Adaptive mechanisms regulate preferred utilization of ketones in the heart and brain of a hibernating mammal during arousal from torpor

Andrews, Matthew T.; Russeth, Kevin P.; Drewes, Lester R.; Henry, Pierre‐Gilles

doi:10.1152/ajpregu.90795.2008

Cited by 115 publications

(98 citation statements)

References 36 publications

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“…The energy stored in FFAs may be recovered by ␤-oxidation to generate ATP or to be converted to heat via nonshivering thermogenesis in brown adipose tissue; the latter process is important for rewarming from torpor and is also now recognized as having therapeutic implications for human obesity (6). In addition, two-carbon acetyl group derivatives of these FFAs are the building blocks for hepatic ketogenesis (10,11), which provides ketone bodies for use in target tissues including heart and brain (1,25). We also found a 10-fold increase in the plasma reservoir of glycerol at arousing.…”

Section: Discussionmentioning

confidence: 99%

“…S1. 1 For simplicity of comparison in the figures, all data for each compound were scaled to the median; i.e., 1.0 on the y-axis represents the median value among all samples in which that compound was detected.…”

Section: Metabolite Analysismentioning

confidence: 99%

“…Previous work to measure metabolite changes in hibernators documents a number of alterations in liver (2,32,36), brain (21,40), brown adipose tissue (13), bile (4), and blood (1,9,24,31) that begin to assess the metabolites cycling in association with hibernation. These data suggest a two-switch model for the circannual rhythm of hibernation whereby the torporarousal cycle is temporally segregated from the summer-winter cycle such that torpor-arousal occurs only in winter (36).…”

mentioning

confidence: 99%

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Metabolic cycles in a circannual hibernator

Epperson¹,

Karimpour-Fard

Hunter

et al. 2011

Physiological Genomics

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nation 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 Ն 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. Ictidomys tridecemlineatus; Spermophilus; ␥-glutamyl; biliverdin; NacetylA YEAR IN THE LIFE OF A HIBERNATOR begins with reproduction in spring, followed by growth in summer, and then massive storage of fat as fall approaches. Hibernation, characterized by months of fasting and dramatic oscillations between states of cold and warm body temperature (T b ), ensues only after adequate fat stores are deposited (7). Most of the fall and winter months are spent in a state of deep torpor in which metabolic, heart, and respiratory rates are reduced to Ͻ5% of their summer equivalents, and body temperature declines to as low as 0°C, or even below (5). However, all hibernating mammals spontaneously reverse torpor at regular intervals by elevating metabolic rate and employing strictly endogenous mechanisms of heat production including shivering and nonshivering thermogenesis. In the thirteen-lined ground squirrel, Ictidomys tridecemlineatus, elevated metabolic rate and T b (ϳ37°C) are maintained in each interbout arousal for ϳ10 -12 h before dropping again to initiate the next ϳ2 wk bout of torpor. Thus, the circannual hibernation rhythm can be viewed as a cycle between summer homeothermy and winter heterothermy, the latter of which is itself a cycle between torpor and arousal (see Fig. 1). These dramatic physiological shifts of hibernation have been postulated to result from intrinsic metabolic cycles (41) that may be revealed by metabolic profiling (42).Previous work to measure metabolite changes in hibernators documents a number of alterations in liver (2, 32, 36), brain (21, 40), brown adipose tissue (13), bile (4), and blood (1, 9, 24, 31) that begin to assess the metabolites cycling in association with hibernation. These data suggest a two-s...

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Section: Discussionmentioning

confidence: 99%

Section: Metabolite Analysismentioning

confidence: 99%

mentioning

confidence: 99%

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Metabolic cycles in a circannual hibernator

Epperson¹,

Karimpour-Fard

Hunter

et al. 2011

Physiological Genomics

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“…With the use of 13 C MRS -hydroxybutyrate (Künnecke et al, 1993;Pan et al, 2002;Andrews et al, 2009), lactate (Hassel and Bråthe, 2000;Tyson et al, 2003;Boumezbeur et al, 2010), and pyruvate (Gonzalez et al, 2005) have been shown to be energy substrates for the brain after i.v. injection, pointing to the existence of the appropriate monocarboxylate transporters at the blood-brain barrier.…”

