Regulationsmechanismen während des Torpors und der zitterfreien Thermogenese: Neue Einblicke und der Einsatz von Magnetresonanztomographie

Säugetiere bevölkern nahezu jede Nische der Erde, weil sie ihre Körpertemperatur unabhängig von der Umgebungstemperatur regulieren können. Diese endotherme Lebensweise ist, besonders für Kleinsäuger, energetisch sehr kostspielig und lässt sich nur durch eine präzise Regulation der Energieausgaben ve...

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Bibliographic Details
Main Author: Grimpo, Kirsten
Contributors: Heldmaier, Gerhard (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2014
Online Access:PDF Full Text
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Mammals are able to regulate their body temperature independent of the ambient temperature and thus inhabit almost every ecological niche all over the world. This endothermic way of life is especially for small mammals energetically expensive and requires a balanced energy management. The mechanisms for metabolic reduction in order to save energy, i.e. torpor, or the increase of energy metabolism in order to defend body temperature against ambient temperatures are complex and barely understood. Measuring oxygen consumption and body temperature of Golden spiny mice (Acomys russatus) revealed that these desert rodents were able to compensate a 50% food restriction when kept at ambient temperatures of 32°C or 35°C. The spiny mice defended their body weight against the reduced energy supply through a 30% reduction of resting metabolic rate compared to ad libitum conditions as well as by using daily torpor. During torpor at these ambient temperatures they maintained their body temperature at a normothermic level whereas they became hypothermic during torpor at ambient temperatures of 23°C or 27°C. This implies that the metabolic reduction during torpor can occur autonomously from a hypothermic body temperature. It demonstrates that torpor is an efficient strategy for saving energy in a variety of habitats and not just in cold environments as previously assumed. Mitochondria are discussed to trigger the regulated metabolic depression in torpor, as it has been hypothesized that a shutdown of cell respiration could be responsible for the rapid reduction of metabolic rate during torpor entrance. For this reason mitochondrial succinate respiration of four tissues (e.g. liver) were investigated from torpid spiny mice but no differences were detected when compared to normometabolic individuals. There was no change in membrane potential or ATP-synthase efficiency of isolated mitochondria during torpor. These results were true for torpid A. russatus with normothermic and hypothermic body temperature and indicate that the decrease of metabolic rate during torpor in this species is not caused by a depression of mitochondrial respiration. In contrast, mitochondrial respiration of liver from winter-acclimated Djungarian hamsters (Phodopus sungorus) was significantly reduced during torpor due to an active inhibition of substrate oxidation. The respiration rates of liver mitochondria correlated with the body temperature of the hamsters, which reached very low values at an ambient temperature of 15°C. In conclusion the active inhibition of mitochondrial respiration seems to be species-specific and more an adaptation to a low body temperature in the torpid state rather than being the cause of torpid state per se. Thus, the intrinsic mechanisms of entrance into torpor still remain unclear. To further elucidate the mechanisms which underlie the regulation of torpor in the Djungarian hamster a combination of indirect calorimetry and magnetic resonance imaging (MRI) was developed. Hardware and software of the experimental setup were optimized so that P. sungorus became torpid inside the 7 Tesla scanner allowing for the first time successful acquirements of imaging, angiography and spectroscopy data in a non-anaesthetized animal. Such functional measurements via MRI promise new insights into the processes of torpor. Another advantage of MRI, its excellent soft tissue contrast, was used for characterization of adipose tissue of anaesthetized animals in vivo. Differences between the white adipose tissue that serves mainly as lipid storage and the thermogenically important brown adipose tissue were detected with MRI and data were validated with ex vivo gas-chromatographic measurements. White adipose tissue had a higher content of unsaturated fatty acid than brown fat. In both tissues the amount of unsaturated fatty acids increased following acclimation to short photoperiod, indicating a contribution of fatty acids to the preparation of torpor behavior and adaptation to cold. The thermogenic function of brown adipose tissue was investigated more closely in the last part of the thesis. Brown adipose tissue is essential for small mammals to reheat from hypothermic states in torpor and to defend normothermic body temperature during cold exposure. For this purpose after noradrenergic stimulation brown adipose tissue generates heat by uncoupling the oxidative phosphorylation from the respiratory chain via uncoupling protein 1 (UCP1) activity. Long term cold exposure results in an increased respiratory capacity of brown adipose tissue and this adaptive non-shivering thermogenesis is mainly attributed to UCP1 induced thermogenesis. However, UCP1-depleted mice increased their capacity of non-shivering thermogenesis after adaptation to cold, indicating a compensatory mechanism of UCP1-dependent thermogenesis. MRI visualized a remodeling of brown adipose tissue in UCP1-KO and wildtype mice following cold acclimation. By using magnetic resonance spectroscopy an advanced lipid metabolism after noradrenergic stimulation was detected that led to an export of fatty acids, the main substrate of non-shivering thermogenesis, from brown adipose tissue. The data suggest an UCP1-independent adjustment of brown adipose tissue to cold exposure and a contribution to lipid metabolism that exceeds the oxidation of fatty acids for UCP1-dependent thermogenesis. The results of the present PhD-Thesis contribute to a better understanding of the energy metabolism in small mammals. They untangle the interactions between an active down-regulation of metabolism, body temperature, ambient temperature and mitochondrial respiration. They discuss the potential of MRI as an innovative method in order to answer physiological questions and stress the role of brown adipose tissue concerning UCP1-independent thermogenesis.