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. 2009 Mar 16;587(Pt 9):1863–1870. doi: 10.1113/jphysiol.2008.167692

A role for nuclear receptors in mammalian hibernation

Clark J Nelson 1, Jessica P Otis 1, Hannah V Carey 1
PMCID: PMC2689326  PMID: 19289545

Abstract

Hibernation is one of the most dramatic examples of phenotypic plasticity in mammals. During periods of food shortage and/or reduced ambient temperatures hibernating mammals become heterothermic, allowing their body temperature to decrease while entering an energy-conserving torpid state. In order to survive the multi-month hibernation season many species engage in hyperphagy, dramatically increasing adipose stores prior to the onset of hibernation. Nuclear receptors are a superfamily of transcription factors many of which bind lipophilic molecules as ligands. They regulate a variety of processes including energy homeostasis, carbohydrate and lipid metabolism, inflammation and circadian rhythm. Given that lipids are integral in the hibernation phenotype they may play important regulatory roles through their interactions with nuclear receptors. Here we review current knowledge and suggest possible roles in mammalian hibernation for peroxisome proliferator-activated receptors (PPARs), farnesoid X receptors (FXRs), liver X receptors (LXRs), retinoid-related orphan receptors (RORs) and Rev-ERBs.

Seasonal hibernation occurs in several orders of mammals and facilitates survival during energetically challenging periods, typically when ambient temperatures (Ta) are low and food resources in the environment are limited (Carey et al. 2003). Substantial energy savings are accrued during the hibernation season due to extended bouts of torpor, when metabolism is severely depressed and body temperature (Tb) declines to slightly above Ta, thus sparing the energy normally required to defend a euthermic Tb. Torpor bouts last from a few days to several weeks and are interrupted by periodic arousals to euthermia that typically last < 24 h (Fig. 1). To fuel metabolism during the hibernation season some species (e.g. chipmunks, hamsters) consume cached food during periodic arousals, whereas others (e.g. ground squirrels, marmots) rely solely on fat stores accumulated during the previous active season, resulting in a lipid-centric metabolism. Additionally, some species enter torpor only when environmental conditions become unfavourable and are thus facultative hibernators (e.g. hamsters, many marsupials) whereas others enter hibernation on a seasonal basis regardless of conditions and are termed obligate hibernators (e.g. ground squirrels, marmots) (Drew et al. 2007).

Figure 1. An example of torpor arousal cycles during the hibernation season in 13-lined ground squirrels.

Figure 1

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Plotted is time of year versus body temperature (Tb). Bottom, enlargement of three torpor–arousal cycles indicating time spent in different parts of the cycle (not to scale). EN, entering torpor; LT, late torpor (≥7 d of continuous torpor); AR, arousing from torpor; IBA, interbout arousal.

Nuclear receptors (NRs) comprise a superfamily of transcription factors that regulate several processes that are altered during the hibernation cycle including lipogenesis, fatty acid and carbohydrate oxidation, cholesterol metabolism, circadian rhythms and metabolic rate (Afman & Muller, 2006; Kohsaka & Bass, 2007; Duez & Staels, 2008; Green et al. 2008). A NR typically has an amino-terminal domain that participates in gene activation, a DNA-binding domain, a hinge region, a ligand binding domain, and a ligand-dependent activation domain that interacts with coactivators/corepressors (Sonoda et al. 2008). Some NRs bind ligands in the cytosol and then migrate to the nucleus where they associate as monomers or homodimers with their respective response elements. Other NRs form heterodimers that are already nuclear-localized and bound to their response elements with a heterodimeric partner. Upon ligand binding, transcriptional repressors are released and transcriptional activators bound, initiating expression of genes that contain appropriate response elements in their promoters. However, the actions of NRs are complex as some NRs are transcriptional repressors and even NRs that activate transcription can in some circumstances act via trans-repression to inhibit gene expression. The majority of NR ligands are lipophilic in nature with many being derived from fatty acids or sterols (notable exceptions are the thyroid hormone receptor and xenobiotic receptor). Other NRs are orphan receptors as they have no known ligands.

It has long been recognized that lipids are critical for successful hibernation due to their role in fuelling the long winter fast. However, the possibility that lipids play other roles in hibernators in addition to energy storage such as signalling and/or regulatory roles has received little attention. Lipids could exert these effects through either genomic or non-genomic mechanisms. Perhaps the most direct way is by alteration of gene expression through NRs, suggesting a potential role for NRs in hibernation physiology. Although some studies have examined NRs in hibernators (Magnus & Henderson, 1988; Okulicz et al. 1988; Zivadinovic & Andjus, 1995; Kojima et al. 2000; Eddy & Storey, 2003; Kabine et al. 2003; Eddy et al. 2005; El Kebbaj et al. 2009), their functional roles remain largely unknown. In this article we highlight some selected NRs that are likely to play roles in hibernation physiology and summarize the evidence for seasonal or state-specific changes in expression of those NRs, their ligands and their target genes (Table 1). We also include information on NR biology in two related phenomena, daily torpor in mice and the dauer state of the nematode Caenorhabditis elegans (C. elegans) because comparison with these models may provide additional insight into mammalian hibernation.

Table 1.

Nuclear receptors mentioned in this article, selected target genes, ligands and reported changes in these ligands for hibernating mammals

NR Target genes Ligand(s) Ligand Δ in Hibernators
PPARα ACOX1, ApoA-I, CYP4A1, PDK4, L-FABP, BMAL, FGF21, HGMCS2, Rev-ERBα Fatty acids Elevated in torpor
PPARβ L-FABP, UCP3, ILK1, PDK4, PTEN, ADRP, PDK1, ANGPTL4 Fatty acids Elevated in torpor
PPARγ UCP1, A-FABP, GLUT4, BMAL, LPL, GK, HRASLS3, Rev-ERBα Fatty acids Elevated in torpor
LXR α, β CYP7A1, ABCA1, ABCG5/G8, SCD-1, LPL, PPARα, Rev-ERBα Oxysterols Cholesterol varies by tissue1
FXR CYP7A1, SREBP1c, PEPCK, VLDLR, ApoC-III Bile acids Unclear
RORα ApoA-I, ApoC-III, BMAL, Rev-ERBα, CYP7B1, SULT2A1 Cholesterol sulfate Elevated upon entrance into torpor
Rev-ERBα ApoA-I, ApoC-III, BMAL, Rev-ERBα, CYP7A1, TLR-4 Heme Biliverdin elevated in AR and IBA2
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1

The precursor of the ligand (cholesterol) is elevated in plasma during hibernation.

