The glucose transporter GLUT12, a new actor in obesity and cancer.

Obesity constitutes a global health epidemic which worsens the main leading death causes such as type 2 diabetes, cardiovascular diseases, and cancer. Changes in the metabolism in patients with obesity frequently lead to insulin resistance, along with hyperglycemia, dyslipidemia and low-grade inflammation, favoring a more aggressive tumor microenvironment. One of the hallmarks of cancer is the reprogramming of the energy metabolism, in which tumor cells change oxidative phosphorylation to aerobic glycolysis or "Warburg effect".

Differential remodeling of subcutaneous white and interscapular brown adipose tissue by long-term exercise training in aged obese female mice.

Obesity exacerbates aging-induced adipose tissue dysfunction. This study aimed to investigate the effects of long-term exercise on inguinal white adipose tissue (iWAT) and interscapular brown adipose tissue (iBAT) of aged obese mice. Two-month-old female mice received a high-fat diet for 4 months.

The Molecular Basis of Glucose Galactose Malabsorption in a Large Swedish Pedigree.

Glucose-galactose malabsorption (GGM) is due to mutations in the gene coding for the intestinal sodium glucose cotransporter SGLT1 (SLC5A1). Here we identify the rare variant Gln457Arg (Q457R) in a large pedigree of patients in the Västerbotten County in Northern Sweden with the clinical phenotype of GGM. The functional effect of the Q457R mutation was determined in protein expressed in oocytes using biophysical and biochemical methods.

Effect of aging and obesity on GLUT12 expression in small intestine, adipose tissue, muscle, and kidney and its regulation by docosahexaenoic acid and exercise in mice.

Obesity is characterized by excessive fat accumulation and inflammation. Aging has also been characterized as an inflammatory condition, frequently accompanied by accumulation of visceral fat. Beneficial effects of exercise and n-3 long-chain polyunsaturated fatty acids in metabolic disorders have been described.

DHA and its derived lipid mediators MaR1, RvD1 and RvD2 block TNF-α inhibition of intestinal sugar and glutamine uptake in Caco-2 cells.

Tumor necrosis factor-alfa (TNF-α) is a pro-inflammatory cytokine highly-involved in intestinal inflammation. Omega-3 polyunsaturated fatty acids (n3-PUFAs) show anti-inflammatory actions. We previously demonstrated that the n3-PUFA EPA prevents TNF-α inhibition of sugar uptake in Caco-2 cells.

GLUT12 Expression in Brain of Mouse Models of Alzheimer's Disease.

The brain depends on glucose as a source of energy. This implies the presence of glucose transporters, being GLUT1 and GLUT3 the most relevant. Expression of GLUT12 is found in mouse and human brain at low levels.

GLUT12 and adipose tissue: Expression, regulation and its relation with obesity in mice.

Aim: The facilitative glucose transporter GLUT12 was isolated from the breast cancer cell line MCF-7 by its homology with GLUT4. GLUT12 is expressed in insulin-sensitive tissues such as adipose tissue. The aim of this work was to investigate GLUT12 expression and hormonal regulation in 3T3-L1 adipocytes and in adipose tissue of lean and diet-induced obese mice.

GLUT12 expression and regulation in murine small intestine and human Caco-2 cells.

GLUT12 was cloned from the mammary cancer cell line MCF-7, but its physiological role still needs to be elucidated. To gain more knowledge of GLUT12 function in the intestine, we investigated GLUT12 subcellular localization in the small intestine and its regulation by sugars, hormones, and intracellular mediators in Caco-2 cells and mice. Immunohistochemical methods were used to determine GLUT12 subcellular localization in human and murine small intestine.

Basolateral presence of the proinflammatory cytokine tumor necrosis factor -α and secretions from adipocytes and macrophages reduce intestinal sugar transport.

