Decreased Glucocorticoid Signaling Potentiates Lipid-Induced Inflammation and Contributes to Insulin Resistance in the Skeletal Muscle of Fructose-Fed Male Rats Exposed to Stress.

Abdulbaset Zidane Shirif,Ivana Elaković,Sanja Kovačević,Ana Djordjevic,Jelena Brkljačić,Ana Teofilović,Gordana Matić

doi:10.3390/ijms22137206

Abdulbaset Zidane Shirif, Ivana Elaković + Show 5 more

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https://doi.org/10.3390/ijms22137206

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Abstract

The modern lifestyle brings both excessive fructose consumption and daily exposure to stress which could lead to metabolic disturbances and type 2 diabetes. Muscles are important points of glucose and lipid metabolism, with a crucial role in the maintenance of systemic energy homeostasis. We investigated whether 9-week fructose-enriched diet, with and without exposure to 4-week unpredictable stress, disturbs insulin signaling in the skeletal muscle of male rats and evaluated potential contributory roles of muscle lipid metabolism, glucocorticoid signaling and inflammation. The combination of fructose-enriched diet and stress increased peroxisome proliferator-activated receptors-α and -δ and stimulated lipid uptake, lipolysis and β-oxidation in the muscle of fructose-fed stressed rats. Combination of treatment also decreased systemic insulin sensitivity judged by lower R-QUICKI, and lowered muscle protein content and stimulatory phosphorylations of insulin receptor supstrate-1 and Akt, as well as the level of 11β-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor. At the same time, increased levels of protein tyrosine phosphatase-1B, nuclear factor-κB, tumor necrosis factor-α, were observed in the muscle of fructose-fed stressed rats. Based on these results, we propose that decreased glucocorticoid signaling in the skeletal muscle can make a setting for lipid-induced inflammation and the development of insulin resistance in fructose-fed stressed rats.

Highlights

The modern lifestyle is commonly challenged by unpredictable stressful events and the consumption of high-calorie processed foods rich in fructose
Having in mind that skeletal muscle is an important organ for whole-body glucose homeostasis and that metabolic disturbances in the muscle could be one of the earliest defects leading to type 2 diabetes (T2D), the aim of this study was to elucidate whether the combination of excessive fructose consumption and chronic unpredictable stress disturbs insulin signaling in the skeletal muscle of male rats through lipid-induced inflammation and changes in glucocorticoid signaling as a potential underlying mechanism for muscle insulin resistance
In order to evaluate the effects of increased fructose consumption, chronic stress exposure and its combination on lipid metabolism we analyzed the expression of genes involved in free fatty acids (FFAs) transport into the cell, lipolysis and β-oxidation

Summary

Introduction

The modern lifestyle is commonly challenged by unpredictable stressful events and the consumption of high-calorie processed foods rich in fructose. Animal and human studies have shown that both chronic stress [1,2] and excessive fructose consumption, in the form of sweetened beverages [3,4], correlate with the development of insulin resistance and related disorders. Studies have shown that insulin resistance in skeletal muscle can occur before the onset of hyperglycemia, even years before a detectable dysfunction of pancreatic β-cells [6]. This is why it is considered that insulin resistance in skeletal muscle is one of the earliest and most important deficiencies in the chain of events that lead to type 2 diabetes (T2D) and metabolic syndrome [6,8]

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