Adiponectin Resistance and Proinflammatory Changes in the Visceral Adipose Tissue Induced by Fructose Consumption via Ketohexokinase-Dependent Pathway

Abstract

An epidemic of obesity and type 2 diabetes is linked with the increase in consumption of fructose-containing sugars, such as sucrose and high-fructose corn syrup. In mammalian cells, fructose is metabolized predominantly via phosphorylation to fructose-1 phosphate by ketohexokinase (KHK) or by alternative pathways. Here we demonstrate that a KHK-dependent pathway mediates insulin resistance and inflammatory changes in the visceral fat in response to high fructose. We used mice (males, C57BL/6 background) including littermate wild-type control and mice lacking both isoforms of KHK (KHK-null). Fructose diet induced metabolic syndrome, including visceral obesity, insulin resistance, proinflammatory changes in the visceral fat (production of proinflammatory adipokines and macrophage infiltration), the endoplasmic reticulum stress signaling, and decrease of the high–molecular weight adiponectin followed by decrease in the downstream signaling. KHK-KO mice consuming the same high-fructose diet remained lean, with normal insulin sensitivity and healthy visceral adipose tissue with normal adiponectin function not distinguishable from the control by any of the tested parameters. This study demonstrates that blocking KHK and redirecting fructose metabolism to alternative pathways is an effective way to prevent visceral obesity and insulin resistance induced by high fructose, a widespread component of Western diets.

Fructose, Glucocorticoids and Adipose Tissue: Implications for the Metabolic Syndrome

“…During nutrient overload and/or disturbances, cellular stress can lead to an impairment of ER function, limiting the capacity of proper protein folding and resulting in an accumulation of unfolded proteins in the ER lumen, ultimately leading to impaired adipocyte maturation. Such a mechanism for fructose-mediated ER-stress induction in adipocytes was reported recently by Marek et al [101]. They provided important mechanistic insight into how fructose consumption not only influences ER redox status via depleting ERO-1α expression but also affects one of the key ER-stress signaling pathways by inducing XBP-1 splicing in the VAT of treated mice.…”

“…They provided important mechanistic insight into how fructose consumption not only influences ER redox status via depleting ERO-1α expression but also affects one of the key ER-stress signaling pathways by inducing XBP-1 splicing in the VAT of treated mice. Since the assembly and secretion of the beneficial anti-inflammatory and insulin-sensitizing adipokine adiponectin is regulated by ER chaperones such as ERO-1α and ERp44 [102], the fructose-mediated depletion of the biologically active high-molecular weight protein adiponectin might be explained by an altered ER homeostasis [101]. Furthermore, this study revealed macrophage infiltration and increased expression of inflammatory cytokines such as monocyte chemoattractant-1 (MCP-1) and tumor necrosis factor-α (TNF-α) in the VAT in response to fructose [101].…”

Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling

“…Even studies exclusively utilizing fructosesweetened drinks to show this association have been contested, as fructose-sweetened drinks provide additional calories, which alone could explain the higher rates of obesity and metabolic complications. In fact, some studies suggest that fructose-increased caloric intake, mediated via leptin resistance (45) and antagonism of GLP-1R action in the brain (46), leads to increased adipogenic potential (47) and visceral adipose tissue inflammation (48). Our model controlled for additional calories ingested from sugarsweetened drinks by comparing the effects of fructose to those of isocaloric glucose, and while both monosaccharides resulted in higher total caloric intake, there was no difference in energy intake between the 2 sugar-supplemented groups.…”

High Dietary Fructose: Direct or Indirect Dangerous Factors Disturbing Tissue and Organ Functions

“…Serum adiponectin concentration is decreased in rodents with increased influx of neutrophils in liver after high fructose intake, suggesting the possible modulation of neutrophil recruitment [156]. In ketohexokinase (KHK)-KO mice, fructose consumption does not change insulin sensitivity, adiponectin sensitivity and visceral obesity, indicating that the burden of MetS is closely associated with fructolysis [157]. Adiponectin receptor 1 (AdipoR1) and AdipoR2 are expressed in liver and skeletal muscle of humans, while AdipoR2 is mostly expressed in liver of rodents.…”