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Elongase 6 and thermogenesis

Final Report Summary - ELOVL6 THERMOGENESIS (Elongase 6 and thermogenesis)

Project objectives
Obesity is the result of a mismatch between energy intake and energy expenditure. The intake of excess calories will result in an increase of lipid supply to the body, both as a result of fat intake via food and an increased de novo synthesis of fatty acids (lipogenesis). Fatty acids can be either stored, exported to other tissues, oxidized or transformed to lipid metabolites. Interfering in the regulation of lipid storage versus oxidation may be a possible future way to treat the negative consequences of obesity.
A fundamental question regarding free fatty acids is how these lipids are targeted to their various fates; oxidation, storage, export or incorporation into more complex lipid species. The roles of fatty acid elongation lipid targeting have so far attracted little attention. Hence, in this project we aimed to investigate if fatty acid chain length is a important determinant controlling the balance of oxidation versus storage of fatty acids. We have primarily investigated the effect of lack of Elovl6, an enzyme responsible for elongating saturated free fatty acids.
Work performed in this project and results obtained so far Elovl6 knock out (KO) mouse
Growth curves of wild type (WT) and KO animals show that though birth weight of KO and WT mice were the same, by day 11, knock out pups were smaller then wild types and the weights continued to diverge until 3 weeks of age. Surprisingly, beyond 3 weeks of age, the KO mice began to catch-up the WT mice and the catch-up growth was complete by 6 weeks. This growth pattern was exhibited by both male and female pups. In order to shed light on possible causes of the growth restriction, we next characterized the body composition and weights of major tissues. No substantial differences in the percentage of contribution of the different organs to total body weight (e.g. liver, white adipose tissue depots, brown adipose tissue) was found, suggesting that the growth restriction is unlikely to be due to a specific pathology in any of the tissues studied. The findings are more consistent with a systemic insult such as energy imbalance/caloric restriction.
To try to identify possible mechanisms involved in compensating for Elovl6 post-weaning we
investigated gene expression changes of genes involved in lipid metabolism in white (WAT) and brown adipose tissue (BAT) in adult mice following the completion of catch up growth. The following summarizes gene expression data taken from 3 month old male mice (WT=8, KO=9). BAT, which expresses relatively high levels of Elovl6, demonstrates gene expression changes in keeping with an up regulation of the lipogenic programme specifically towards an increased in the expression of alternative elongases. These changes may constitute an attempt to compensate for the lack of Elovl6. A similar response was seen in subcutaneous WAT.
In summary: the loss of Elovl6 in mice results in a marked phenotype characterized by failure to thrive followed by spontaneous and complete catch up growth. Our data support the hypothesis that disruption of fatty acid chain length could alter energy balance and result in reduced weight gain. We speculate that this is particularly relevant in tissues with high metabolic rates and a dependence on lipid for fuel, such as BAT. We further postulate that the switch in fuel source at weaning is responsible for the recovery. This in turn maybe mediated by the activation of compensatory elongases.
Expected final results and their potential impact and use
The data obtained in this project show a clear impact of fatty acid chain length modification on growth and development. This is a whole new finding that greatly contributes to our understanding of the role of fatty acid metabolism in growth and development and may ultimately lead to the possible identification of inherited errors of metabolism. Moreover, it gives direction to further research of the role of fatty acid elongation in the development of obesity.