2

The catabolite of the ligand (biliverdin) is altered.

Gene names: ABCA1, ATP binding cassette transporter A1; ABCG, ATP-binding cassette transporter G 5 and 8; ACOX1, acyl CoA oxidase 1; ADRP, adipose differentiation-related protein; ANGPTL4, angiopoietin-like protein 4; A-FABP, adipocyte type fatty acid-binding protein; ApoA-I, apolipoprotein A-I; ApoC-III, apolipoprotein C-III; BMAL, brain and muscle aryl hydrocarbon receptor nuclear translocator-like; CYP4A1, cytochrome P450 4A1; CYP7A1, cholesterol 7-α hydroxylase; CYP7B1, 25-hydroxycholesterol 7α-hydroxylase; FGF21, fibroblast growth factor 21; FXR, farnesoid X receptor; GK, glucokinase; GLUT4, glucose transporter 4; HMGCS2, hydroxy methylglutaryl coenzyme A synthase 2; HRASLS3, HRas-like-supressor 3; ILK1, integrin-linked kinase 1; L-FABP, liver type fatty acid-binding protein; LPL, lipoprotein lipase; LXR, liver X receptor; PDK1, phosphoinositide-dependent kinase 1; PDK4, pyruvate dehydrogenase kinase 4; PEPCK, phosphoenolpyruvate carboxykinase;PPARα, peroxisome proliferator-activated receptor α; PPARβ, peroxisome proliferator-activated receptor β; PPARγ, peroxisome proliferator-activated receptor γ; PTEN, phosphatase and tensin homologue deleted on chromosome 10; RORα, retinoid-related orphan receptors α; SCD1, stearoyl-coenzymeA desaturase 1; SREBP1c, sterol regulatory element binding protein 1C; SULT2A1, sulfotransferase 2A1; TLR-4, toll-like receptor 4; UCP1, uncoupling protein 1; UCP3, uncoupling protein 3; VLDLR, very low density lipoprotein receptor.

Nuclear receptors in hibernators

Peroxisome proliferator-activated receptors (PPARs)

The PPARs play essential roles in regulating lipid metabolism. There are three members of the peroxisome proliferator-activated receptor (PPAR) family, PPARα, β/δ and γ. While all PPAR isoforms are widely expressed throughout the body, PPARα is most highly expressed in liver and muscle, PPARγ is expressed at high levels in white and brown adipose tissues and PPARβ is more widely expressed. The endogenous ligands that activate PPARs are poorly defined but are generally thought to be fatty acids, particularly unsaturated fatty acids and oxidized forms such as eicosanoids. These transcription factors are typically constitutively bound to their cognate response elements in the nucleus as heterodimers in combination with the retinoid X receptor (RXR). Ligand binding leads to removal of a corepressor (such as nuclear receptor corepressor) and subsequent binding to a coactivator (such as PPARγ-coactivator (PGC-1α)) and other auxiliary proteins that allow transcription of genes that contain a PPAR response element within their promoter. Functionally, these transcription factors allow the safe deposition and consumption of fatty acid stores while helping avoid the inflammatory risks associated with these processes (Nunn et al. 2007). PPARs have also been linked to the integration of nutritional information and circadian rhythms (Kohsaka & Bass, 2007; Green et al. 2008).

Although not exhaustively analysed, the PPARs are the most well studied and discussed NRs in the hibernation literature (Buck et al. 2002). This is not surprising, given the well documented fluctuations of PPAR ligands (fatty acids) in plasma and tissues of hibernators (Florant et al. 1990; Dark, 2005; Barger et al. 2006; Serkova et al. 2007). Differential mRNA or protein expression of PPAR isoforms and PGC-1α have been reported in three hibernating species: bat (Eddy & Storey, 2003), 13-lined ground squirrel (Eddy et al. 2005), and jerboa (Kabine et al. 2003; El Kebbaj et al. 2009). Interestingly, El Kebbaj and colleagues (2009) reported differential splicing of PPARα in pre-hibernating and hibernating jerboas as compared to non-hibernators resulting in variable activation of target genes. Multiple PPAR target genes are differentially expressed during the annual hibernation cycle. These include pyruvate dehydrogenase kinase 4, which regulates the shift from carbohydrates to fat as a fuel source during the hibernation season (Andrews et al. 1998; Brauch et al. 2005); hydroxymethylglutaryl coenzyme A synthase 2 (HMGCS2) (Epperson et al. 2004), the rate-limiting enzyme in ketone body synthesis; apolipoprotein A-I (ApoA-I) (Epperson & Martin, 2002; Epperson et al. 2004; Martin et al. 2008), the major protein in high-density lipoprotein particles; and enzymes that control peroxisomal fatty acid oxidation, including acyl-CoA oxidase 1, carnitine octanyltransferase, and peroxisomal bifunctional enzyme (Epperson & Martin, 2002; Kabine et al. 2003; Williams et al. 2005; Yan et al. 2008; El Kebbaj et al. 2009).

Farnesoid X receptors (FXRs)

The FXRs are major regulators of bile acid (BA) metabolism, and are expressed at highest levels in enterohepatic organs (liver and intestine). FXR binds BA as ligands and through its target genes plays important roles in cholesterol, triglyceride and glucose metabolism (Kalaany & Mangelsdorf, 2006; Cariou & Staels, 2007). FXR affects gene expression by interaction with RXR, forming a heterodimer that recruits transcriptional activators. Activation of FXR reduces BA levels through multiple mechanisms but primarily by downregulating expresson of cholesterol 7-α hydroxylase (CYP7A1), the rate-limiting enzyme in BA synthesis.

