Improved glucose homeostasis in mice overexpressing human UCP3: a role for AMP-kinase?

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Abstract
OBJECTIVE: An unexplained phenotype of mice overexpressing human UCP3 is their improved glucose homeostasis. Since overexpression of UCP3 might affect the energy charge of the cell, we investigated whether these mice have an increased AMP-activated protein kinase (AMPK) activity. METHODS: Mitochondrial localisation of UCP3 was determined by immunoelectronmicroscopy and AMPK activity was measured in medial gastrocnemius of control mice and mice overexpressing human UCP3. RESULTS: Mice overexpressing human UCP3 had 5.8 fold higher levels of UCP3 protein, for which mitochondrial localisation was confirmed by immunoelectronmicroscopy. The ATP/AMP ratio was significantly lower in mice over-expressing UCP3 compared to the wild-type (10.9±1.6 vs 20.4±1.9 AU, P=0.03). Over-expression of UCP3 resulted in increased AMPK α1 activity (1.23±0.05 vs 1.00±0.06 normalized values, P=0.004) and a tendency towards increased AMPK α2 activity (1.18±0.08 vs 1.00±0.10 normalized values, P=0.08). CONCLUSION: Increased AMPK activity provides a plausible explanation for the improved glucose tolerance characteristic for these mice.

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