We have previously demonstrated in Caco-2 cells that tumor necrosis factor-α (TNF-α) inhibits sugar uptake, acting from the apical membrane, by decreasing the expression of the Na -glucose cotransporter SGLT1 in the brush border membrane. The goal was to investigate the hypothesis that TNF-α from abdominal adipose tissue (adipocytes and macrophages) would decrease sugar and amino acid transport acting from the basolateral membrane of the enterocytes. TNF-α placed in the basal compartment of Caco-2 cells decreased α-methyl- d-glucose (αMG) and glutamine uptake.

EPA blocks TNF-α-induced inhibition of sugar uptake in Caco-2 cells via GPR120 and AMPK.

The aim of the present work was to investigate in Caco-2 cells whether eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, could block the inhibitory effect of tumor necrosis factor-α (TNF-α) on sugar transport, and identify the intracellular signaling pathways involved. After pre-incubation of the Caco-2 cells with TNF-α and EPA for 1 hr, EPA prevented the inhibitory effect of the cytokine on α-methyl-d-glucose (αMG) uptake (15 min) and on SGLT1 expression at the brush border membrane, measured by Western blot. The ERK1/2 inhibitor PD98059 and the AMPK activator AICAR also prevented the inhibitory effect of TNF-α on both αMG uptake and SGLT1 expression.

Cardiotrophin-1 decreases intestinal sugar uptake in mice and in Caco-2 cells.

Aim: Cardiotrophin-1 (CT-1) is a member of the IL-6 family of cytokines with a key role in glucose and lipid metabolism. In the current investigation, we examined the in vivo and in vitro effects of CT-1 treatment on intestinal sugar absorption in different experimental models.

Methods: rCT-1 effects on α-Methyl-D-glucoside uptake were assessed in everted intestinal rings from wild-type and CT-1(-/-) mice and in Caco-2 cells.

Trans-resveratrol induces a potential anti-lipogenic effect in lipopolysaccharide-stimulated enterocytes.

A DNA microarray analysis was conducted in Caco-2 cells to analyse the protective effects of trans-resveratrol on enterocyte physiology and metabolism in pro-inflammatory conditions. Cells were pre-treated with 50 μΜ of trans-resveratrol and, subsequently, lipopolysaccharide (LPS) was added for 48 h. The microarray analysis revealed 121 genes differentially expressed between resveratrol-treated and non-treated cells (B> 0, is the odd thatthe gene is differentially expressed).

Modulation of intestinal L-glutamate transport by luminal leptin.

Leptin is secreted into the digestive tract and contributes to the absorption of dietary molecules by regulating transporters activity. Here, we studied the effect of luminal leptin on the intestinal transport of L-glutamate, an important component of human diet. We examined the effect of leptin on L-glutamate uptake in rat intestine in vitro measuring glutamate-induced short-circuit current (Isc) in Ussing chambers and L-[(3)H (U)]-glutamate uptake in jejunal everted rings.

Fluorescent nucleoside derivatives as a tool for the detection of concentrative nucleoside transporter activity using confocal microscopy and flow cytometry.

The abundance and function of transporter proteins at the plasma membrane are likely to be crucial in drug responsiveness. Functional detection of human concentrative nucleoside transporters (hCNTs) is of interest for predicting drug sensitivity because of their ability to transport most nucleoside-derived drugs. In the present study, two fluorescent nucleoside analogues, uridine-furan and etheno-cytidine, were evaluated as tools to study in vivo nucleoside transporter-related functions.

Functional characterization of the human facilitative glucose transporter 12 (GLUT12) by electrophysiological methods.

GLUT12 is a member of the facilitative family of glucose transporters. The goal of this study was to characterize the functional properties of GLUT12, expressed in Xenopus laevis oocytes, using radiotracer and electrophysiological methods. Our results showed that GLUT12 is a facilitative sugar transporter with substrate selectivity: d-glucose ≥ α-methyl-d-glucopyranoside (α-MG) > 2-deoxy-d-glucose(2-DOG) > d-fructose = d-galactose.

