-
[show abstract]
[hide abstract]
ABSTRACT: Long INterspersed Element one (LINE-1, or L1), is a widely distributed, autonomous retrotransposon in mammalian genomes. During retrotransposition, L1 RNA functions first as a dicistronic mRNA and then as a template for cDNA synthesis. Previously, we defined internal ribosome entry sequences (IRESs) upstream of both ORFs (ORF1 and ORF2) in the dicistronic mRNA encoded by mouse L1. Here, RNA affinity chromatography was used to isolate cellular proteins that bind these regions of L1 RNA. Four proteins, the heterogeneous nuclear ribonucleoproteins (hnRNPs) R, Q and L, and nucleolin (NCL), appeared to interact specifically with the ORF2 IRES. These were depleted from HeLa cells to examine their effects on L1 IRES-mediated translation and L1 retrotransposition. NCL knockdown specifically reduced the ORF2 IRES activity, L1 and L1-assisted Alu retrotransposition without altering L1 RNA or protein abundance. These findings are consistent with NCL acting as an IRES trans-acting factor (ITAF) for ORF2 translation and hence a positive host factor for L1 retrotransposition. In contrast, hnRNPL knockdown dramatically increased L1 retrotransposition as well as L1 RNA and ORF1 protein, indicating that this cellular protein normally interferes with retrotransposition. Thus, hnRNPL joins a small, but growing list of cellular proteins that are potent negative regulators of L1 retrotransposition.
Nucleic Acids Research 11/2012; · 8.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hibernating ground squirrels maintain homeostasis despite extreme physiological challenges. In winter, these circannual hibernators fast for months while cycling between prolonged periods of low blood flow and body temperature, known as torpor, and short interbout arousals (IBA), where more typical mammalian parameters are rapidly restored. Here we examined the kidney proteome for changes that support the dramatically different physiological demands of the hibernator's year. We identified proteins in 150 two-dimensional gel spots that altered by at least 1.5-fold using liquid chromatography and tandem mass spectrometry. These data successfully classified individuals by physiological state and revealed three dynamic patterns of relative protein abundance that dominated the hibernating kidney: 1) a large group of proteins generally involved with capturing and storing energy were most abundant in summer; 2) a select subset of these also increased during each arousal from torpor; and 3) 14 spots increased in torpor and early arousal were enriched for plasma proteins that enter cells via the endocytic pathway. Immunohistochemistry identified α(2)-macroglobulin and albumin in kidney blood vessels during late torpor and early arousal; both exhibited regional heterogeneity consistent with highly localized control of blood flow in the glomeruli. Furthermore, albumin, but not α(2)-macroglobulin, was detected in the proximal tubules during torpor and early arousal but not in IBA or summer animals. Taken together, our findings indicate that normal glomerular filtration barriers remain intact throughout torpor-arousal cycles but endocytosis, and hence renal function, is compromised at low body temperature during torpor and then recovers with rewarming during arousal.
Physiological Genomics 05/2012; 44(14):717-27. · 2.73 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: During the torpor phase of mammalian hibernation when core body temperature is near 4°C, the autonomic system continues to
maintain respiration, blood pressure and heartbeat despite drastic reductions in brain activity. In addition, the hibernator’s
neuronal tissues enter into a protected state in which the potential for ischemia–reperfusion injury is markedly minimized.
Evolutionary adaptations for continued function and neuroprotection throughout cycles of torpor and euthermia in winter are
predicted to manifest themselves partly in changes in the brainstem proteome. Here, we compare the soluble brainstem protein
complement from six summer active ground squirrels and six in the early torpor (ET) phase of hibernation. Thirteen percent
of the ~1,500 quantifiable 2D gel spots alter significantly from summer to ET; the proteins identified in these differing
spots are known to play roles in energy homeostasis via the tricarboxylic acid cycle (8 proteins), cytoarchitecture and cell
motility (14 proteins), anabolic protein processes (13 proteins), redox control (11 proteins) and numerous other categories
including protein catabolism, oxidative phosphorylation, signal transduction, glycolysis, intracellular protein trafficking
and antiapoptotic function. These protein changes represent, at least in part, the molecular bases for restructuring of cells
in the brainstem, a shift away from glucose as the primary fuel source for brain in the winter, and the generation of a streamlined
mechanism capable of efficient and rapid energy production and utilization during the torpor and arousal cycles of hibernation.
