Study of GLUT12 expression and regulation in small intestine and adipose tissue, and the possible implication of the transporter in obesity, alzheimer's disease and cancer

Resumen

The maintenance of glucose homeostasis is vital for the organism, that explain the existence of 14 GLUTs members in the SLC2 family of glucose transporters. Nevertheless, only the physiological role of GLUT1-5 is clearly established. GLUT12 is one of the less investigated members of Class III of the SLC2 family, which displays unique functional properties, but whose physiological role in the organism still needs to be elucidated. In the present work we show GLUT12 intracellular and perinuclear location in human and murine enterocytes and mouse adipocytes. This localization can be explained by the presence of the internalization dileucine motifs at the N‐ and C‐terminal ends, which are also present in other members of Class III and GLUT4. In the human enterocyte cell line Caco-2 and the mouse 3T3-L1 derived adipocytes, insulin induces GLUT12 translocation to the membrane suggesting its participation on sugar uptake during postprandial periods. The pro-inflammatory cytokine TNF-α also promotes GLUT12 translocation to the membrane. In contrast, it has been demonstrated that TNF‐α induces internalization of SGLT1 in enterocytes and of GLUT4 in adipocytes, suggesting that GLUT12 would be a compensatory mechanism during inflammation. Contrary to GLUT4, leptin and adiponectin induce GLUT12 internalization in adipocytes. We confirm these results in mouse ex vivo studies. In Caco-2 cells, H+ enhances GLUT12 transport. This characteristic could be related to the fact that Class III includes the H+/myoinositol transporter and thus, GLUT12 could use the proton gradient to contribute to glucose transport in acidic environments such as small intestine and kidney, where GLUT12 is also expressed. Furthermore, GLUT12 trafficking to the membrane and sugar transport are increased by the activation of PKC, AKT, and AMPK and the inhibition of ERK1/2. Obesity is characterized by hyperplasia and hypertrophy of the adipose tissue, and systemic inflammation. Fat accumulation and weight gain lead to hyperlipidemia, hyperglycemia, hyperinsulinemia and hypercholesterolemia that affect other organs. In this excessive nutrient intake condition, GLUT12 protein is downregulated in small intestine and adipose tissue, most probably in relation with insulin resistance, as we found that GLUT12 response to insulin is lost in the obese mice. In Alzheimer¿s disease (AD) there is a reduction in the glucose transport and utilization by the brain, this is accompanied by a decrease on GLUT1 and GLUT3 expression. We demonstrate that GLUT12 is upregulated in the frontal cortex of mouse models of AD (Tg2576 and APP/PS1), as well as in response to Aβ-oligomers i.c.v injection. This may indicate a compensatory mechanism of GLUT12 to counterbalance the reduction of the main GLUTs in the brain. Aging is one of the main risks for the development of AD. Global studies on aged tissues have emphasized the importance of inflammation in aging and the decrease of sugar uptake found in different tissues. We found that GLUT12 is also upregulated in the brain of aged mice and the accelerated senescent mouse model SAMP8. Interestingly, aging also increases GLUT12 expression in small intestine, adipose tissue and kidney. Cancer and aging share a common origin, the time-dependent accumulation of cellular damage. GLUT12 is upregulated in human colon adenocarcinoma, hepatocellular carcinoma and uterine tumors, where the tumor suppressor p53 is decreased. In conclusion, under basal conditions, GLUT12 is mainly intracellularly expressed. Stimulus such as glucose and insulin trigger GLUT12 translocation to the membrane, indicating that GLUT12 could contribute to glucose homeostasis in postprandial periods. GLUT12 is upregulated in aging, Alzheimer's disease and cancer while is downregulated in obesity. These suggest that GLUT12 would act as a backup or compensatory glucose transporter which could be a candidate to be explored as a therapeutic target.