Fructose enriched diet

Our research showed that the effects of fructose enriched diet on male rats visceral adipose tissue (VAT) and hepatic lipid and carbohydrate metabolisms are highly dependent on the concentration of fructose used in the diet. Namely, diet consisting of the 60% aqueous solution of fructose and regular chow led to adipocyte proliferation and the development of visceral adiposity dependent on the increased peroxisome proliferator-activated receptor gamma (PPARγ) activity, in concert with an increase in the 11βHSD1-dependent prereceptor metabolism of glucocorticoids and the glucocorticoid receptor (GR) activation in VAT ^[1],[2],[3]. On the other hand, 10% fructose enriched diet did not lead to the visceral adiposity development, but it induced blood pressure increments caused by the changes in the adipose cell membrane levels of the angiotensin receptor^[4]. However, the key signs of hepatic GR activation and gluconeogenesis (phosphoenolpyruvate carboxykinase (PEPCK)) remained unchanged^[5]. Nevertheless, a hepatic inflammatory process characterized by NFκB activation and increased TNFα gene expression was shown in both forms of fructose enriched diets, together with the negative consequences of 60% fructose on both hepatic and systemic insulin sensitivity ^[6],[7]. We were able to link fructose consumption to high blood triglycerides, SREBP1 dependent increase in hepatic de novo lipogenesis and decreased liver β-oxidation ^{[8], [9], [10]}, as well. Our study also confirmed that the perturbations of the central regulation of energy balance, i.e. leptin resistance, form the basis of the visceral adiposity development in our high fructose model. Namely, unlike 10% fructose enrichment, 60% fructose spiked diet leads to the hypothalamic leptin resistance, mechanistically involving the leptin receptor (ObRb) decrement together with a rise in Suppressor of cytokine signaling 3 (SOCS3) transcription, and the consequent increase in the hypothalamic levels of the orexigenic neuropeptide Y (NPY). This implies a role of glucocorticoids, since NPY transcription is directly regulated by GR ^2,[11],[12]. Synaptic plasticity was also changed after 60% fructose enriched diet, while 10% fructose did not influence it, but it did lead to the development of the metabolic inflammation and hippocampal insulin resistance^[13].

Apart from their important role in the pathogenesis of the metabolic disorders, glucocorticoids are best known for their anti-inflammatory and immunosuppressive functions, antagonistically regulated by the macrophage migration inhibitory factor (MIF). With that in mind, we used a genetically modified, MIF deficient (MIF^-/-) mouse model to explore the role of glucocorticoid hormones in the lipid metabolism regulation in visceral adipose tissue of MIF mice fed with the 20% fructose-enriched diet. We showed that in these mice the fructose-enriched diet led to the plasma triglycerides increase together with increased visceral adipose tissue lipogenesis and visceral obesity development. This was congruent with a significant increase of the glucocorticoid prereceptor metabolism enzymes and the nuclear GR levels, which led us to the conclusion that, since these metabolic effects of dietary fructose enrichment were present in MIF^-/- mice only, they are most likely consequent to the local glucocorticoid signaling activation, stimulated by the attenuation of MIF-regulated inflammation^[14]. We also studied the effects of the fructose-enriched diet on the hippocampal insulin sensitivity, neural plasticity and behavior in this model. MIF^-/- mice showed a decreased systemic and local insulin sensitivity, together with anxiety-like behaviours most probably due to the decreased PSA/NCAM-linked neural plasticity^[15].

Women are much more susceptible to MS-related disturbances than men, but the largest bulk of MS research was done in male rat models. Thus, we directed a whole line of research to the metabolic disturbances in female rats fed with the diet spiked with 10% fructose in the first nine weeks after weaning. We found that changes in GR activity, as well as the changes in VAT inflammatory and redox statuses are linked with visceral adiposity in this model. Namely, GR hormone binding capacity and affinity was reduced, as well as the transcription of GR iRNA and its protein levels. This was, however, paralleled with a stimulated 11β-HSD1- and H6PDH- dependent glucocorticoid prereceptor metabolism, and its increased concentration in visceral adipose tissue. Key glucocorticoid-regulated lipogenic and lipolytic factors (hormone sensitive lipase (HSL), sterol regulatory element binding protein 1c (SREBP 1c)), remained unchanged. This showed that the intracellular glucocorticoid increase can lead to a negative regulation of GR and its inability to influence female VAT lipid metabolism^[16]. On the other hand, the changes visceral adipose tissue inflammatory status and its system of antioxidative defence in female rats on a 10% fructose spiked diet, were linked with the increased visceral adiposity, but not with the changes in VAT insulin signaling. Namely, nuclear levels of the nuclear factor κB (NFκB ) and the expressions of proinflammatory cytokine IL-1β were increased, whereas the levels of superoxide dismutase (SOD) and glutathione peroxidase were decreased. Insulin receptor substrate (IRS-1) and its inhibitory forms (pIRS1-Ser³⁰⁷) remained unchanged^[17].

[1] Djordjevic A, Veličković N, Bursać B, Teofilović A, Matić G. (2017) The role of glucocorticoid hormones in diet-induced diseases. Biol Serb 39(1): 16-25.

[2] Bursać B, Djordjevic A, Vasiljevic A, Vojnović Milutinović D, Veličković N, Nestorović N, Matić G,. (2013) Fructose consumption enhances glucocorticoid action in rat visceral adipose tissue. J Nutr Biochem 24 (6): 1166-72.