Although dietary lipid digestion is minimal in hibernators that rely solely on fat stores for fuel, BAs are still produced during the hibernation season, probably during interbout arousals to euthermia. There are two reports of seasonal changes in gall bladder bile in ground squirrels and bears (Jones & Zollman, 1997; Otis et al. 2008). Both reported minimal effects of hibernation on total BA concentrations; however, these were static measurements and thus may not accurately reflect the total BA pool. Plasma BA levels were reported to be slightly reduced during hibernation in bears (Sola et al. 2006). Using an isolated perfused liver model, we found that bile flow from livers harvested from interbout arousal hibernators was similar to that in summer squirrels but bile flow from torpid livers was lower than both euthermic groups (Lindell et al. 2005). Expressions of FXR mRNA and CYP7A1 protein are reduced in liver of hibernating vs. summer ground squirrels (Otis et al. 2008; Otis & Carey, 2009). The mRNA and protein levels of ApoA-I, which is negatively regulated by FXR, are elevated during the hibernation season in ground squirrels (Epperson & Martin, 2002; Epperson et al. 2004; Martin et al. 2008). Protein expression of the FXR target gene phosphoenolpyruvate carboxykinase (PEPCK) 2, the rate-limiting enzyme involved in gluconeogenesis, is elevated in livers of hibernating vs. summer ground squirrels (Epperson et al. 2004). However, reports on changes in PEPCK activity in hibernating ground squirrels are mixed (Green et al. 1984; Staples & Hochachka, 1998).

Liver X receptors (LXRs)

The LXRs LXRα and LXRβ are involved in cholesterol and lipid homeostasis. They regulate similar sets of genes, but have somewhat different tissue distributions with LXRα expressed strongly in liver and LXRβ more widely expressed (Zelcer & Tontonoz, 2006). The LXRs are primarily known as sterol sensors, binding oxysterols (oxidized derivatives of cholesterol) as ligands. LXRs are typically bound constitutively to their respective DNA response elements with repression released upon ligand binding. Oxysterol-activated LXRs increase transcription of genes related to reverse cholesterol transport to facilitate cholesterol clearance from peripheral tissues to the liver for excretion in bile; these include the cholesterol transporter ATP binding cassette transporter A1 (ABCA1) and the apolipoprotein, ApoE. LXR target genes also include PPARα (Colin et al. 2008).

Although oxidized cholesterol has not been measured in hibernating species, plasma cholesterol levels are known to increase during hibernation (Konttinen et al. 1964; Wenberg & Holland, 1973; Laplaud et al. 1989; Russom et al. 1992). In contrast, cholesterol content of some tissues falls during hibernation (Goldman, 1975; Kolomiytseva et al. 2003, 2008). Interestingly, administration of a high-cholesterol diet (which elevates both plasma and liver cholesterol) prior to the start of hibernation increases torpor bout length and depth in chipmunks (Geiser et al. 1997). Expression of the LXR target gene lipoprotein lipase increases in hibernation while fatty acid synthase decreases (Wilson et al. 1992; Mostafa et al. 1993). Expression of the cholesterol transporter ABCA1 is elevated in intestine of hibernating vs. summer ground squirrels (Otis & Carey, 2009).

Retinoid-related orphan receptors (RORs) and Rev-ERBs

The RORs and Rev-ERBs influence a variety of physiological processes including lipid metabolism, the inflammatory response, and circadian rhythms. Both have several isoforms and can differ in their tissue expression patterns (Emery & Reppert, 2004), although RORα and Rev-ERBα tend to be found in common tissues including liver, adipose tissue, skeletal muscle, brain and vasculature. Indeed, these two NRs are often discussed in combination, as they typically act in a reciprocal and antagonistic fashion at the ROR response element with RORα acting as a transcriptional activator and Rev-ERBα as a repressor (Green et al. 2008). RORα and Rev-ERBα have long been regarded as orphan NRs and the identities of their endogenous ligands are still under debate. Recently, however, evidence has emerged to suggest that cholesterol sulfate may serve as a ligand for RORα (Kallen et al. 2004; Kim et al. 2008), and Rev-ERBα may bind heme (Burris, 2008). There is growing evidence that these NRs play key roles in integrating circadian rhythms and metabolism, making them potential regulators of hibernation physiology (Duez & Staels, 2008; Green et al. 2008).

There is some evidence that ligands of RORα and Rev-ERBα are altered during the annual hibernation cycle. Using a metabolomic approach in liver tissue, we observed the lowest levels of cholesterol sulfate in hibernating squirrels late in a torpor bout, and a gradual rise in levels during arousal with a peak reached as animals enter the next torpor bout (Nelson et al. 2009). Plasma cholesterol sulfate levels also peak in aroused hibernators (Nelson & Carey, unpublished data). Hepatic biliverdin levels are low in torpid hibernators and rise over 15-fold upon arousal, peaking during the interbout arousal period (Nelson et al. 2009). This pattern may reflect fluctuations in haeme levels during torpor-arousal cycles as biliverdin is a byproduct of haeme catabolism.

