Glucocorticoid treatment facilitates development of a metabolic syndrome in ovariectomized Macaca Mulatta fed a high fat diet

Highlights

• We reported for the first time that the endocrine and physiological changes in response to chronic and high dose of GCs in non-human primates, and the effects of withdrawal of a long-term treatment, which led to recovery from metabolic disorders.

• We used ovariectomized monkeys to mimic the situation of perimenopausal and postmenopausal women, and might be used as potential models of Cushing’s syndrome or MetS in non-human primates.

• The lipid and glucose related factors including leptin and GLUT4 play important roles in the GCs effect.

Abstract

Metabolic syndrome (MetS) is characterized by a cluster of key features, which include abdominal obesity, insulin resistance, hypertension, and dyslipidemia. The aim of this study was to assess the impact of elevated glucocorticoid levels on the development of MetS in middle-aged female rhesus monkeys (Macaca Mulatta) after ovariectomy. Six female ovariectomized rhesus monkeys (9–13 years) were randomly assigned to either a control group (normal diet, n = 3) or a group in which MetS was facilitated (n = 3). The MetS group fed with HFD (15% fat) and received oral prednisone acetate treatment (50 mg/day). After 24 months, the GCs treatment was withdrawn with continuation of high-fat feeding for a further 12 months. After 24 months, the MetS group displayed a significant increase in body weight and abdominal circumference. Additionally, the MetS animals displayed abnormal serum lipids, insulin resistance and impaired glucose tolerance. Histology of liver biopsies indicated marked accumulation of lipid droplets in hepatocytes of MetS animals. Withdrawal of GCs treatment led to recovery from above-mentioned metabolic disorders. Whereas GCs treatment increased leptin expression, it lowered expression of adiponectin and other factors in adipose tissue. Expression of Hydroxy-steroid dehydrogenase-1 and glucose transporter type-4 in the livers of MetS animals were reduced. We conclude that in the context of high fat diet, high levels of exogenous GCs contribute to the development of MetS in non-human primates.

Introduction

Metabolic syndrome (MetS) is characterized by a cluster of key features, which include abdominal obesity, insulin resistance, hypertension, and dyslipidemia. The prevalence of MetS has increased significantly throughout the World [1], [18], [42]. The development of experimental models to mimic the pathological features of MetS in humans would advance our understanding of pathogenesis as well as assisting therapeutic strategies. In this respect, non-human primates (NHP) may provide the best model, because of their similarity to humans, in terms of lipoprotein profiles and genetic makeup [6], [40]. Aged NHP may develop MetS spontaneously but such cases are rare and there is a slow pathological progression to MetS [14], [15], [16], [34]. In a previous study, we demonstrated that a high-fat diet causes dyslipidemia and impaired glucose tolerance in rhesus monkeys but with a much slower progression than in rodents [24].

Dysregulation of the hypothalamic-pituitaryadrenal (HPA) axis occurs in many metabolic disorders, including obesity, diabetes and MetS [17], [34], [36], [44], [45], but how elevated glucocorticoid (GCs) levels might contribute to the development of these conditions is not fully understood. Cortisol is the main naturally occurring glucocorticoid (GCs) in humans and NHP and high cortisol levels increase the total mass of adipose tissue, and promote ectopic fat accumulation [26], [32], [39]. Although GCs are regular medications for a broad spectrum of clinical conditions, long-term, high dose treatments cause central obesity in most patients, synonymous with Cushing’s syndrome [10], [12], [21], [37]. For example, one study reported that a 4-week treatment of mice with 100 μg/ml corticosterone in drinking water led to rapid weight gain, increased adiposity, elevated plasma leptin, insulin and triglyceride levels, hyperphagia, and reduce locomotion [20]. Another study in mice showed that 7 weeks of dexamethasone treatment combined with a high-fat diet showed that GCs facilitated diet-induced obesity, liver steatosis and dyslipidemia [35]. The classical example of an association between high circulating GCs and obesity/MetS is that of Cushing’s syndrome, but the actions of GCs are multitudinous and the exact means by which GCs might promote MetS in humans is not well understood [23]. The metabolic effect of long-term treatment with exogenous GCs in NHPs is also poorly understood.

The incidence of MetS also increases with age, as reported for perimenopausal women [46]. We hypothesized that ovariectomized rhesus monkeys might be more susceptible to MetS, due to loss of gonadal steroids and we further hypothesized that this might be facilitated by GCs. Thus, in the present study we aimed to investigate how long-term treatment with a high dose of GCs impacted upon metabolic function in ovariectomized Rhesus monkeys fed a high-fat diet.