Low-temperature carbon utilization is regulated by novel gene activity in the heart of a hibernating mammal

Abstract

Hibernation is a physiological adaptation characterized by dramatic decreases in heart rate, body temperature, and metabolism, resulting in long-term dormancy. Hibernating mammals survive for periods up to 6 mo in the absence of food by minimizing carbohydrate catabolism and using triglyceride stores as their primary source of fuel. The cellular and molecular mechanisms underlying the changes from a state of activity to the hibernating state are poorly understood; however, the selective expression of genes offers one level of control. To address this problem, we used a differential gene expression screen to identify genes that are responsible for the physiological characteristics of hibernation in the heart of the thirteen-lined ground squirrel (Spermophilus tridecemlineatus). Here, we report that genes for pancreatic lipase and pyruvate dehydrogenase kinase isozyme 4 are up-regulated in the heart during hibernation. Pancreatic lipase is normally expressed exclusively in the pancreas, but when expressed in the hibernating heart it liberates fatty acids from triglycerides at temperatures as low as 0°C. Pyruvate dehydrogenase kinase isozyme 4 inhibits carbohydrate oxidation and depresses metabolism by preventing the conversion of pyruvate to Ac-CoA. The resulting anaerobic glycolysis and low-temperature lipid catabolism provide evidence that adaptive changes in cardiac physiology are controlled by the differential expression of genes during hibernation.Maintenance of normal physiological function in mammals usually requires a constant body temperature of approximately 37°C. Lowering body temperature 10-15°C for an extended period of time often leads to hypothermic dysfunction of several organ systems, while lowering the temperature 30°C below the optimum usually results in death (1). An exception is seen in hibernating mammals. Certain ''deep'' hibernators lower their body temperature to 2-7°C, reduce their heart rate from 300 beats/min to 2-10 beats/min, and lessen their O 2 consumption as much as 50-fold (2). This amazing transformation of whole-animal physiology is completely reversible and serves as an adaptation to conserve energy reserves during extended periods of harsh climate and little or no food. Energy reserves in the form of fat sustain vital functions during long bouts of torpor and support periodic rewarming to euthermic temperatures during interbout arousals. Despite years of work on the ecology and physiology of hibernation in mammals, the underlying molecular genetic basis of this adaptation has received little attention.The reduction in metabolism that accompanies the hypothermia of hibernation is not only a function of thermodynamics, but also the result of precisely regulated metabolic reactions (3). Hibernating mammals survive the entire winter without feeding by limiting their carbohydrate catabolism and using fat stores as their primary source of fuel (reviewed in ref.2). We have begun to address the genetic control of this process by using a differential gene expression screen (4) ...

Rapid and reversible changes in intrahippocampal connectivity during the course of hibernation in European hamsters

“…Fatty acids mobilized from adipose tissue are transported to the heart, where they are stored as mitochondrial-associated triglyceride droplets. Lipolysis by phospholipases provides a steady release of fatty acids at low temperatures, supplying substrate for mitochondrial beta-oxidation and the generation of ATP by oxidative phosphorylation (27,28). These results provide support to the notion that physiological adaptations that take place during hibernation are controlled by differential genetic expression (2).…”

Arousal from hibernation and BAT thermogenesis against cold: central mechanism and molecular basis

“…A partial list of changes in gene expression associated with hibernation includes: increased alpha-globulin mRNA and protein (Srere et al, 1992) and decreased hibernation-related proteins (Takamatsu et al, 1993) in liver, increased UCP-1 mRNA in BAT (Boyer et al, 1998;Liu et al, 1998;Hashimoto et al, 1999b), increased lipase and UCP-2 mRNA in white adipose tissue (Wilson et al, 1992;Boyer et al, 1998), increased glyceraldehyde-3-phosphate dehydrogenase and UCP-3 mRNA in skeletal muscle (Soukri et al, 1996;Boyer et al, 1998), increased pancreatic lipase mRNA and protein and pyruvate dehydrogenase kinase mRNA and protein in heart (Andrews et al, 1998), increased in early immediate genes and decreased prostaglandin synthase mRNA in brain (O'Hara et al, 1999) and increased c-Fos in SCN of the hypothalamus and neuropeptide Y mRNA in the arcuate nucleus (Bitting et al, 1994;El Ouezzani et al, 2001). …”

Natural selection and adaptive evolution of leptin

“…During the periods of hibernation, adipose tissue plays as the fundamental source of energy helping animals to sustain life [16]. A wealthy of previous physiological studies has shown that the level of serum leptin regulated the metabolism and food intake in hibernating species, including bats, squirrels, rats, and shrews [29,[91][92][93][94][95][96][97][98][99].…”

“…It is important in regulating feeding behavior, energy metabolism and body mass [11][12][13][14][15][16]. The level of plasma leptin is generally regarded as a signal to direct the central nervous system (CNS) to regulate food intake and energy expenditure, which is an important pathway of metabolism to maintain constancy of the adipose mass [12,14,17,18].…”