Could GLUT12 be a Potential Therapeutic Target in Cancer Treatment? A Preliminary Report.

Background: Recent studies proposed GLUT12 to be a major glucose transporter involved in the glycolytic metabolism of cancer cells.

Methods: GLUT12 expression was determined by immunohistochemistry in a selection of cancer cell lines and a tumour spheroid model.

Results: GLUT12 expression was high in A549 and RH-36; low in HT29; and absent in NB-EB cancer cell lines.

In vivo regulation of intestinal absorption of amino acids by leptin.

Leptin is secreted by the gastric mucosa and is able to reach the intestinal lumen and bind to its receptors located in the apical membranes of enterocytes. We have previously demonstrated that apical leptin inhibits uptake of amino acids in rat intestine in vitro and in Caco-2 cells. The aim of the present work was to investigate the effect of leptin on absorption of amino acids using in vivo techniques, which generate situations closer to physiological conditions.

Expression of the glucose transporter GLUT12 in Alzheimer's disease patients.

Alzheimer's disease (AD) might be conceptualized as a metabolic disease with progressive impairment of the brain's capacity to utilize glucose. One of the last glucose transporters discovered is GLUT12. The aim of the present work was to investigate the expression of GLUT12 in frontal cortex from AD patients.

Helichrysum and grapefruit extracts inhibit carbohydrate digestion and absorption, improving postprandial glucose levels and hyperinsulinemia in rats.

Several plant extracts rich in flavonoids have been reported to improve hyperglycemia by inhibiting digestive enzyme activities and SGLT1-mediated glucose uptake. In this study, helichrysum ( Helichrysum italicum ) and grapefruit ( Citrus × paradisi ) extracts inhibited in vitro enzyme activities. The helichrysum extract showed higher inhibitory activity of α-glucosidase (IC50 = 0.

TNFα regulates sugar transporters in the human intestinal epithelial cell line Caco-2.

Purpose: During intestinal inflammation TNFα levels are increased and as a consequence malabsorption of nutrients may occur. We have previously demonstrated that TNFα inhibits galactose, fructose and leucine intestinal absorption in animal models. In continuation with our work, the purpose of the present study was to investigate in the human intestinal epithelial cell line Caco-2, the effect of TNFα on sugar transport and to identify the intracellular mechanisms involved.

Basal leptin regulates amino acid uptake in polarized Caco-2 cells.

Leptin is secreted by gastric mucosa and is able to reach the intestinal lumen where its receptors are located in the apical membrane of the enterocytes. We have previously demonstrated that apical leptin inhibits sugar and amino acids uptake in vitro and glucose absorption in vivo. Since leptin receptors are also expressed in the basolateral membrane of the enterocytes, the aim of the present work was to investigate whether leptin acting from the basolateral side could also regulate amino acid uptake.

Leptin regulates sugar and amino acids transport in the human intestinal cell line Caco-2.

Aim: Studies in rodents have shown that leptin controls sugars and glutamine entry in the enterocytes by regulating membrane transporters. Here, we have examined the effect of leptin on sugar and amino acids absorption in the human model of intestinal cells Caco-2 and investigated the transporters involved.

Methods: Substrate uptake experiments were performed in Caco-2 cells, grown on plates, in the presence and the absence of leptin, and the expression of the different transporters in brush border membrane vesicles was analysed by Western blot.

Functional analysis of the human concentrative nucleoside transporter-1 variant hCNT1S546P provides insight into the sodium-binding pocket.

SLC28 genes, encoding concentrative nucleoside transporter proteins (CNT), show little genetic variability, although a few single nucleotide polymorphisms (SNPs) have been associated with marked functional disturbances. In particular, human CNT1S546P had been reported to result in negligible thymidine uptake. In this study we have characterized the molecular mechanisms responsible for this apparent loss of function.