The role of glucocorticoid hormones in diet-induced metabolic diseases

Abstract

Excessive fructose intake promotes the development of metabolic syndrome through the deregulation of metabolic pathways in the hypothalamus, liver and adipose tissue, which play crucial roles in metabolic homeostasis by responding to the body’s nutritional and energy requirements. Variable amounts and modes of fructose intake have been shown to result in different patterns of expression of metabolic disturbances, which generally include adiposity, insulin and leptin resistance, dyslipidemia and hypertension. We explored the possible mediatory role of glucocorticoid signaling on the effects of two different dietary fructose loads on hypothalamic leptin sensitivity and hepatic and adipose tissue lipid metabolism, which are responsible for the development of signs of metabolic syndrome. Experimental rats were provided with 10% and 60% fructose solutions ad libitum over a period of nine weeks. Our results revealed that the applied fructose had different impacts on leptin and glucocorticoid signaling and different consequences on visceral adiposity and hepatic lipid metabolism. Only rats maintained on the high-burden 60% fructose diet accumulated visceral fat through the activation of adipogenic transcription factors and adipogenesis. This was paralleled by diminished glucocorticoid signaling in the adipose tissue and the establishment of the state of hypothalamic leptin resistance. The high-burden dietary fructose triggered hepatic de novo lipogenesis and a concomitant inhibition of β oxidation. Consumption of 10% fructose enhanced glucocorticoid signaling and lipolysis in the adipose tissue, creating a circulatory influx of free fatty acids and providing substrates for enhanced β oxidation and triglyceride synthesis in the liver. In summary, our results show that a long-term high dietary fructose load leads to hypothalamic leptin resistance, the development of visceral adiposity and increased hepatic de novo lipogenesis. Glucocorticoids regulate adipocyte storage functionality and thus may indirectly contribute to the observed changes in hepatic lipid metabolism, aggravating the metabolic disturbance.