Glucose transporter-8 (GLUT8) mediates glucose intolerance and dyslipidemia in high-fructose diet-fed male mice

Mol Endocrinol. 2013 Nov;27(11):1887-96. doi: 10.1210/me.2013-1137. Epub 2013 Sep 12.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Animals
  • Blood Glucose
  • Blood Pressure
  • Cells, Cultured
  • Diet
  • Dyslipidemias / genetics*
  • Dyslipidemias / metabolism
  • Fructose / administration & dosage
  • Fructose / metabolism*
  • Glucose Intolerance / genetics*
  • Glucose Intolerance / metabolism
  • Glucose Transport Proteins, Facilitative / genetics*
  • Glucose Transport Proteins, Facilitative / metabolism
  • Homeostasis
  • Insulin / blood
  • Intestinal Absorption
  • Male
  • Metabolic Syndrome / genetics
  • Metabolic Syndrome / metabolism*
  • Mice
  • Mice, 129 Strain
  • Mice, Knockout
  • PPAR gamma / metabolism
  • Thermogenesis

Substances

  • Blood Glucose
  • Glucose Transport Proteins, Facilitative
  • Insulin
  • PPAR gamma
  • Slc2a8 protein, mouse
  • Fructose