KeywordsThirteen-lined ground squirrel-
Spermophilus tridecemlineatus
-
Ictidomys tridecemlineatus
-DIGE proteomics-Hibernation
Journal of Comparative Physiology B 04/2012; 180(4):599-617. · 1.97 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Mammalian hibernation is characterized by profound reductions in body temperature (T
b) and metabolic, heart and respiratory rates. These reductions are characteristic of torpor, which is temporally confined
to winter. Hibernators including ground squirrels are heterothermic in winter, cycling between multiday periods of torpor
with low T
b and brief periods of rewarming. In contrast, ground squirrels remain homeothermic during summer, like non-hibernating mammals.
The transition between the homeothermic and heterothermic phases of the circannual rhythm of hibernation is often overlooked
in hibernation studies. Here, we examined the use of torpor throughout the fall transition in laboratory-housed 13-lined ground
squirrels by recording core body temperature with an implanted data logger. As is typical of laboratory-based hibernation
studies, animals were kept in standard housing prior to being moved into a cold, dark room to simulate natural hibernation
conditions. Significantly, the vast majority of both male and female ground squirrels expressed torpor in the fall while still
housed conventionally and prior to cold exposure. The expression of torpor was not predicted by body weight or age, rather
it appears to be preprogrammed in a time-dependent manner that is independent of, yet enhanced by, environmental cues. The
timing and duration of these torpor bouts occurring prior to cold exposure were also remarkably sporadic. Thus, it is not
possible to know with certainty which animals are torpor-naive before cold exposure in the absence of continuous measurement
of body temperature. We conclude that fall animals encompass variable points in the transition between summer and winter phases
of the circannual cycle of hibernation, thereby confounding studies in which they are used as non-hibernating controls. Conversely,
these fall transition animals offer unique opportunities to define the molecular changes that accompany and enable hibernation.
KeywordsSciurid-
Ictidomys tridecemlineatus
-
Spermophilus
Journal of Comparative Physiology B 04/2012; 180(8):1165-1172. · 1.97 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The hibernator's heart functions continuously and avoids damage across the wide temperature range of winter heterothermy. To define the molecular basis of this phenotype, we quantified proteomic changes in the 13-lined ground squirrel heart among eight distinct physiological states encompassing the hibernator's year. Unsupervised clustering revealed a prominent seasonal separation between the summer homeotherms and winter heterotherms, whereas within-season state separation was limited. Further, animals torpid in the fall were intermediate to summer and winter, consistent with the transitional nature of this phase. A seasonal analysis revealed that the relative abundances of protein spots were mainly winter-increased. The winter-elevated proteins were involved in fatty acid catabolism and protein folding, whereas the winter-depleted proteins included those that degrade branched-chain amino acids. To identify further state-dependent changes, protein spots were re-evaluated with respect to specific physiological state, confirming the predominance of seasonal differences. Additionally, chaperone and heat shock proteins increased in winter, including HSPA4, HSPB6, and HSP90AB1, which have known roles in protecting against ischemia-reperfusion injury and apoptosis. The most significant and greatest fold change observed was a disappearance of phospho-cofilin 2 at low body temperature, likely a strategy to preserve ATP. The robust summer-to-winter seasonal proteomic shift implies that a winter-protected state is orchestrated before prolonged torpor ensues. Additionally, the general preservation of the proteome during winter hibernation and an increase of stress response proteins, together with dephosphorylation of cofilin 2, highlight the importance of ATP-conserving mechanisms for winter cardioprotection.
Physiological Genomics 09/2011; 43(22):1263-75. · 2.73 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The physiology of small mammalian hibernators shifts profoundly over a year, from summer homeothermy to winter heterothermy. Torpor-arousal cycles define high-amplitude tissue activity fluctuations in winter, particularly for skeletal muscle, which contributes to the energetically demanding rewarming process via shivering. To better understand the biochemistry underlying summer-winter and torpor-arousal transitions, we applied two-dimensional gel electrophoresis coupled with liquid chromatography/mass spectrometry/mas spectrometry to the soluble proteins from hindlimb muscle of 13-lined ground squirrels (Ictidomys tridecemlineatus) in two summer and six winter states. Two hundred sixteen protein spots differed by sampled state. Significantly, intrawinter protein adjustment was a minor component of the dataset despite large discrepancies in muscle activity level among winter states; rather, the bulk of differences (127/138 unequivocally identified proteins spots) occurred between summer and winter. We did not detect any proteomic signatures of skeletal muscle atrophy in this hibernator nor any differential seasonal regulation of protein metabolism. Instead, adjustments to metabolic substrate preferences dominated the detected proteomic differences. Pathways of carbohydrate metabolism (glycolysis and gluconeogenesis) were summer enriched, whereas the winter proteome was enriched for fatty acid β-oxidation. Nevertheless, our data suggest that some reliance on carbohydrate reserves is maintained during winter. Phosphoglucomutase (PGM1), which reversibly prepares glucose subunits for either glycolysis or glycogenesis, showed apparent winter state-specific phosphorylation. PGM1 was phosphorylated during rewarming and dephosphorylated by interbout arousal, implying that glucose supplements lipid fuels during rewarming. This, along with winter elevation of TCA cycle enzymes, suggests that hindlimb muscles are primed for rapid energy production and that carbohydrates are an important fuel for shivering thermogenesis.