Nuclear receptors in facultative torpor and dauer states

Mice can enter a hypometabolic and hypothermic state in response to food deprivation and cool ambient temperatures. Torpor in mice is relatively shallow, with minimum Tb generally above 20°C and torpor bout lengths that last less than 24 h (Geiser, 2004; Swoap, 2008). The absence of pre-torpor fattening, relatively high Tb and lack of multi-day torpor bouts distinguish torpor in mice from most hibernators, yet the two phenomena share metabolic depression and reduced Tb as a mechanism to reduce energy demands. Recent findings that implicate NRs in torpor behaviour in mice are worth considering for their potential roles in hibernation. FXR-knockout mice enter torpor more readily upon fasting than do wild-type mice (Cariou et al. 2007), suggesting a potential role for FXR ligands in metabolic depression. Overexpression of fibroblast growth factor 21 (FGF21), a target of PPARα, induces torpor in mice after a 24 h fast (Inagaki et al. 2007) and increases expression of several genes that are upregulated during hibernation, such as HMGCS2. FGF21 also induced the expression of pancreatic lipases in liver (Inagaki et al. 2007). This resembles the hibernation-induced expression of pancreatic lipase in heart and white adipose tissue in ground squirrels (Andrews et al. 1998; Bauer et al. 2001) and is likely to facilitate lipid oxidation and fuel delivery to key metabolic tissues at low Tb. However, the effects of FGF21 on Tb and metabolism are complex as its administration to mice with diet-induced obesity actually increased Tb and oxygen consumption (Coskun et al. 2008; Xu et al. 2009). Activation of PPARα via dietary supplementation with bezafibrate, a PPARα agonist, induced a modest reduction in Tb and elevated expression of neuropeptide Y (NPY) in the hypothalamus (Chikahisa et al. 2008). This peptide is a mediator of fasting-induced torpor in mice (Swoap, 2008) and Siberian hamsters (Dark & Pelz, 2008). Its mRNA is also elevated in hibernating jerboas (El Ouezzani et al. 2001). Although a study in ground squirrels reported no change in hypothalamic NPY during hibernation (Reuss et al. 1990), further studies are warranted to determine the extent of PPARα/NPY signalling in metabolic regulation of daily torpor and hibernation.

Insights into the role of NRs in mammalian hibernation may also come from studies on regulation of the dauer phenotype. During larval development of C. elegans, a decision is made to either follow reproductive growth or enter a diapause state known as dauer, depending on environmental conditions such as food availability and crowding (Fielenbach & Antebi, 2008). The nuclear receptor with a clearly established role in this phenotype is dauer forming (DAF)-12, which under unfavourable conditions promotes fat storage, dauer formation and long life. DAF-12 is most similar to the vertebrate vitamin D, pregnane and adrostane receptors but it also has strong homology to LXRα and β (Ludewig et al. 2004; Magner & Antebi, 2008). Environmental signals affect production of the DAF-12 ligands, bile acid-like steroids known as dafachronic acids (Motola et al. 2006). A similar bile acid, 25S-cholestenoic acid is a ligand for both DAF-12 and LXR (Fielenbach & Antebi, 2008). Another C. elegans NR that governs moulting, NHR-23 is orthologous to RORα (Magner & Antebi, 2008). Thus, vertebrates and worms may share similar NRs that regulate cyclical activities like moulting, circadian rhythms and perhaps hibernation cycles.

Potential roles of NRs in hibernation

The overwhelming evidence that nuclear receptors are critical regulators of metabolic control makes it highly likely that they participate in the seasonal regulation of the hibernation phenotype, and possibly the dynamic events that occur during torpor–arousal cycles in hibernators. Studies that manipulate NR expression, their ligands or target genes in hibernating species will be important in establishing a mechanistic link between NR biology and the metabolic cycles associated with hibernation. Other aspects of hibernation that are not well understood may also be dependent on NR signalling. For example, hibernation provides protection against tissue injury induced by inflammation and ischaemia–reperfusion (I/R) as suggested by studies in gut, liver and brain (Frerichs & Hallenbeck, 1998; Lindell et al. 2005; Kurtz et al. 2006). Several of the NRs mentioned here have been shown to negatively regulate the inflammatory response and be protective in models of I/R injury (Delerive et al. 2001a,b; Jetten, 2004; Li et al. 2007; Nunn et al. 2007; Morales et al. 2008). Given the evidence that many NR ligands and target genes are altered during hibernation, it is tempting to speculate that at least some NR-regulated pathways are involved in hibernation-induced protection from I/R injury.

Whether circadian rhythms still operate during hibernation has been investigated by several laboratories (Heller & Ruby, 2004; Revel et al. 2007). Recently, several circadian clock-related genes including period (PER), cryptochrome (CRY), brain and muscle aryl hydrocarbon receptor nuclear translocator-like (BMAL), and circadian locomotor output cycle kaput protein (CLOCK) were reported to change significantly during torpor-arousal cycles in multiple tissues of arctic ground squirrels, which provided molecular evidence that circadian rhythms may resume during interbout arousals (Yan et al. 2008). The NRs RORα, Rev-ERBα and PPARs have been implicated in the integration of circadian rhythms, nutritional status and metabolism (Kohsaka & Bass, 2007; Duez & Staels, 2008; Green et al. 2008). Given the accumulating evidence for changes in ligands for these NRs during the hibernation cycle, it is interesting to speculate that through their interactions with the circadian machinery they help coordinate metabolic processes during interbout arousals and entry into the next torpor bout.

Acknowledgments

We thank Dr Steven Swoap for constructive comments on this manuscript.

Glossary

Abbreviations

ABCA1

ATP binding cassette transporter A1

ApoA-I

apolipoprotein A-I

BA

bile acid

BMAL

brain and muscle aryl hydrocarbon receptor nuclear translocator-like

CLOCK

circadian locomotor output cycle kaput protein

CRY

cryptochrome

CYP7A1

cholesterol 7-α hydroxylase

DAF-12

dauer forming 12

FGF21

fibroblast growth factor 21

FXR

farnesoid X receptor

HMGCS2

hydroxymethylglutaryl coenzyme A synthase 2

I/R

ischaemia–reperfusion

LXR

liver X receptor

NPY

neuropeptide Y

NR

nuclear receptor

PEPCK

phosphoenolpyruvate carboxykinase

PER

period

PGC-1α

PPARγ-coactivator 1α

PPAR

peroxisome proliferator-activated receptor

ROR

retinoid-related orphan receptors

RXR

retinoid X receptor

Ta

ambient temperature

Tb

body temperature

Author contributions

C.J.N., J.P.O. and H.V.C. contributed to the conception and design of this paper, the drafting of the article, critical revision and final approval of the published version.