Section: Identification Of Alternative Substrates For Brain Energy Mementioning

confidence: 99%

13C Magnetic Resonance Spectroscopy in Neurobiology - Its Use in Monitoring Brain Energy Metabolism and in Identifying Novel Metabolic Substrates and Metabolic Pathways

Hassel¹

2012

Magnetic Resonance Spectroscopy

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“…tween carbohydrate-and fat-based metabolism, a delicate balance of kinases and phosphatases and changes in gene expression [15][16][17]. While massive fat depots serve as the main source of metabolic fuel throughout the winter [18], phosphorylation of tau during obligate hibernation seems to be a reversible consequence of hypothermia [19,20].…”

mentioning

confidence: 99%

The Alzheimer's Disease-Diabetes Angle: Inevitable Fate of Aging or Metabolic Imbalance Limiting Successful Aging

Bierhaus

Nawroth

2009

JAD

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Modern societies face the increasing burden of agerelated diseases, in particular Alzheimer's disease (AD) and type 2 diabetes (T2D). While numerous epidemiological studies have described the incidence of both diseases in the Western world and extensively defined common environmental risk factors, only little is known on the pathomechanisms linking both diseases [1][2][3]. Thus, it is not yet clear whether both diseases represent the endpoint of aged, exhausted, and dysfunctional cells having reached their maximal life expectancy or whether AD and T2D are the consequences of living in superabundance including excessive food supply, work demands, psychosocial stress, and an excessive sedentary life style [4][5][6][7][8][9]. Evidence for the latter is provided by the fact that high adiposity increases the risk of AD [10][11][12] and T2D [10,13] and implies that the progressive loss of energy balance is one underlying pathomechanism of both diseases.Interestingly, mammalian hibernators such as ground squirrels and hamsters demonstrate comparable and annual recurrent periods of obesity with concomitant insulin resistance and key features of AD such as tau phosphorylation [14,15]. These pathologies, however, are reversed by a time-dependent metabolic shift be- * Corresponding author: Angelika Bierhaus, PhD, Department of Medicine I, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Tel.: +49 6221 564752; Fax: +49 6221 564754; E-mail: angelika bierhaus@med.uni-heidelberg.de.tween carbohydrate-and fat-based metabolism, a delicate balance of kinases and phosphatases and changes in gene expression [15][16][17]. While massive fat depots serve as the main source of metabolic fuel throughout the winter [18], phosphorylation of tau during obligate hibernation seems to be a reversible consequence of hypothermia [19,20]. These changes gradually decrease over a period of months until the animals emerge from hibernation each spring [18]. Thus, fat storage and tau phosphorylation occur predictably on an annual basis, but subsequent fasting depletes fat during the course of winter and ensures that each spring the obese hibernator emerges lean [18]. Another example for a phylogenetic conserved adaptive response to energetic stress is provided by hummingbirds [21], which consume a high sugar diet and seasonally develop hyperglycemia and obesity, which is normalized during the breeding season [21]. Thus, hibernating mammals and hummingbirds provide an extreme example of the utility of accumulating body resources in nutrient-rich times for later use during times of fasting.These observations, however, indicate that mechanisms have to exist that enable cells to re-program their metabolism and maintain accurate energy balance despite repeated situations of excessive energy surplus. Fasting periods might also change and/or normalize gene expression patterns and activate cellular defense mechanisms that protect cells from being impaired by subsequent nutrition supply [18]. Noteworthy, centenarians seem to be eq...

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Adaptive mechanisms regulate preferred utilization of ketones in the heart and brain of a hibernating mammal during arousal from torpor

Cited by 115 publications

References 36 publications

Metabolic cycles in a circannual hibernator

Metabolic cycles in a circannual hibernator

13C Magnetic Resonance Spectroscopy in Neurobiology - Its Use in Monitoring Brain Energy Metabolism and in Identifying Novel Metabolic Substrates and Metabolic Pathways

The Alzheimer's Disease-Diabetes Angle: Inevitable Fate of Aging or Metabolic Imbalance Limiting Successful Aging

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