Life and death: thermogenesis, metabolism and membranes

Currently, research on maximum sustained metabolic rate concentrates on the importance of heat dissipation in lactating females. It has been shown that due to the exothermic process of milk production and because they digest very large quantities of food, females raising young are constrained by hyperthermia in their energy intake. Reportedly, females allow their body temperature to increase by 1.2 and the unanswered question in this context is what determines the upper limit of body temperature. We intend to test the hypothesis that oxidative stress might determine this limit. Therefore we propose to perform a series of experiments in lactating mice from the MF1 strain which involve manipulations of body temperature while assessing oxidative stress, antioxidant activity and gene expression of uncoupling proteins. At the end of our study we will be able to identify the physiological importance of oxidative damage in response to sustained energy intake, a topic which will be of interest for many scientific groups working in the fields of metabolism and aging. Another newly generated hypothesis in context with body temperature regulation in mammals suggests that certain membrane constituents, n-3 polyunsaturated fatty acids, may modulate thermogenic capacity in mammals. Thus, we hypothesise that in parallel with changes in core body temperature, membrane fatty acid composition is adjusted accordingly, with n-3 polyunsaturated fatty acids having a particular role for thermogenesis. To test our hypothesis we will use lactating mice from the MF1 strain in addition to the model system of the long-lived Ames dwarf mouse. Importantly, Ames dwarf mice also have lower body temperatures and presumably impaired thermoregulation while at the same time possessing muscle membrane phospholipids rich in n-3 polyunsaturated fatty acids. We will keep animals on diets enriched with both n-3 or n-6 fatty acids and will establish a control on an isocaloric saturated diet. In all experimental animals we will measure body temperature with implanted transmitters and tissue fatty acid composition. In another group of animals we will assess proton leak in isolated liver mitochondria. This part of the project will identify the role of membrane bound fatty acids for modulation of body temperature in mammals.

Raising young and providing offspring with milk is the most energy demanding physiological process. What are the long-term effects and consequences of such a high energy expenditure on mammals? Are they trading in high investment into young over a shorter lifespan? What role do metabolically very important fatty acid molecules play? Over the course of the Elise Richter project we tried to find out how the high energy demands affect body temperature and milk production in the mouse model. Females raising young over 3 weeks of lactation produce large amounts of milk and were found to have a 2C higher body core temperature. Also we found out that there was no increase in oxidative stress during this time. While the traditional view was that increased energy expenditure brings about more damage to biomolecules such as proteins, lipids and DNA, we found no change in those parameters related to lactation. Most likely the very efficient buffering anti-oxidative mechanisms counteract the process. We found that mitochondrial fatty acid composition in lactating females is shifted towards omega-6 fatty acids. As parturition and lactation require large changes in physiology we identified another piece of the jigsaw that reinforces our view of fatty acids as important pacemakers of metabolism. Our new and exciting results show that the link between oxidative stress and aging as well as the traditional view of optimal rearing conditions ask for revision. While females with peak energy expenditures were usually kept at room temperature conditions, we are now proposing to create situations under which females can cool down and rest at lower ambient temperatures and get access to chilled drinking water. Finally, we suggest that a long and healthy is not contradictory to a high energy expenditure. Rather, adaptations that involve tissue fatty acid compositional give rise to changes in energy allocation but not to increased oxidative stress.