References

  1. Afman L, Muller M. Nutrigenomics: from molecular nutrition to prevention of disease. J Am Diet Assoc. 2006;106:569–576. doi: 10.1016/j.jada.2006.01.001. [DOI] [PubMed] [Google Scholar]
  2. Andrews MT, Squire TL, Bowen CM, Rollins MB. Low-temperature carbon utilization is regulated by novel gene activity in the heart of a hibernating mammal. Proc Natl Acad Sci USA. 1998;95:8392–8397. doi: 10.1073/pnas.95.14.8392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barger JL, Barnes BM, Boyer BB. Regulation of UCP1 and UCP3 in arctic ground squirrels and relation with mitochondrial proton leak. J Appl Physiol. 2006;101:339–347. doi: 10.1152/japplphysiol.01260.2005. [DOI] [PubMed] [Google Scholar]
  4. Bauer VW, Squire TL, Lowe ME, Andrews MT. Expression of a chimeric retroviral-lipase mRNA confers enhanced lipolysis in a hibernating mammal. Am J Physiol Regul Integr Comp Physiol. 2001;281:R1186–R1192. doi: 10.1152/ajpregu.2001.281.4.R1186. [DOI] [PubMed] [Google Scholar]
  5. Brauch KM, Dhruv ND, Hanse EA, Andrews MT. Digital transcriptome analysis indicates adaptive mechanisms in the heart of a hibernating mammal. Physiol Genomics. 2005;23:227–234. doi: 10.1152/physiolgenomics.00076.2005. [DOI] [PubMed] [Google Scholar]
  6. Buck MJ, Squire TL, Andrews MT. Coordinate expression of the PDK4 gene: a means of regulating fuel selection in a hibernating mammal. Physiol Genomics. 2002;8:5–13. doi: 10.1152/physiolgenomics.00076.2001. [DOI] [PubMed] [Google Scholar]
  7. Burris TP. Nuclear hormone receptors for heme: REV-ERBα and REV-ERBβ are ligand-regulated components of the mammalian clock. Mol Endocrinol. 2008;22:1509–1520. doi: 10.1210/me.2007-0519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Carey HV, Andrews MT, Martin SL. Mammalian hibernation: cellular and molecular responses to depressed metabolism and low temperature. Physiol Rev. 2003;83:1153–1181. doi: 10.1152/physrev.00008.2003. [DOI] [PubMed] [Google Scholar]
  9. Cariou B, Bouchaert E, Abdelkarim M, Dumont J, Caron S, Fruchart JC, Burcelin R, Kuipers F, Staels B. FXR-deficiency confers increased susceptibility to torpor. FEBS Lett. 2007;581:5191–5198. doi: 10.1016/j.febslet.2007.09.064. [DOI] [PubMed] [Google Scholar]
  10. Cariou B, Staels B. FXR: a promising target for the metabolic syndrome? Trends Pharmacol Sci. 2007;28:236–243. doi: 10.1016/j.tips.2007.03.002. [DOI] [PubMed] [Google Scholar]
  11. Chikahisa S, Tominaga K, Kawai T, Kitaoka K, Oishi K, Ishida N, Rokutan K, Sei H. Bezafibrate, a peroxisome proliferator-activated receptors agonist, decreases body temperature and enhances electroencephalogram delta-oscillation during sleep in mice. Endocrinology. 2008;149:5262–5271. doi: 10.1210/en.2008-0285. [DOI] [PubMed] [Google Scholar]
  12. Colin S, Bourguignon E, Boullay AB, Tousaint JJ, Huet S, Caira F, Staels B, Lestavel S, Lobaccaro JM, Delerive P. Intestine-specific regulation of PPARα gene transcription by liver X receptors. Endocrinology. 2008;149:5128–5135. doi: 10.1210/en.2008-0637. [DOI] [PubMed] [Google Scholar]
  13. Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, Moller DE, Kharitonenkov A. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology. 2008;149:6018–6027. doi: 10.1210/en.2008-0816. [DOI] [PubMed] [Google Scholar]
  14. Dark J. Annual lipid cycles in hibernators: integration of physiology and behavior. Ann Rev Nutr. 2005;25:469–497. doi: 10.1146/annurev.nutr.25.050304.092514. [DOI] [PubMed] [Google Scholar]
  15. Dark J, Pelz KM. NPY Y1 receptor antagonist prevents NPY-induced torpor-like hypothermia in cold-acclimated Siberian hamsters. Am J Physiol Regul Integr Comp Physiol. 2008;294:R236–245. doi: 10.1152/ajpregu.00587.2007. [DOI] [PubMed] [Google Scholar]
  16. Delerive P, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol. 2001;169:453–459. doi: 10.1677/joe.0.1690453. [DOI] [PubMed] [Google Scholar]
  17. Delerive P, Monte D, Dubois G, Trottein F, Fruchart-Najib J, Mariani J, Fruchart JC, Staels B. The orphan nuclear receptor RORα is a negative regulator of the inflammatory response. EMBO Rep. 2001;2:42–48. doi: 10.1093/embo-reports/kve007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Drew KL, Buck CL, Barnes BM, Christian SL, Rasley BT, Harris MB. Central nervous system regulation of mammalian hibernation: implications for metabolic suppression and ischemia tolerance. J Neurochem. 2007;102:1713–1726. doi: 10.1111/j.1471-4159.2007.04675.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Duez H, Staels B. The nuclear receptors Rev-erbs and RORs integrate circadian rhythms and metabolism. Diab Vasc Dis Res. 2008;5:82–88. doi: 10.3132/dvdr.2008.0014. [DOI] [PubMed] [Google Scholar]
  20. Eddy SF, Morin P, Jr, Storey KB. Cloning and expression of PPARγ and PGC-1α from the hibernating ground squirrel, Spermophilus tridecemlineatus. Mol Cell Biochem. 2005;269:175–182. doi: 10.1007/s11010-005-3459-4. [DOI] [PubMed] [Google Scholar]