[3] Bursać B, Vasiljević A, Nestorović N, Veličković N, Vojnović Milutinović D, Matić G, Djordjevic A. (2014) High-fructose diet leads to visceral adiposity and hypothalamic leptin resistance in male rats - do glucocorticoids play a role? J Nutr Biochem 25 (4): 446-455.

[4] Matić G, Veličkovic N, Djordjevic A, Vojnović Milutinović D, Elaković I, Nestorov J, Bursać B, Vasiljević A, Nikolić M, Dundjerski J. Glucocorticoid signaling in the liver and adipose tissue of male and female fructose fed rats. Metabolism, Diet and Disease conference, 2012, Washington DC, USA, BMC Proceedings, 6(3) Abstract P35, pp. S22.

[5] Vasiljevic A, Veličković N, Bursać B, Djordjevic A, Vojnović Milutinović D, Nestorović N, Matić G. (2013) Enhanced prepreceptor glucocorticoid metabolism and lipogenesis impair insulin signaling in the liver of fructose-fed rats. J Nutr Biochem 24 (11): 1790-7.

[6] Veličković N, Djordjevic A, Vasiljevic A, Bursać B, Vojnović Milutinović D, Matić G. (2013) Tissue-specific regulation of inflammation by macrophage migration inhibitory factor and glucocorticoids in fructose-fed Wistar rats. Br J Nutr 110 (3): 456-65.

[7] Vasiljević A, Bursać B, Djordjevic A, Milutinović DV, Nikolić M, Matić G, Veličković N. (2014) Hepatic inflammation induced by high-fructose diet is associated with altered 11betaHSD1 expression in the liver of Wistar rats. Eur J Nutr 53 (6): 1393-1340.

[8] Teofilović A, Bursać B, Djordjevic A, Vojnović Milutinović D, Matić G, Veličković N. (2016) High dietary fructose load aggravates lipid metabolism in the liver of Wistar rats through imbalance between lipogenesis and fatty acid oxidation. Turk J Biol 6(40):1235-1242.

[9] Veličković N, Teofilović A, Djordjevic A, Milutinović DV, Bursać B, Matić G. High dietary fructose load affects oxidation and lipogenesis without increasing lipid deposition in the liver of Wistar rat. Hot topic conference: Dietary Sugars, Obesity & Metabolic Disease Risk, World Obesity Society, Berlin, Germany, June 29-30, 2015, pp. 33.

[10] Petrović S, Veličković N, Teofilović A, Djordjevic A, Arsić A, Ristić-Medić D, Vučić V. The effects of high-fructose diet on fatty acid profile of total plasma lipids in rats. Joint Meeting of National Physiological Societies, Serbian Physiological Society and Hungarian Physiological Society, "New perspectives in physiological research- Young investigator forum", May 25-27, 2017, Subotica, Serbia, Аbstract book, pp. 95.

[11] Djordjevic A, Bursać B, Vojnović Milutinović D, Nestorov J, Nikolić M, Nestorović N, Vasiljević A, Veličković N, Elaković I, Matić G. (2014) The role of hypothalamic leptin signalling and glucocorticoids in fructose diet-induced visceral adiposity of rats. ESE Basic Endocrinology Course on “Neuroendocrinology”, European Society of Endocrinology, Amsterdam, Netherlands, January 15-17: pp. 12.

[12] Djordjevic A, Vojnović Milutinović D, Veličković N, Nestorov J, Bursać B, Teofilović A, Matić G. (2015) The effects of different fructose loads on hypothalamic inflammation, leptin and insulin sensitivity and visceral adiposity in male rats. 6^th Swiss Winter Confrerence on Ingestive Behavior, Swiss Society for Nutrition, St. Moritz, Switzerland, February 28-March 5: pp. 34.

[13] Djordjevic A, Bursać B, Veličković N, Vasiljević A, Matić G. (2015) The impact of different fructose loads on insulin sensitivity, inflammation, and PSA-NCAM-mediated plasticity in the hippocampus of fructose-fed male rats. Nutr Neurosci 18: 66-75.

[14] Gligorovska L, Bursać B, Djordjevic A, Teofilović A, Veličković N, Milutinović DV, Matić G. (2016) Glucocorticoid signaling and inflammation in the adipose tissue of macrophage migration inhibitory factor-knockout mice kept on fructose-enriched diet, 2^nd Belgrade International Molecular Life Science Conference for Students, Belgrade, Serbia, February 10-13: pp. 19

[15] Djordjevic A, Bursać B, Veličković N, Gligorovska G, Ignjatović D, Tomić M, Matić G. (2017) Disturbances of systemic and hippocampal insulin sensitivity in macrophage migration inhibitory factor (MIF) knockout male mice lead to behavioral changes associated with decreased PSA-NCAM levels. Horm Behav 96: 95–103.

[16] Kovačević S, Nestorov J, Matić G, Elaković I. (2014) Dietary fructose-related adiposity and glucocorticoid receptor function in visceral adipose tissue of female rats. Eur J Nutr. 53: 1409-1420.

[17] Kovačević S, Nestorov J, Matić G, Elaković I. (2017) Fructose‑enriched diet induces inflammation and reduces antioxidative defense in visceral adipose tissue of young female rats. Eur J Nutr. 56: 151-160.