Central role for differential gene expression in mammalian hibernation.

Abstract

Mammalian hibernators experience dramatic reductions in body temperature, metabolic rate, respiratory rate, and heart rate during hibernation. These changes are precisely controlled and reversible with only internally driven mechanisms, suggesting specific biochemical regulation. We present a model that integrates our observations of differential liver gene expression during preparation for, and maintenance of, the hibernating state, with the known phylogenetic interspersion of hibernating species in several major mammalian lineages. This model predicts a major role for the differential expression of existing mammalian genes in the biochemical regulation of hibernation.Hibernation is an adaptive strategy that is used by species in several mammalian orders to conserve energy in cold or inhospitable environments. During hibernation, these mammals dramatically lower their metabolic, heart, and respiratory rates as well as their body temperature in a precisely controlled manner. This strategy helps some, particularly small, mammals to survive cold winter conditions in temperate climates when food and water are scarce yet the demand for metabolic heat generation is high. Hibernating species are frequently closely related to nonhibernating species and are found in five orders of eutherian mammals as well as in a few species of marsupials and monotremes (ref. 1 and Fig. 1). The adaptive significance of hibernation, coupled with the interspersed phylogenetic distribution of hibernating species among mammals, makes hibernation an ideal model system to test the hypothesis that the molecular basis of important adaptive events during evolution involves mechanisms that lead to the differential regulation of existing genes and not the invention of new genes (reviewed in ref.3).The evolutionary origin of hibernation is unknown; either of two hypotheses can explain the interspersed nature of the distribution of extant hibernating species throughout Mammalia. One postulates that the common ancestor of all mammals was a hibernator, but the ability to hibernate was lost independently along multiple lineages. The alternative proposes that the common ancestor of all mammals was not a hibernator, and the ability to hibernate has been gained independently along multiple lineages (Fig. 1). With either scenario, we predict that a small number of regulatory changes determine the phenotype of hibernation, rather than the de novo creation or loss of numerous hibernation-specific biochemical functions, encoded by a collection of hibernation-specific genes. Thus, hibernation must be the result of a reprogramming of existing mammalian biochemical capabilities through the differential expression of existing genes.There is little evidence in the literature for differential gene expression during hibernation, although there are a few reports that demonstrate increases or decreases (4) in the amount of specific proteins relative to the active state. Mitochondrial uncoupling protein (thermogenin) is an example of a protein that increases i...

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

“…In contrast to the decreased levels of plasma HSPC in chipmunks, blood alpha2 macroglobin levels and activity and liver mRNA are increased in hibernating ground squirrel. These increases probably occurred in the preparatory phase preceding hibernation (Srere et al, 1992).…”

“…Although the overall level of mRNA appears slightly decreased or constant during hibernation (Srere et al, 1992;Frerichs et al, 1998) the rate of in vivo synthesis of cerebral mRNA is 8-fold reduced (Bocharova et al, 1992) -a factor which should be considered when determining if changes measured in the level of mRNA transcription result from changes during hibernation or are residual from changes implemented preceding entrance to the hibernating state.…”

“…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). …”

Elevated expression of protein biosynthesis genes in liver and muscle of hibernating black bears (Ursus americanus)

“…The molecular and genetic basis of hibernation in small mammals has only recently begun to be described, and little is known about its evolutionary history. Hibernating species have been found in diverse families among seven orders of mammals (26), however, and the interspersed phylogenetic distribution of hibernating and nonhibernating species has led to the hypothesis that rather than requiring the creation of novel gene products, hibernation results from the differential expression of genes that exist widely among mammals (35).…”

Are long chain acyl CoAs responsible for suppression of mitochondrial metabolism in hibernating 13-lined ground squirrels?

“…There is even one species of bird, Phalaenoptilus nuttallii, that is a documented hibernator (Geiser, 2004). This curious distribution across many distantly related taxa suggests that the ability to hibernate was perhaps a common ancestral trait, and is conserved within the genomes of all mammals, but only expressed in a small few (Srere et al, 1992). One of the most widely studied of these hibernating species is the 13-lined ground squirrel (Rodentia: Sciuridae, Ictydomys tridecemlineatus), the species used in all work related to this thesis.…”