  21. Eddy SF, Storey KB. Differential expression of Akt, PPARγ, and PGC-1 during hibernation in bats. Biochem Cell Biol. 2003;81:269–274. doi: 10.1139/o03-056. [DOI] [PubMed] [Google Scholar]
  22. El Kebbaj Z, Andreoletti P, Mountassif D, Kabine M, Schohn H, Dauca M, Latruffe N, El Kebbaj MS, Cherkaoui-Malki M. Differential regulation of peroxisome proliferator-activated receptor (PPAR)-α1 and truncated PPARα2 as an adaptive response to fasting in the control of hepatic peroxisomal fatty acid β-oxidation in the hibernating mammal. Endocrinology. 2009;150:1192–1201. doi: 10.1210/en.2008-1394. [DOI] [PubMed] [Google Scholar]
  23. El Ouezzani S, Lafon P, Tramu G, Magoul R. Neuropeptide Y gene expression in the jerboa arcuate nucleus: modulation by food deprivation and relationship with hibernation. Neurosci Lett. 2001;305:127–130. doi: 10.1016/s0304-3940(01)01825-0. [DOI] [PubMed] [Google Scholar]
  24. Emery P, Reppert SM. A rhythmic Ror. Neuron. 2004;43:443–446. doi: 10.1016/j.neuron.2004.08.009. [DOI] [PubMed] [Google Scholar]
  25. Epperson LE, Dahl T, Martin SL. Quantitative analysis of liver protein expression during hibernation in the golden-mantled ground squirrel. Mol Cell Proteomics. 2004;3:920–933. doi: 10.1074/mcp.M400042-MCP200. [DOI] [PubMed] [Google Scholar]
  26. Epperson LE, Martin SL. Quantitative assessment of ground squirrel RNA levels in multiple stages of hibernation. Physiol Genomics. 2002;10:93–102. doi: 10.1152/physiolgenomics.00004.2002. [DOI] [PubMed] [Google Scholar]
  27. Fielenbach N, Antebi A. C. elegans dauer formation and the molecular basis of plasticity. Genes Dev. 2008;22:2149–2165. doi: 10.1101/gad.1701508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Florant GL, Nuttle LC, Mullinex DE, Rintoul DA. Plasma and white adipose tissue lipid composition in marmots. Am J Physiol Regul Integr Comp Physiol. 1990;258:1123–1131. doi: 10.1152/ajpregu.1990.258.5.R1123. [DOI] [PubMed] [Google Scholar]
  29. Frerichs KU, Hallenbeck JM. Hibernation in ground squirrels induces state and species-specific tolerance to hypoxia and aglycemia: an in vitro study in hippocampal slices. J Cereb Blood Flow Metab. 1998;18:168–175. doi: 10.1097/00004647-199802000-00007. [DOI] [PubMed] [Google Scholar]
  30. Geiser F. Metabolic rate and body temperature reduction during hibernation and daily torpor. Annu Rev Physiol. 2004;66:239–274. doi: 10.1146/annurev.physiol.66.032102.115105. [DOI] [PubMed] [Google Scholar]
  31. Geiser F, Kenagy GJ, Wingfield JC. Dietary cholesterol enhances torpor in a rodent hibernator. J Comp Physiol [B] 1997;167:416–422. doi: 10.1007/s003600050091. [DOI] [PubMed] [Google Scholar]
  32. Goldman SS. Cold resistance of the brain during hibernation. III. Evidence of a lipid adaptation. Am J Physiol. 1975;228:834–838. doi: 10.1152/ajplegacy.1975.228.3.834. [DOI] [PubMed] [Google Scholar]
  33. Green CB, Takahashi JS, Bass J. The meter of metabolism. Cell. 2008;134:728–742. doi: 10.1016/j.cell.2008.08.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Green CJ, Brosnan JT, Fuller BJ, Lowry M, Stubbs M, Ross BD. Effect of hibernation on liver and kidney metabolism in 13-lined ground squirrels. Comp Biochem Physiol B. 1984;79:167–171. doi: 10.1016/0305-0491(84)90009-9. [DOI] [PubMed] [Google Scholar]
  35. Heller HC, Ruby NF. Sleep and circadian rhythms in mammalian torpor. Annu Rev Physiol. 2004;66:275–289. doi: 10.1146/annurev.physiol.66.032102.115313. [DOI] [PubMed] [Google Scholar]
  36. Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V, Elmquist JK, Gerard RD, Burgess SC, Hammer RE, Mangelsdorf DJ, Kliewer SA. Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell Metab. 2007;5:415–425. doi: 10.1016/j.cmet.2007.05.003. [DOI] [PubMed] [Google Scholar]
  37. Jetten AM. Recent advances in the mechanisms of action and physiological functions of the retinoid-related orphan receptors (RORs) Curr Drug Targets Inflamm Allergy. 2004;3:395–412. doi: 10.2174/1568010042634497. [DOI] [PubMed] [Google Scholar]
  38. Jones JD, Zollman PE. Black bear (Ursus americanus) bile composition: seasonal changes. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1997;118:387–390. doi: 10.1016/s0742-8413(97)00176-x. [DOI] [PubMed] [Google Scholar]
  39. Kabine M, Clemencet MC, Bride J, El Kebbaj MS, Latruffe N, Cherkaoui-Malki M. Changes of peroxisomal fatty acid metabolism during cold acclimatization in hibernating jerboa (Jaculus orientalis) Biochimie. 2003;85:707–714. doi: 10.1016/s0300-9084(03)00117-2. [DOI] [PubMed] [Google Scholar]
  40. Kalaany NY, Mangelsdorf DJ. LXRS and FXR: the yin and yang of cholesterol and fat metabolism. Annu Rev Physiol. 2006;68:159–191. doi: 10.1146/annurev.physiol.68.033104.152158. [DOI] [PubMed] [Google Scholar]
  41. Kallen J, Schlaeppi JM, Bitsch F, Delhon I, Fournier B. Crystal structure of the human RORα ligand binding domain in complex with cholesterol sulfate at 2.2 A. J Biol Chem. 2004;279:14033–14038. doi: 10.1074/jbc.M400302200. [DOI] [PubMed] [Google Scholar]
