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Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice.

ABSTRACT: Fructose intake from added sugars correlates with the epidemic rise in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Fructose intake also causes features of metabolic syndrome in laboratory animals and humans. The first enzyme in fructose metabolism is fructokinase, which exists as two isoforms, A and C. Here we show that fructose-induced metabolic syndrome is prevented in mice lacking both isoforms but is exacerbated in mice lacking fructokinase A. Fructokinase C is expressed primarily in liver, intestine, and kidney and has high affinity for fructose, resulting in rapid metabolism and marked ATP depletion. In contrast, fructokinase A is widely distributed, has low affinity for fructose, and has less dramatic effects on ATP levels. By reducing the amount of fructose for metabolism in the liver, fructokinase A protects against fructokinase C-mediated metabolic syndrome. These studies provide insights into the mechanisms by which fructose causes obesity and metabolic syndrome.

SUBMITTER: Ishimoto T

PROVIDER: S-EPMC3306692 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice.

Ishimoto Takuji T Lanaspa Miguel A MA Le Myphuong T MT Garcia Gabriela E GE Diggle Christine P CP Maclean Paul S PS Jackman Matthew R MR Asipu Aruna A Roncal-Jimenez Carlos A CA Kosugi Tomoki T Rivard Christopher J CJ Maruyama Shoichi S Rodriguez-Iturbe Bernardo B Sánchez-Lozada Laura G LG Bonthron David T DT Sautin Yuri Y YY Johnson Richard J RJ

Proceedings of the National Academy of Sciences of the United States of America 20120227 11

Fructose intake from added sugars correlates with the epidemic rise in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Fructose intake also causes features of metabolic syndrome in laboratory animals and humans. The first enzyme in fructose metabolism is fructokinase, which exists as two isoforms, A and C. Here we show that fructose-induced metabolic syndrome is prevented in mice lacking both isoforms but is exacerbated in mice lacking fructokinase A. Fructokinase C is express ...[more]

PMID: 22371574

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Project description:Fructose stimulates vasopressin in humans and can be generated endogenously by activation of the polyol pathway with hyperosmolarity. We hypothesized that fructose metabolism in the hypothalamus might partly control vasopressin responses after acute dehydration. Wild-type and fructokinase-knockout mice were deprived of water for 24 h. The supraoptic nucleus was evaluated for vasopressin and markers of the aldose reductase-fructokinase pathway. The posterior pituitary vasopressin and serum copeptin levels were examined. Hypothalamic explants were evaluated for vasopressin secretion in response to exogenous fructose. Water restriction increased serum and urine osmolality and serum copeptin in both groups of mice, although the increase in copeptin in wild-type mice was larger than that in fructokinase-knockout mice. Water-restricted, wild-type mice showed an increase in vasopressin and aldose reductase mRNA, sorbitol, fructose and uric acid in the supraoptic nucleus. In contrast, fructokinase-knockout mice showed no change in vasopressin or aldose reductase mRNA, and no changes in sorbitol or uric acid, although fructose levels increased. With water restriction, vasopressin in the pituitary of wild-type mice was significantly less than that of fructokinase-knockout mice, indicating that fructokinase-driven vasopressin secretion overrode synthesis. Fructose increased vasopressin release in hypothalamic explants that was not observed in fructokinase-knockout mice. In situ hybridization documented fructokinase mRNA in the supraoptic nucleus, paraventricular nucleus and suprachiasmatic nucleus. Acute dehydration activates the aldose reductase-fructokinase pathway in the hypothalamus and partly drives the vasopressin response. Exogenous fructose increases vasopressin release in hypothalamic explants dependent on fructokinase. Nevertheless, circulating vasopressin is maintained and urinary concentrating is not impaired.New & noteworthyThis study increases our understanding of the mechanisms leading to vasopressin release under conditions of water restriction (acute dehydration). Specifically, these studies suggest that the aldose reductase-fructokinase pathways may be involved in vasopressin synthesis in the hypothalamus and secretion by the pituitary in response to acute dehydration. Nevertheless, mice undergoing water restriction remain capable of maintaining sufficient vasopressin (copeptin) levels to allow normal urinary concentration. Further studies of the aldose reductase-fructokinase system in vasopressin regulation appear indicated.

Project description:BackgroundCurrently, energy obtained from hypercaloric diets has been part of the obesity and type 2 diabetes mellitus (T2DM) epidemics from childhood to old age. Treatment alternatives have been sought from plants, minerals, and trace elements with metabolic effects. Vanadyl sulfate (VS) has been investigated as a hypoglycemic compound in animal and human studies showing effective insulin-mimetic properties. This characteristic encompasses several molecules that have beneficial pleiotropic effects. The aim was to determine the antiobesity, hypoglycemic, and hypolipidemic effects of VS on fructose-induced metabolic syndrome in aged rats.Material and methodsFive groups of male Wistar rats were made, each with six rats: two groups with normal diet (ND) and three with high-fructose diet (HFD). The first ND group was treated with saline solution (SS), the second with VS; treatment for HFD groups was in the first group with SS, second with VS, and third with metformin. Weight, body mass index (BMI), blood glucose, and lipidic profile were measured; water, food, fructose and energy consumption were also determined. All parameters were compared among groups.Results and discussionAlthough obese rats treated with VS presented anorexia, oligodipsia, and a marked weight loss in the first two weeks. They recovered food and water intake in the third week with a slow recovery of some weight weeks later. VS normalized blood glucose level and decreased triglyceride and insulin levels in obese rats. These results suggest that vanadyl sulfate shows antiobesity, hypoglycemic, and hypolipidemic properties in old obese rats and could be useful as an alternative, additional, and potent preventive treatment for obesity and T2DM control in elderly obese and poorly controlled diabetic patients.ConclusionVS could play an important role in the treatment of metabolic syndrome, contributing to a decrease in obesity and T2DM, through different ways, such as euglycemia, satiety, weight loss, and lipid profile optimization, among others. However, more research is needed to confirm this suggestion.

Dataset Information

Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice.

Publications

Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice.

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