title: Glucose transporter-8 (GLUT8) mediates glucose intolerance and dyslipidemia in high-fructose diet-fed male mice.
abstract: Members of the glucose transporter (GLUT) family of membrane-spanning hexose transporters are subjects of intensive investigation for their potential as modifiable targets to treat or prevent obesity, metabolic syndrome, and type 2 diabetes mellitus. Mounting evidence suggests that the ubiquitously expressed class III dual-specificity glucose and fructose transporter, GLUT8, has important metabolic homeostatic functions. We therefore tested the hypothesis that GLUT8 mediates the deleterious metabolic effects of chronic high-fructose diet exposure. Here we demonstrate resistance to high-fructose diet-induced glucose intolerance and dyslipidemia concomitant with enhanced oxygen consumption and thermogenesis in GLUT8-deficient male mice. Independent of diet, significantly lower systolic blood pressure both at baseline and after high-fructose diet feeding was also observed by tail-cuff plethysmography in GLUT8-deficient mice vs wild-type controls. Resistance to fructose-induced metabolic dysregulation occurred in the context of enhanced hepatic peroxisome proliferator antigen receptor-γ (PPARγ) protein abundance, whereas in vivo hepatic adenoviral GLUT8 overexpression suppressed hepatic PPARγ expression. Taken together, these findings suggest that GLUT8 blockade prevents fructose-induced metabolic dysregulation, potentially by enhancing hepatic fatty acid metabolism through PPARγ and its downstream targets. We thus establish GLUT8 as a promising target in the prevention of diet-induced obesity, metabolic syndrome, and type 2 diabetes mellitus in males.
authors.affiliation: MD, Department of Obstetrics and Gynecology, Washington University in St Louis School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110. moleyk@wustl.edu.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: DeBosch
authors.forename: Zhouji
authors.initials: Z
authors.lastname: Chen
authors.forename: Brian N
authors.initials: BN
authors.lastname: Finck
authors.forename: Maggie
authors.initials: M
authors.lastname: Chi
authors.forename: Kelle H
authors.initials: KH
authors.lastname: Moley
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose; D001794:Blood Pressure; D002478:Cells, Cultured; D004032:Diet; D050171:Dyslipidemias / Q000235:genetics* / Q000378:metabolism; D005632:Fructose / Q000008:administration & dosage / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics* / Q000378:metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics* / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000097:blood; D007408:Intestinal Absorption; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D047495:PPAR gamma / Q000378:metabolism; D022722:Thermogenesis
chemical_list: D001786:Blood Glucose; D051246:Glucose Transport Proteins, Facilitative; D007328:Insulin; D047495:PPAR gamma; C498628:Slc2a8 protein, mouse; D005632:Fructose
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