AJP Regulatory Integrative and Comparative Physiology 08/2011; 301(5):R1440-52. · 3.34 Impact Factor
-
08/2011: pages 189 - 209; , ISBN: 9780470960660
-
[show abstract]
[hide abstract]
ABSTRACT: Long interspersed nuclear element-1 is a highly abundant mammalian retrotransposon that comprises 17% of the human genome. L1 retrotransposition requires the protein encoded by open reading frame-1 (ORF1p), which binds single-stranded RNA with high affinity and functions as a nucleic acid chaperone. ORF1p has been shown to adopt a homo-trimeric, asymmetric dumbbell-shaped structure. However, its atomic-level structure and mechanism of RNA binding remains poorly understood. Here, we report the results of a site-directed spin labeling electron paramagnetic resonance (SDSL-EPR) study of 27 residues within the RNA binding region of the full-length protein. The EPR data are compatible with the large RNA binding lobe of ORF1p containing a RNA recognition motif (RRM) domain and a carboxyl-terminal domain (CTD) that are predicted from crystallographic and NMR studies of smaller fragments of the protein. Interestingly, the EPR data indicate that residues in strands β3 and β4 of the RRM are structurally unstable, compatible with the previously observed sensitivity of this region to proteolysis. Affinity measurements and RNA-dependent EPR spectral changes map the RNA binding site on ORF1p to residues located in strands β3 and β4 of the RRM domain and to helix α1 of the CTD. Complementary in vivo studies also identify residues within the RRM domain that are required for retrotransposition. We propose that in the context of the full-length trimeric protein these distinct surfaces are positioned adjacent to one another providing a continuous surface that may interact with nucleic acids.
Protein Science 07/2011; 20(7):1231-43. · 2.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hibernation is an energy-saving strategy used by diverse species of mammals to survive winter. It is characterized by cycles between multi-day periods of torpor with low body temperature (T(b)), and short periods of rapid, spontaneous rewarming. The ability to retain cellular integrity and function throughout torpor and rewarming is a key attribute of hibernation. Livers from winter hibernators are resistant to cellular damage induced by cold storage followed by warm reperfusion. Identifying proteins that differ between the summer-sensitive and winter-protected phenotypic states is one useful approach that may elucidate the molecular mechanisms that underlie this protection. Here we employ a novel quantitative proteomics screening strategy whereby a newly-weaned 13-lined ground squirrel was metabolically labeled by ingesting heavy-isotope substituted ((15)N) Spirulina. The liver protein extract from this animal provided a common reference for quantitative evaluation of protein differences by its addition to extracts from pooled samples of summer active (SA) or winter entrance (Ent) phase hibernating ground squirrels. We identified 61 significantly different proteins between the two groups and compared them to proteins identified previously in the same samples using 2D gels. Of the 20 proteins common to the two datasets, the direction and magnitude of their differences were perfectly concordant for 18, providing confidence that both sets of altered proteins reflect bona fide differences between the two physiological states. Furthermore, the 41 novel proteins recovered in this study included many new enzymes in pathways identified previously: specifically, additional enzymes belonging to the urea cycle, amino acid and carbohydrate degradation, and lipid biosynthetic pathways were decreased, whereas enzymes involved in ketone body synthesis, fatty acid utilization, protein synthesis and gluconeogenesis were increased in the samples from entrance hibernators compared to summer active animals, providing additional specific evidence for the importance of these pathways in the hibernating phenotype.
