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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online July 18, 2003 as doi:10.1096/fj.02-1163fje. |
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Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, and Center of Animal Biotechnology and Gene Therapy. Universitat Autònoma de Barcelona. E-08193-Bellaterra, Spain
2Correspondence: E-mail: fatima.bosch{at}uab.es
SPECIFIC AIMS
The transcription factor c-Myc induces hepatic glucose uptake and utilization and blocks gluconeogenesis. In this study, we examined whether hepatic overexpression of c-myc counteracted obesity and insulin resistance induced by a high-fat diet.
PRINCIPAL FINDINGS
1. Transgenic mice overexpressing c-myc were protected from diet-induced obesity and insulin resistance
After 3 months on a high-fat diet, control mice (Fat-Con) gained 
40% in body weight and became obese. In contrast, transgenic mice fed this diet (Fat-Tg) remained lean and showed an increase of only 20%, which was similar to that observed in control (Std-Con) and transgenic (Std-Tg) mice fed a standard diet. Food intake was similar in control and transgenic mice. Overexpression of c-myc did not lead to proliferation or transformation in the liver.
In addition, Fat-Con mice became hyperglycemic and hyperinsulinemic in both fed and fasted conditions, indicating that they had developed insulin resistance. However, Fat-Tg mice showed normal levels of blood glucose and insulin, indicating they had developed neither obesity nor insulin resistance. Moreover, when an intraperitoneal glucose tolerance test was performed in overnight-fasted mice, glucose disposal by Fat-Tg mice was greater than Fat-Con mice, similar to that observed in Std-Con mice.
2. c-myc overexpression induced the expression and activity of key genes involved in the control of hepatic glycolysis
The expression of genes that regulate hepatic metabolism was also analyzed. In the liver of Fat-Con mice, the expression of glucokinase (GK) and L-type pyruvate kinase (L-PK) genes decreased (50%) relative to Std-Con (Fig. 1
). However, Fat-Tg mice expressed high levels of GK (2.5-fold increase) and L-PK (3-fold) mRNA levels compared with Fat-Con (Fig. 1)
. The overexpression of c-Myc in transgenic mice also led to an increase (2.5-fold) in the expression of sterol regulatory element binding protein-1c (SREBP-1c) compared with control mice on both standard and high-fat diets (Fig. 1)
. Fat-Tg mice had levels of c-myc mRNA similar to those observed in transgenic mice fed a standard diet (Fig. 1)
. The changes in GK and L-PK mRNA levels were parallel to the enzyme activity. The reduction of glucokinase activity in Fat-Con mice was associated with a decrease in the intracellular concentration of glucose 6-phosphate (50%) and in glycogen content (40%). In contrast, Fat-Tg mice showed similar levels of these metabolites to control mice fed a standard diet both in fed and fasted conditions.
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3. Decreased gene expression of gluconeogenic genes in the liver of Fat-Tg mice
When the phosphoenolpyruvate carboxykinase (PEPCK) gene expression was analyzed, Fat-Con mice showed a marked increase in the expression of this gene compared with Std-Con mice (Fig. 2
). In contrast, transgenic mice fed a high-fat diet showed a reduction (4-fold) in the expression of this gene compared with Fat-Con mice (Fig. 2)
. The decrease in the expression of PEPCK in the liver of Fat-Tg transgenic animals was parallel to a decrease in the glucose transporter 2 (GLUT2) mRNA levels (Fig. 2)
, which were also increased in the liver of Fat-Con mice. The mRNA levels of PEPCK and GLUT2 genes in the liver of Fat-Tg mice were similar to those observed in control mice fed a standard diet (Fig. 2)
.
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4. Down-regulation in the expression of genes involved in energy metabolism in the liver of Fat-Tg mice
The decrease in PEPCK gene expression was parallel to a decrease (3-fold) in PPAR
gene expression in the liver of Std-Tg compared with Std-Con mice (Fig. 2)
. Moreover, PPAR mRNA levels were reduced (3-fold) in the liver of Fat-Tg mice compared with Fat-Con mice and were similar to those observed in Std-Tg mice (Fig. 2)
. In contrast, Fat-Con mice showed an increase (3-fold) in the expression of PPAR compared with Std-Con (Fig. 2)
. Furthermore, the high-fat diet induced a threefold increase in UCP2 gene expression in the liver of control mice (Fig. 2)
. However, normalization of the expression of PPAR gene observed in Fat-Tg mice resulted in UCP2 mRNA levels similar to those observed in Std-Con mice (Fig. 2)
.
CONCLUSIONS AND SIGNIFICANCE
Transgenic mice overexpressing c-myc fed a high-fat diet were lean and showed higher increased hepatic glucose uptake and utilization than control mice. In addition, these transgenic mice lessened hyperglycemia and hyperinsulinemia in both fed and fasted conditions. Moreover, overexpression of c-Myc in the liver counteracted the development of obesity and insulin resistance induced by a high-fat diet by restoring the expression and activity of key enzymes involved in the control of hepatic metabolism. An E-box motif 5'-CACGTG-3', which could be bound by c-Myc, has recently been described in the promoter region of these enzymes. It is possible that c-Myc controls, through transcriptional activation/repression, a network that regulates energy turnover (PPAR and UCP2 genes) and glucose metabolism (GK, PEPCK, and SREBP1-c genes). Furthermore, our results indicate that hepatic overexpression of c-myc is enough for normalization of insulin resistance, indicating the key role of the liver in the control of whole-body glucose homeostasis (Fig. 3
). This transgenic model also suggests that engineering the liver to both increase glucose uptake and utilization and block glucose production may be a useful approach to prevent obesity and insulin resistance.
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-1163fje; doi: 10.1096/fj.02-1163fje 
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Significantly different from the corresponding value in control mice on the same diet (Std-Tg vs. Std-Con and Fat-Tg vs. Fat-Con; *P<0.05; **P<0.01). 
Significantly different from the corresponding value in same genotype animals on different diet (Std-Con vs. Fat-Con; *P<0.05). Left panel: a representative Northern blot hybridized with c-myc, GK, L-PK, and SREBP1-c and with ß-actin-specific probes is presented.