  42. Kim EJ, Yoo YG, Yang WK, Lim YS, Na TY, Lee IK, Lee MO. Transcriptional activation of HIF-1 by RORα and its role in hypoxia signaling. Arterioscler Thromb Vasc Biol. 2008;28:1796–1802. doi: 10.1161/ATVBAHA.108.171546. [DOI] [PubMed] [Google Scholar]
  43. Kohsaka A, Bass J. A sense of time: how molecular clocks organize metabolism. Trends Endocrinol Metab. 2007;18:4–11. doi: 10.1016/j.tem.2006.11.005. [DOI] [PubMed] [Google Scholar]
  44. Kojima M, Takamatsu N, Ishii T, Kondo N, Shiba T. HNF-4 plays a pivotal role in the liver-specific transcription of the chipmunk HP-25 gene. Eur J Biochem. 2000;267:4635–4641. doi: 10.1046/j.1432-1327.2000.01499.x. [DOI] [PubMed] [Google Scholar]
  45. Kolomiytseva IK, Perepelkina NI, Patrushev IV, Popov VI. Role of lipids in the assembly of endoplasmic reticulum and dictyosomes in neuronal cells from the cerebral cortex of Yakutian ground squirrel (Citellus undulatus) during hibernation. Biochemistry (Mosc) 2003;68:783–794. doi: 10.1023/a:1025039101706. [DOI] [PubMed] [Google Scholar]
  46. Kolomiytseva IK, Perepelkina NI, Zharikova AD, Popov VI. Membrane lipids and morphology of brain cortex synaptosomes isolated from hibernating Yakutian ground squirrel. Comp Biochem Physiol B Biochem Mol Biol. 2008;151:386–391. doi: 10.1016/j.cbpb.2008.08.001. [DOI] [PubMed] [Google Scholar]
  47. Konttinen A, Rajasalmi M, Sarajas HS. Fat metabolism of the hedgehog during the hibernating cycle. Am J Physiol. 1964;207:845–848. doi: 10.1152/ajplegacy.1964.207.4.845. [DOI] [PubMed] [Google Scholar]
  48. Kurtz CC, Lindell SL, Mangino MJ, Carey HV. Hibernation confers resistance to intestinal ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol. 2006;291:G895–901. doi: 10.1152/ajpgi.00155.2006. [DOI] [PubMed] [Google Scholar]
  49. Laplaud PM, Saboureau M, Beaubatie L, el-Omari B. Seasonal variations of plasma lipids and lipoproteins in the hedgehog, an animal model for lipoprotein (a) metabolism: relation to plasma thyroxine and testosterone levels. Biochim Biophys Acta. 1989;1005:143–156. doi: 10.1016/0005-2760(89)90180-x. [DOI] [PubMed] [Google Scholar]
  50. Li YT, Swales KE, Thomas GJ, Warner TD, Bishop-Bailey D. Farnesoid X receptor ligands inhibit vascular smooth muscle cell inflammation and migration. Arterioscler Thromb Vasc Biol. 2007;27:2606–2611. doi: 10.1161/ATVBAHA.107.152694. [DOI] [PubMed] [Google Scholar]
  51. Lindell SL, Klahn SL, Piazza TM, Southard JH, Carey HV. Natural resistance to liver cold ischemia-reperfusion injury associated with the hibernation phenotype. Am J Physiol Gastrointest Liver Physiol. 2005;288:G473–480. doi: 10.1152/ajpgi.00223.2004. [DOI] [PubMed] [Google Scholar]
  52. Ludewig AH, Kober-Eisermann C, Weitzel C, Bethke A, Neubert K, Gerisch B, Hutter H, Antebi A. A novel nuclear receptor/coregulator complex controls C. elegans lipid metabolism, larval development, and aging. Genes Dev. 2004;18:2120–2133. doi: 10.1101/gad.312604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Magner DB, Antebi A. Caenorhabditis elegans nuclear receptors: insights into life traits. Trends Endocrinol Metab. 2008;19:153–160. doi: 10.1016/j.tem.2008.02.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Magnus TH, Henderson NE. Thyroid hormone resistance in hibernating ground squirrels, Spermophilus richardsoni. I. Increased binding of triiodo-L-thyronine and L-thyroxine by serum proteins. Gen Comp Endocrinol. 1988;69:352–360. doi: 10.1016/0016-6480(88)90025-1. [DOI] [PubMed] [Google Scholar]
  55. Martin SL, Epperson LE, Rose JC, Kurtz CC, Ane C, Carey HV. Proteomic analysis of the winterprotected phenotype of hibernating ground squirrel intestine. Am J Physiol Regul Integr Comp Physiol. 2008;295:R316–R328. doi: 10.1152/ajpregu.00418.2007. [DOI] [PubMed] [Google Scholar]
  56. Morales JR, Ballesteros I, Deniz JM, Hurtado O, Vivancos J, Nombela F, Lizasoain I, Castrillo A, Moro MA. Activation of liver X receptors promotes neuroprotection and reduces brain inflammation in experimental stroke. Circulation. 2008;118:1450–1459. doi: 10.1161/CIRCULATIONAHA.108.782300. [DOI] [PubMed] [Google Scholar]
  57. Mostafa N, Everett DC, Chou SC, Kong PA, Florant GL, Coleman RA. Seasonal changes in critical enzymes of lipogenesis and triacylglycerol synthesis in the marmot (Marmota flaviventris) J Comp Physiol [B] 1993;163:463–469. doi: 10.1007/BF00346930. [DOI] [PubMed] [Google Scholar]
  58. Motola DL, Cummins CL, Rottiers V, Sharma KK, Li T, Li Y, Suino-Powell K, Xu HE, Auchus RJ, Antebi A, Mangelsdorf DJ. Identification of ligands for DAF-12 that govern dauer formation and reproduction in C. elegans. Cell. 2006;124:1209–1223. doi: 10.1016/j.cell.2006.01.037. [DOI] [PubMed] [Google Scholar]
  59. Nelson CJ, Otis JP, Martin SL, Carey HV. Anaylsis of the hibernation cycle using LC-MS based metabolomics in ground squirrel liver. Physiol Genomics. 2009;37:43–51. doi: 10.1152/physiolgenomics.90323.2008. [DOI] [PubMed] [Google Scholar]
