Glucose transporter 10 modulates adipogenesis via an ascorbic acid-mediated pathway to protect mice against diet-induced metabolic dysregulation

Abstract

The development of type 2 diabetes mellitus (T2DM) depends on interactions between genetic and environmental factors, and a better understanding of gene-diet interactions in T2DM will be useful for disease prediction and prevention. Ascorbic acid has been proposed to reduce the risk of T2DM. However, the links between ascorbic acid and metabolic consequences are not fully understood. Here, we report that glucose transporter 10 (GLUT10) maintains intracellular levels of ascorbic acid to promote adipogenesis, white adipose tissue (WAT) development and protect mice from high-fat diet (HFD)-induced metabolic dysregulation. We found genetic polymorphisms in SLC2A10 locus are suggestively associated with a T2DM intermediate phenotype in non-diabetic Han Taiwanese. Additionally, mice carrying an orthologous human Glut10 G128E variant (Glut10 G128E mice) with compromised GLUT10 function have reduced adipogenesis, reduced WAT development and increased susceptibility to HFD-induced metabolic dysregulation. We further demonstrate that GLUT10 is highly expressed in preadipocytes, where it regulates intracellular ascorbic acid levels and adipogenesis. In this context, GLUT10 increases ascorbic acid-dependent DNA demethylation and the expression of key adipogenic genes, Cebpa and Pparg. Together, our data show GLUT10 regulates adipogenesis via ascorbic acid-dependent DNA demethylation to benefit proper WAT development and protect mice against HFD-induced metabolic dysregulation. Our findings suggest that SLC2A10 may be an important HFD-associated susceptibility locus for T2DM.

Vitamin C rescues high-fat diet-induced predisposition to metabolic dysregulation in GLUT10 deficient mouse model

“…2B, C and D). These observations are consistent with our previous ndings 9 . Most importantly, AA supplementation attenuated HFD-induced increases in FBG, HbA1c and insulin levels (Fig.…”

“…We then compared the changes in body weight and metabolism-related parameters in WT and GLUT10 G128E mice fed with CD or HFD and with or without AA supplementation. GLUT10 G128E mice gained more weight on a HFD than did WT mice, similar to the results of our previous study 9 (Fig. 1D and E).…”

“…2B, C and D). Moreover, HFD-fed GLUT10 G128E mice exhibited a more profound reduction in glucose tolerance and insulin sensitivity compared with HFD-fed WT mice 9 . Here we showed that AA signi cantly improved the HFD-induced glucose intolerance and insulin resistance in GLUT10 G128E mice, as measured by the glucose tolerance test (GTT) and insulin resistance test (ITT), respectively (Fig.…”

“…We found that GLUT10 transports the oxidized form of AA (dehydroascorbic acid) and regulates intracellular AA status in broblasts, aortic smooth muscle cells (ASMCs), and adipocytes using GLUT10 de cient cells 9;19;20 , and these results were then validated in broblasts from ATS patients by other groups 21;22 . Interestingly, our studies on the effects of GLUT10 genetic variants on metabolism using a mouse model that carries a rare human genetic variant of SLC2A10 (GLUT10 G128E mice) revealed that GLUT10 G128E mice have impaired WAT development and are highly sensitive to HFD-induced obesity and metabolic dysregulation compared with WT mice 9 .…”

Restoration of mRNA Expression of Solute Carrier Proteins in Liver of Diet-Induced Obese Mice by Metformin

“…However, GLUT10 is found to mediate ascorbic uptake in cells in a recent study. Glut10 was studied in adipocytes through genetic analysis, in which mutation-induced inactivation of Glut10 gene impaired adipogenesis and reduced adipose tissue development via an ascorbic acid-mediated pathway leading to insulin resistance, suggesting that Glut10 may mediate ascorbic acid uptake in cells ( 26 ). However, the role of Glut10 ( Slc2a10 ) remains unknown in the control of insulin sensitivity in the liver.…”