Comparative Biochemistry and Physiology Part D Genomics and Proteomics 06/2011; 6(2):163-70. · 1.72 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hibernation as manifested in ground squirrels is arguably the most plastic and extreme of physiological phenotypes in mammals. Homeostasis is challenged by prolonged fasting accompanied by heterothermy, yet must be facilitated for survival. We performed LC and GC-MS metabolomic profiling of plasma samples taken reproducibly during seven natural stages of the hibernator's year, three in summer and four in winter (each n ≥ 5), employing a nontargeted approach to define the metabolite shifts associated with the phenotype. We quantified 231 named metabolites; 106 of these altered significantly, demarcating a cycle within a cycle where torpor-arousal cycles recur during the winter portion of the seasonal cycle. A number of robust hibernation biomarkers that alter with season and winter stage are identified, including specific free fatty acids, antioxidants, and previously unpublished modified amino acids that are likely to be associated with the fasting state. The major pattern in metabolite levels is one of either depletion or accrual during torpor, followed by reversal to an apparent homeostatic level by interbout arousal. This finding provides new data that strongly support the predictions of a long-standing hypothesis that periodic arousals are necessary to restore metabolic homeostasis.
Physiological Genomics 05/2011; 43(13):799-807. · 2.73 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Retrotransposition amplifies LINE-1 (L1) to high copy number in mammalian genomes. The L1 protein encoded by ORF1 (ORF1p) is required for retrotransposition. This dependence on ORF1p was investigated by mutating three highly conserved residues, R238, R284 and Y318 to alanine, thereby inactivating retrotransposition. R284A and Y318A were rescued by further substituting the alanine with the appropriate conservative amino acid, e.g. lysine or phenylalanine, respectively, whereas R238K remained inactive. Quantification of the steady-state levels of L1 RNA and ORF1p failed to discriminate active from inactive variants, indicating loss of L1 retrotransposition resulted from loss of function rather than reduced expression. The two biochemical properties known for ORF1p are high-affinity RNA binding and nucleic acid chaperone activity. Only R238A/K exhibited significantly reduced RNA affinities. The nucleic acid chaperone activities of the remaining paired mutants were assessed by single-molecule DNA stretching and found to mirror retrotransposition activity. To further examine ORF1p chaperone function, their energetic barriers to DNA annealing and melting were derived from kinetic work. When plotted against each other, the ratio of these two activities distinguished functional from non-functional ORF1p variants. These findings enhance our understanding of the requirements for ORF1p in LINE-1 retrotransposition and, more generally, nucleic acid chaperone function.
Nucleic Acids Research 03/2011; 39(13):5611-21. · 8.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Mammalian hibernation is characterized by profound reductions in body temperature (T(b)) and metabolic, heart and respiratory rates. These reductions are characteristic of torpor, which is temporally confined to winter. Hibernators including ground squirrels are heterothermic in winter, cycling between multiday periods of torpor with low T(b) and brief periods of rewarming. In contrast, ground squirrels remain homeothermic during summer, like non-hibernating mammals. The transition between the homeothermic and heterothermic phases of the circannual rhythm of hibernation is often overlooked in hibernation studies. Here, we examined the use of torpor throughout the fall transition in laboratory-housed 13-lined ground squirrels by recording core body temperature with an implanted data logger. As is typical of laboratory-based hibernation studies, animals were kept in standard housing prior to being moved into a cold, dark room to simulate natural hibernation conditions. Significantly, the vast majority of both male and female ground squirrels expressed torpor in the fall while still housed conventionally and prior to cold exposure. The expression of torpor was not predicted by body weight or age, rather it appears to be preprogrammed in a time-dependent manner that is independent of, yet enhanced by, environmental cues. The timing and duration of these torpor bouts occurring prior to cold exposure were also remarkably sporadic. Thus, it is not possible to know with certainty which animals are torpor-naive before cold exposure in the absence of continuous measurement of body temperature. We conclude that fall animals encompass variable points in the transition between summer and winter phases of the circannual cycle of hibernation, thereby confounding studies in which they are used as non-hibernating controls. Conversely, these fall transition animals offer unique opportunities to define the molecular changes that accompany and enable hibernation.
Journal of Comparative Physiology B 11/2010; 180(8):1165-72. · 1.97 Impact Factor
-
Sandra L Martin
[show abstract]
[hide abstract]
ABSTRACT: Long interspersed element-1 (LINE-1, or L1) is a non-long terminal repeat (LTR) retrotransposon that has amplified to hundreds of thousands of copies in mammalian evolution. A small number of the individual copies of L1 are active retrotransposons which are presently replicating in most species, including humans and mice. L1 retrotransposition begins with transcription of an active element and ends with a newly inserted cDNA copy, a process which requires the two element-encoded proteins to act in cis on the L1 RNA. The ORF1 protein (ORF1p) is a high-affinity, non-sequence-specific RNA binding protein with nucleic acid chaperone activity, whereas the ORF2 protein (ORF2p) supplies the enzymatic activities for cDNA synthesis. This article reviews the nucleic acid chaperone properties of ORF1p in the context of L1 retrotransposition.
