from a number of studies suggested that GCs up-regulate the expression of lipase enzymes, such as adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL), through genomic effects to increase lipolysis [14], [15], [16]. Whereas other studies also suggested that, high amounts of GCs may also have an antilipolytic role and increase lipid accumulation [14], [17]. It seems likely that both prolipolytic and antilipolytic mechanisms might exist, and different regional adipose tissues probably have various prolipolytic or antilipolytic activities. Decreases in lipolysis, particularly in specific adipose depots, may also contribute to excess adipose accumulation. In this study, we hypothesized that GCs-induced fat differential distribution is the result of the disparity of adipogenic and lipolytic effects between VAT and SAT.
Section snippets
Animal experiment
The experiments were carried out on 4-month, female Sprague-Dawley rats (Shanghai Slack Laboratory Animal Co., Ltd, China) weighing 260–300 g, housed individually under standard environmental conditions (light from 6 AM to 6 PM, temperature 21 ± 1 °C, rat chow ad libitum). All experimental protocols were reviewed and approved by the Animal Welfare Committee at the Institute of Experimental Medicine, University of South China. The animals were randomly assigned to two groups: control group (n = 16)
Methylprednisolone affects the body weight and adipose mass of rats
The average food consumption reduced after methylprednisolone treatment for 12 weeks. Consistent with the food intake, rats injected with methylprednisolone also showed significant changes in weight gain after 12 weeks. Methylprednisolone tended to attenuate body weight gain. At the end of the feeding period, there was an increase in VAT mass in the methylprednisolone-treated rats compared with that in control rats (p < 0.05) (Fig. 1). However, no obvious changes of SAT mass were observed in the
Discussion
Central obesity and long-term glucocorticoid exposure are both characterized by visceral fat enlargement and increased risk for metabolic diseases. GCs have been proposed to be both adipogenic and lipolytic in action within adipose tissue, although it is unknown whether these actions can occur simultaneously. GCs increased VAT mass significantly, but not SAT mass, which is consistent with the central adiposity phenotype seen in Cushing’s syndrome. In this study, we demonstrate that
Acknowledgments
This study was supported by the National Natural Science Foundation of China (Nos: 81070667; 81270925), Hunan Provincial Natural Science Foundation of China (No: 12JJ2050) and the construct program of the key discipline in Hunan province.
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The first two authors contributed equally to this paper.