Molekulski mehanizmi metaboličke regulacije u hibernaciji i tokom aklimacije na hladnoću kod tekunice (Spermophilus citellus)
Molecular mechanisms of metabolic regulation in hibernation and during cold-acclimation in European ground squirrel (Spermophilus citellus)
Doctoral thesis (Published version)
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The phenomenon of hibernation is a fascinating example of plasticity in mammals. Hibernating mammals are subjected to a complex series of biochemical, physiological and behavioral changes in response to seasonal energy-demanding periods coupled with reduced food availability. The aim of the thesis was to investigate metabolic changes in the key tissues and organs of the ground squirrel, responsible for maintaining overall energy homeostasis - brown and white adipose tissue (BAT and WAT), skeletal muscle and liver, during the acclimation to low temperature, as well as in the hibernation. Effects of acclimation/hibernation on metabolic remodeling in the tissues and organs of the ground squirrel were determined by: mitochondrial capacity (gene and/or protein expression of the components of the respiratory chain and ATP synthase); thermogenic capacity (uncoupling protein 1 content), the expression profile of the key metabolic enzymes involved in: glycolysis, β-oxidation, Krebs cycle, glycogen and triglycerides metabolism. Furthermore, transcription factors involved in the metabolic regulation, as well as antioxidant enzymes, were examined. In parallel, we examined the changes in BAT and WAT depots on the structural and ultrastructural level. Males of the European ground squirrel Spermophilus citellus were divided into two groups in early September: the control group, kept at room temperature (22 ± 1 º C) and a group acclimated to low temperature (4 ± 1 ºC). Active, euthermic ground squirrels, which did not enter into deep hibernation during acclimation, were sacrificed after 1, 3, 7, 12, or 21 days. Ground squirrels that entered hibernation were sacrificed after 2-5 days of hibernation (continuous rectal temperature of 4 ºC). BAT, subcutaneous, retroperitoneal and epididimal WAT (sWAT, rWAT and eWAT), skeletal muscle (musculus quadriceps) and liver were sampled. Parallel, in order to examine the mechanisms of metabolic regulation in the BAT specific for hibernation, comparative study with rats acclimated to low temperatures, was made. Results show that, when hibernating animals are exposed to low temperature, the cellular metabolism in all examined tissues/organs is initially subordinated to maintaining euthermia, i.e. thermogenic process. In the early period of the cold-exposure, shivering and nonshivering thermogenesis is induced in the muscle and BAT, respectively. Although these processes are metabolically supported by the breakdown of glucose, the production of heat in both thermogenic organs is associated with energy imbalance. This is likely responsible for suppression of energy consumption pathways (primarly thermogenesis) during the extended acclimation period, and for preparation of ground squirrel to a state of hypothermia/hypometabolism. In the early period of acclimation, the fuel for thermogenesis is preferentially provided from visceral WAT depots (particularly eWAT), wherein decreased adipocyte surface profile, a result of intensive lipolysis, is observed. Later, during exposure to cold, when the thermogenic capacity in BAT is suppressed, activity of AMP-activated protein kinase is induced in all three WAT depots, lipolysis and energy-consuming pathways are "blocked" and oxidative metabolism is stimulated. Liver is central coordinator of the lipid and carbohydrate metabolism during cold acclimation. In the deep hibernation, thermogenic capacity of BAT and skeletal muscle is significantly suppressed. It seems that hypoxia-inducible factor-1 (HIF-1) plays a central role in the metabolic remodeling of the thermogenic organs in hibernation, by both suppressing the energy-demanding, thermogenic processes, and also, by inducing glycolytic pathway, an important component of energy homeostasis in hypometabolic conditions. Similar metabolic reprogramming occurs in the visceral WAT depots. In hibernation, liver shows analogous metabolic strategy as in fasting conditions: induction of lipid catabolism and suppression of glucose degradation, with the simultaneous induction of gluconeogenesis. Results indicate that capacity for lipid oxidation is increased in all tested tissues/organs, except in visceral WAT depots, during hibernation. In BAT, the intensification of fatty acid oxidation pathways primarily serves to maintain the necessary level of thermogenesis, whereas in skeletal muscle and liver this is associated with adaptation to hypothermic/hypometabolic conditions of hibernation. Noticeable lower level of interorgan communication, when it comes to lipid metabolism, suggests that tissues establish a certain degree of autonomy during hibernation. In general, it can be concluded that characteristic tissue-dependent remodeling of the energy metabolism is the central axis and the precause of physiological plasticity of hibernators that provides them many advantages over the nonhibernating counterparts, and the survival under adverse environmental conditions, whether they are active and euthermic or lethargic and hypothermic.
Keywords:Ground squirrel; Hibernation; Energy metabolism; Cold acclimation; Transcription regulation; Antioxidant defense
Source:University of Belgrade, Faculty of Biology, 2014, 1-191
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