Mitochondrial proton leak and uncoupling protein expression in transgenic mice and human obesity.

Mitochondrial proton leak and uncoupling protein expression in transgenic mice and human obesity.

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Title: Mitochondrial proton leak and uncoupling protein expression in transgenic mice and human obesity.
Author: Monemdjou, Shadi.
Abstract: The significance of the uncoupling protein-1 (UCP1) in brown adipose tissue (BAT) thermogenesis has been well defined. However, the absence of significant amounts of BAT in adult humans, and the desire to reveal the mechanisms modulating skeletal muscle thermogenesis, led to the search for other proteins homologous to UCP1 which could also mediate thermogenesis by uncoupling oxidative phosphorylation. This search led to the discovery of Ucp2 and Ucp3 genes, as well as Ucp4 and brain mitochondrial carrier protein-1 (BMCP1). Ucp3 is of particular interest as a potential mediator of thermogenesis because it is selectively expressed at moderately high levels in human skeletal muscle, a tissue that contributes significantly to resting energy expenditure. In this thesis we attempt to elucidate the true physiological role of the UCP1 homologues, and of UCP3 specifically, by examining mitochondrial proton leak and UCP3 protein expression in: (1) mice that do not express Ucp3 ( Ucp3-knockout mice), (2) transgenic mice that overexpress human Ucp3 in their skeletal muscle (UCP-3Tg mice), (3) and finally in a distinct population of women who differ in their rate of weight loss. Our studies with the Ucp3-knockout mice show that the mitochondrial proton conductance is reduced in skeletal muscle mitochondria when UCP3 is absent. This result supports the hypothesis that UCP3 is a significant contributor to proton leak in skeletal muscle, and that the remaining UCPs in muscle (e.g., UCP2) do not compensate for the loss of UCP3. Mice overexpressing human UCP3 in skeletal muscle have total Ucp3 mRNA expression that is 66-fold greater than normal, and despite an increase in food intake, they are more lean than controls. Our results from human studies have provided the first ever measurements of proton leak in human muscle mitochondria. We examined the role of UCP3 and mitochondrial proton leak in patients on an energy restricted diet (900 kcal/day) who were identified as either diet-responsive or diet-resistant. Our results indicate that the state 4 oxygen consumption is 51% higher in the diet-responsive subjects compared to the diet-resistant ones. In addition, Ucp3 mRNA expression was found to be 25% greater in skeletal muscle of diet-responsive compared to diet-resistant individuals, suggesting that the upregulation of this protein could be responsible for the differences seen in the rate of weight loss. (Abstract shortened by UMI.)
Date: 2002
URI: http://hdl.handle.net/10393/6433

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