RNA biology 11/2010; 7(6):706-11. · 5.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hibernators are unique among mammals in their ability to survive extended periods of time with core body temperatures near freezing and with dramatically reduced heart, respiratory, and metabolic rates in a state known as torpor. To gain insight into the molecular events underlying this remarkable physiological phenotype, we applied a proteomic screening approach to identify liver proteins that differ between the summer active (SA) and the entrance (Ent) phase of winter hibernation in 13-lined ground squirrels. The relative abundance of 1,600 protein spots separated on two-dimensional gels was quantitatively determined using fluorescence difference gel electrophoresis, and 74 unique proteins exhibiting significant differences between the two states were identified using liquid chromatography followed by tandem mass spectrometry (LC-MS/MS). Proteins elevated in Ent hibernators included liver fatty acid-binding protein, fatty acid transporter, and 3-hydroxy-3-methylglutaryl-CoA synthase, which support the known metabolic fuel switch to lipid and ketone body utilization in winter. Several proteins involved in protein stability and protein folding were also elevated in the Ent phase, consistent with previous findings. In contrast to transcript screening results, there was a surprising increase in the abundance of proteins involved in protein synthesis during Ent hibernation, including several initiation and elongation factors. This finding, coupled with decreased abundance of numerous proteins involved in amino acid and nitrogen metabolism, supports the intriguing hypothesis that the mechanism of protein preservation and resynthesis is used by hibernating ground squirrels to help avoid nitrogen toxicity and ensure preservation of essential amino acids throughout the long winter fast.
AJP Regulatory Integrative and Comparative Physiology 11/2009; 298(2):R329-40. · 3.34 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A hallmark of hibernation in mammals is metabolic flexibility, which is typified by reversible bouts of metabolic depression (torpor) and the seasonal shift from predominantly carbohydrate to lipid metabolism from summer to winter. To provide new insight into the control and consequences of hibernation, we used LC/MS-based metabolomics to measure differences in small molecules in ground squirrel liver in five activity states: summer, entering torpor, late torpor, arousing from torpor, and interbout arousal. There were significant alterations both seasonally and within torpor-arousal cycles in enzyme cofactor metabolism, amino acid catabolism, and purine and pyrimidine metabolism, with observed metabolites reduced during torpor and increased upon arousal. Multiple lipids also changed, including 1-oleoyllysophosphatidylcholine, cholesterol sulfate, and sphingosine, which tended to be lowest during torpor, and hexadecanedioic acid, which accumulated during a torpor bout. The results reveal the dramatic alterations that occur in several classes of metabolites, highlighting the value of metabolomic analyses in deciphering the hibernation phenotype.
Physiological Genomics 01/2009; 37(1):43-51. · 2.73 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: L1 is a ubiquitous interspersed repeated sequence in mammals that achieved its high copy number by autonomous retrotransposition. Individual L1 elements within a genome differ in sequence and retrotransposition activity. Retrotransposition requires two L1-encoded proteins, ORF1p and ORF2p. Chimeric elements were used to map a 15-fold difference in retrotransposition efficiency between two L1 variants from the mouse genome, T(FC) and T(Fspa), to a single amino acid substitution in ORF1p, D159H. The steady-state levels of L1 RNA and protein do not differ significantly between these two elements, yet new insertions are detected earlier and at higher frequency in T(FC), indicating that it converts expressed L1 intermediates more effectively into new insertions. The two ORF1 proteins were purified and their nucleic acid binding and chaperone activities were examined in vitro. Although the RNA and DNA oligonucleotide binding affinities of these two ORF1 proteins were largely indistinguishable, D159 was significantly more effective as a nucleic acid chaperone than H159. These findings support a requirement for ORF1p nucleic acid chaperone activity at a late step during L1 retrotransposition, extend the region of ORF1p that is known to be critical for its functional interactions with nucleic acids, and enhance understanding of nucleic acid chaperone activity.