  60. Nunn AV, Bell J, Barter P. The integration of lipid-sensing and anti-inflammatory effects: how the PPARs play a role in metabolic balance. Nucl Recept. 2007;5:1. doi: 10.1186/1478-1336-5-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Okulicz WC, Darrow JM, Goldman BD. Uterine steroid hormone receptors during the estrous cycle and during hibernation in the Turkish hamster (Mesocricetus brandti) Biol Reprod. 1988;38:597–604. doi: 10.1095/biolreprod38.3.597. [DOI] [PubMed] [Google Scholar]
  62. Otis JP, Carey HV. Hibernation increases cholesterol and apolipoprotein A-I levels in ground squirrels. FASEB J. 2009 2009 Experimental Biology Meeting Abstract #982.2 http://submissions.miracd.com/eb2009/itinerary/login.asp. [Google Scholar]
  63. Otis JP, Hagey LR, Nelson CJ, Carey HV. Effects of hibernation on bile composition and hepatic FXR expression in ground squirrels. In: McKechnie AE, Lovegrove BG, editors. Hypometabolism in Animals: Torpor, Hibernation, and Cryobiology. Pietermaritzburg: University of KwaZulu-Natal; 2008. pp. 49–56. [Google Scholar]
  64. Reuss S, Hurlbut EC, Speh JC, Moore RY. Neuropeptide Y localization in telencephalic and diencephalic structures of the ground squirrel brain. Am J Anat. 1990;188:163–174. doi: 10.1002/aja.1001880206. [DOI] [PubMed] [Google Scholar]
  65. Revel FG, Herwig A, Garidou ML, Dardente H, Menet JS, Masson-Pevet M, Simonneaux V, Saboureau M, Pevet P. The circadian clock stops ticking during deep hibernation in the European hamster. Proc Natl Acad Sci U S A. 2007;104:13816–13820. doi: 10.1073/pnas.0704699104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Russom JM, Guba GR, Sanchez D, Tam CF, Lopez GA, Garcia RE. Plasma lipoprotein cholesterol concentrations in the golden-mantled group squirrel (Spermophilus lateralis): a comparison between pre-hibernators and hibernators. Comp Biochem Physiol B Biochem Mol Biol. 1992;102:573–578. doi: 10.1016/0305-0491(92)90049-w. [DOI] [PubMed] [Google Scholar]
  67. Serkova NJ, Rose JC, Epperson LE, Carey HV, Martin SL. Quantitative analysis of liver metabolites in three stages of the circannual hibernation cycle in 13-lined ground squirrels by NMR. Physiol Genomics. 2007;31:15–24. doi: 10.1152/physiolgenomics.00028.2007. [DOI] [PubMed] [Google Scholar]
  68. Sola S, Garshelis DL, Amaral JD, Noyce KV, Coy PL, Steer CJ, Iaizzo PA, Rodrigues CM. Plasma levels of ursodeoxycholic acid in black bears, Ursus americanus: seasonal changes. Comp Biochem Physiol C Toxicol Pharmacol. 2006;143:204–208. doi: 10.1016/j.cbpc.2006.02.002. [DOI] [PubMed] [Google Scholar]
  69. Sonoda J, Pei L, Evans RM. Nuclear receptors: decoding metabolic disease. FEBS Lett. 2008;582:2–9. doi: 10.1016/j.febslet.2007.11.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Staples JF, Hochachka PW. The effect of hibernation status and cold-acclimation on hepatocyte gluconeogenesis in the golden-mantled ground squirrel (Spermophilus lateralis) Can J Zool. 1998;76:1734–1740. [Google Scholar]
  71. Swoap SJ. The pharmacology and molecular mechanisms underlying temperature regulation and torpor. Biochem Pharmacol. 2008;76:817–824. doi: 10.1016/j.bcp.2008.06.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Wenberg GM, Holland JC. The circannual variations in the total serum lipids and cholesterol with respect to body weight in the woodchuck (Marmota monax) Comp Biochem Physiol A Comp Physiol. 1973;44:577–583. doi: 10.1016/0300-9629(73)90509-4. [DOI] [PubMed] [Google Scholar]
  73. Williams DR, Epperson LE, Li W, Hughes MA, Taylor R, Rogers J, Martin SL, Cossins AR, Gracey AY. Seasonally hibernating phenotype assessed through transcript screening. Physiol Genomics. 2005;24:13–22. doi: 10.1152/physiolgenomics.00301.2004. [DOI] [PubMed] [Google Scholar]
  74. Wilson BE, Deeb S, Florant GL. Seasonal changes in hormone-sensitive and lipoprotein lipase mRNA concentrations in marmot white adipose tissue. Am J Physiol Regul Integr Comp Physiol. 1992;262:R177–R181. doi: 10.1152/ajpregu.1992.262.2.R177. [DOI] [PubMed] [Google Scholar]
  75. Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M, Sivits G, Vonderfecht S, Hecht R, Li YS, Lindberg RA, Chen JL, Jung DY, Zhang Z, Ko HJ, Kim JK, Veniant MM. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes. 2009;58:250–259. doi: 10.2337/db08-0392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Yan J, Barnes BM, Kohl F, Marr TG. Modulation of gene expression in hibernating arctic ground squirrels. Physiol Genomics. 2008;32:170–181. doi: 10.1152/physiolgenomics.00075.2007. [DOI] [PubMed] [Google Scholar]
  77. Zelcer N, Tontonoz P. Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest. 2006;116:607–614. doi: 10.1172/JCI27883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Zivadinovic D, Andjus RK. In vitro and in vivo thermal activation of steroid-receptor complexes from rats and ground squirrels (Spermophilus citellus) Comp Biochem Physiol B Biochem Mol Biol. 1995;110:451–462. doi: 10.1016/0305-0491(94)00138-k. [DOI] [PubMed] [Google Scholar]

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