Modulation of hepatic inflammation and energy-sensing pathways in the rat liver by high-fructose diet and chronic stress

Purpose High-fructose consumption and chronic stress are both associated with metabolic inflammation and insulin resistance. Recently, disturbed activity of energy sensor AMP-activated protein kinase (AMPK) was recognized as mediator between nutrient-induced stress and inflammation. Thus, we analyzed the effects of high-fructose diet, alone or in combination with chronic stress, on glucose homeostasis, inflammation and expression of energy sensing proteins in the rat liver. Methods In male Wistar rats exposed to 9-week 20% fructose diet and/or 4-week chronic unpredictable stress we measured plasma and hepatic corticosterone level, indicators of glucose homeostasis and lipid metabolism, hepatic inflammation (pro- and anti-inflammatory cytokine levels, Toll-like receptor 4, NLRP3, activation of NF kappa B, JNK and ERK pathways) and levels of energy-sensing proteins AMPK, SIRT1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha). Results High-fructose diet led to glucose intolerance, activation of NF kappa B and JNK pathways and increased intrahepatic IL-1 beta, TNF alpha and inhibitory phosphorylation of insulin receptor substrate 1 on Ser(307). It also decreased phospho-AMPK/AMPK ratio and increased SIRT1 expression. Stress alone increased plasma and hepatic corticosterone but did not influence glucose tolerance, nor hepatic inflammatory or energy-sensing proteins. After the combined treatment, hepatic corticosterone was increased, glucose tolerance remained preserved, while hepatic inflammation was partially prevented despite decreased AMPK activity. Conclusion High-fructose diet resulted in glucose intolerance, hepatic inflammation, decreased AMPK activity and reduced insulin sensitivity. Chronic stress alone did not exert such effects, but when applied together with high-fructose diet it could partially prevent fructose-induced inflammation, presumably due to increased hepatic glucocorticoids

Induction of metabolic syndrome by excess fructose consumption

Fructose is an important nutritive component of foods such as honey and fruit, but this easily available sweetener may contribute to increased caloric consumption from overeating. Fructose is now a major component of the Western diet, with increased consumption associated with obesity, metabolic syndrome, and cardiovascular disorders in observational and short-term intervention studies, mainly in animal models. Rodent studies have identifi ed possible mechanisms for the adverse effects of fructose when ingested in large amounts. Fructose promoted de novo lipogenesis, infl ammation, and increased sympathetic tone. These mechanisms induced hepatic insulin resistance, increased total and visceral fat mass with accumulation of ectopic fat in the liver and skeletal muscle, and dyslipidemia. Fructose reduced leptin and insulin signals for satiety, caused structural and functional damage to the heart and blood vessels, and disrupted the diversity of the gut microbiota. These early effects may initiate the development of the metabolic syndrome. Despite this evidence from rodents, there are few long-term intervention studies in humans, especially at a moderate dose. The defi nition of prudent fructose consumption is needed, but this will require carefully controlled dose–response studies in humans