Nucleic Acids Research 10/2008; 36(18):5845-54. · 8.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Mammalian hibernators display two unique characteristics that can be exploited for major advancements in surviving blood loss: (1) metabolism is carefully manipulated to achieve controlled reductions in oxygen demand of tissues for energy conservation, and the effect is fully reversible; and (2) hibernators tolerate massive changes in cardiac function, ventilation, tissue perfusion/ reperfusion, and intermediary metabolism that have similarities to shock and other trauma states, yet they are fully protected. Our team-oriented project integrated physiology, pathophysiology, and functional proteomics and metabolomics to identify novel candidate protection strategies based on these characteristics. We demonstrated that hibernators are highly protected against severe blood loss and mesenteric ischemia-reperfusio injury, and we identified several candidate proteins and metabolites that may contribute to hibernation-induced protection in these models.
09/2008;
-
[show abstract]
[hide abstract]
ABSTRACT: The intestine of hibernating ground squirrels is protected against damage by ischemia-reperfusion (I/R) injury. This resistance does not depend on the low body temperature of torpor; rather, it is exhibited during natural interbout arousals that periodically return hibernating animals to euthermia. Here we use fluorescence two-dimensional difference gel electrophoresis (DIGE) to identify protein spot differences in intestines of 13-lined ground squirrels in the sensitive and protected phases of the circannual hibernation cycle, comparing sham-treated control animals with those exposed to I/R. Protein spot differences distinguished the sham-treated summer and hibernating samples, as well as the response to I/R between summer and hibernating intestines. The majority of protein changes among these groups were attributed to a seasonal difference between summer and winter hibernators. Many of the protein spots that differed were unambiguously identified by high-pressure liquid chromatography followed by tandem mass spectrometry of their constituent peptides. Western blot analysis confirmed significant upregulation for three of the proteins, albumin, apolipoprotein A-I, and ubiquitin hydrolase L1, that were identified in the DIGE analysis as increased in sham-treated hibernating squirrels compared with sham-treated summer squirrels. This study identifies several candidate proteins that may contribute to hibernation-induced protection of the gut during natural torpor-arousal cycles and experimental I/R injury. It also reveals the importance of enterocyte maturation in defining the hibernating gut proteome and the role of changing cell populations for the differences between sham and I/R-treated summer animals.
AJP Regulatory Integrative and Comparative Physiology 08/2008; 295(1):R316-28. · 3.34 Impact Factor
-
Sandra L Martin
[show abstract]
[hide abstract]
ABSTRACT: Mammalian hibernators such as ground squirrels store massive amounts of fat each autumn. These fat depots serve as the main source of metabolic fuel throughout the winter, gradually decreasing over a period of months until the animals emerge from hibernation each spring. Fat deposition occurs on an approximately annual, i.e. on a circannual, basis. Although this rhythm occurs in the absence of environmental temperature and light cues, it is entrained by the length of daylight, with peak fat deposition occurring as days shorten in the autumn. Here we examine the circ-annual cycle of hibernation, and then explore the similarities and differences between the obligatory, yet reversible, natural obesity and accompanying insulin resistance of natural hibernation, and the pandemic of human obesity and metabolic syndrome.
Diabetes & Vascular Disease Research 07/2008; 5(2):76-81. · 2.12 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Thirteen-lined ground squirrels and other circannual hibernators undergo profound physiological changes on an annual basis, transitioning from summer homeothermy [body temperature (T(b)) approximately 37 degrees C] to winter heterothermy (T(b) cycling between 0 degrees C and 37 degrees C). We hypothesize that these physiological changes are reflected in biochemical changes that provide mechanistic insights into, and biomarkers for, hibernation states. Here we report the results of an NMR-based metabolomics analysis of liver extracts from ground squirrels in three distinct physiological states of circannual hibernation: summer active (SA), late torpor (LT), and reentering torpor (Ent) after one of the euthermic arousals. Of the 43 identified and quantified metabolites, 36 differed among these three states and fell into two patterns of variation: 1) SA differed from both of the two winter states; or 2) the two winter states differed from each other, but one of the two was not different from SA. Concentrations of hepatic glucose, lactate, alanine, succinate, beta-hydroxybutyrate, glutamine, and betaine were identified as robust hepatic biomarkers that together distinguish among animals in these three states of the circannual hibernation rhythm. These data are consistent with a proposed two-switch model of hibernation, in which setting the summer-winter switch to winter enables expression of a distinct torpor-arousal switch. The summer-winter switch is characterized by the metabolites associated with the well-known switch from carbohydrate to lipid fuel utilization during hibernation. The torpor-arousal switch is characterized by the accumulation of metabolites of nitrogen (glutamine) and phospholipid (betaine) catabolism in LT with the capacity to act as protective osmolytes.
Physiological Genomics 10/2007; 31(1):15-24. · 2.73 Impact Factor
