Fructose Induces Visceral Adipose Tissue Inflammation and Insulin Resistance Even Without Development of Obesity in Adult Female but Not in Male Rats

Abstract

Introduction: Obesity and related metabolic disturbances are frequently related to modern lifestyle and are characterized by excessive fructose intake. Visceral adipose tissue (VAT) inflammation has a central role in the development of insulin resistance, type 2 diabetes (T2D), and metabolic syndrome. Since sex-related differences in susceptibility and progression of metabolic disorders are not yet fully understood, our aim was to examine inflammation and insulin signaling in VAT of fructose-fed female and male adult rats.Methods: We analyzed effects of 9-week 10% fructose-enriched diet on energy intake, VAT mass and histology, and systemic insulin sensitivity. VAT insulin signaling and markers of VAT inflammation, and antioxidative defense status were also evaluated.Results: The fructose diet had no effect on VAT mass and systemic insulin signaling in the female and male rats, while it raised plasma uric acid, increased PPARγ level in the VAT, and initiated the development of a distinctive population of small adipocytes in the females. Also, adipose tissue insulin resistance, evidenced by increased PTP1B and insulin receptor substrate 1 (IRS1) inhibitory phosphorylation and decreased Akt activity, was detected. In addition, fructose stimulated the nuclear accumulation of NFκB, increased expression of proinflammatory cytokines (IL-1β, IL-6, and TNFα), and protein level of macrophage marker F4/80, superoxide dismutase 1, and glutathione reductase. In contrast to the females, the fructose diet had no effect on plasma uric acid and VAT inflammation in the male rats, but less prominent alterations in VAT insulin signaling were observed.Conclusion: Even though dietary fructose did not elicit changes in energy intake and led to obesity in the females, it initiated the proliferation of small-sized adipocytes capable of storing fats further. In contrast to the males, this state of VAT was accompanied with enhanced inflammation, which most likely contributed to the development of insulin resistance. The observed distinction could possibly originate from sex-related differences in uric acid metabolism. Our results suggest that VAT inflammation could precede obesity and start even before the measurable increase in VAT mass, making it a silent risk factor for the development of T2D. Our results emphasize that adipose tissue dysfunction, rather than its simple enlargement, could significantly contribute to the onset and development of obesity and related metabolic disorders.

Appetite–regulating hormones in rats with fructose-induced metabolic changes

“…The same authors suggest a disrupted connection between the peripheral and central appetite regulatory mechanisms. Moreover, fructose-enriched diet has been shown to induce brain oxidative stress, including hypothalamic inflammation (Nabil et al 2020;Kovačević et al 2021), which could further contribute to the impaired signaling.…”

“…This puts the role of many additional factors (such as body composition, age, sex and insulin resistance), which may be of a significance for the peripheral hormonal responses in the energy homeostasis, appetite regulation and development of obesity (Yunker et al 2021). In a study of Kovačević et al (2021), fructose diet caused a greater extent of adipose tissue inflammation and insulin signaling impairment in female than in male rats. Interestingly, fructose overconsumption was not accompanied by obesity, which puts adipose tissue dysfunction at an earlier stage in the development of metabolic disorders and weight gain.…”

Micropatterned Primary Hepatocyte Co-Culture (HEPATOPAC) for Fatty Liver Disease Modeling and Drug Screening

“…In vivo studies have demonstrated differences between high fat, high fructose or glucose, and a combination diet on numerous fatty liver related phenotypes including body weight, lipid and glucose metabolism, insulin resistance, and liver triglycerides 37,38 . Fructose, in particular, has been demonstrated as a major contributor to insulin resistance, increased body weight, oxidative stress, and in ammation [39][40][41][42][43] .…”

Oxidative stress in obesity and insulin resistance

“…A fructose-enriched diet induces the development of IR in the white adipose tissue of the adult female Wistar rats, although it did not lead to obesity and systemic IR. Thus, the protein levels of SOD1 and GR were increased in white adipose tissue of fructose-fed female rats, compared to the control group, which probably serve to prevent intracellular RONS accumulation and oxidative damage of macromolecules [78]. However, as obesity progresses, the amount and activity of the AOS components become depleted, increasing susceptibility to oxidative tissue damage [79].…”

“…Moreover, the administration of the insulin-sensitizing drug pioglitazone to HFCD-induced IR rats reduced MDA level and improved GSH level, compared to the non-treated IR-induced group of rats [83]. Perirenal, epididymal, and brown adipose tissues of male Wistar rats SOD, CAT, GPx activities Decreased [82] Liver of male C57BL/6 mice Mn-SOD protein level Decreased [29] Heart of male C57BL/6J mice CAT protein level/CAT activity Increased [76] Visceral adipose tissue of female Wistar rats Mn-SOD, GPx protein levels/Cu/Zn-SOD, GR protein levels Decreased/unchanged [81] Primary hepatocytes of male C57BL/6J mice GSH content, GPx, and GR activities Decreased [31] Soleus muscle of Wistar male rats Total GSH level/Mn-SOD, CAT, GPx expression Decreased/unchanged [77] Plasma samples and heart of male fa/fa ZR SOD/GPx activities Decreased/unchanged [30] Serum of male Albino rats MDA level/GSH level Increased/decreased [83] White adipose tissue of female Wistar rats SOD1 and GR protein levels Increased [78] Ref: reference…”