Proteomic and Transcriptomic Changes in Hibernating Grizzly Bears Reveal Metabolic and Signaling Pathways that Protect against Muscle Atrophy

Mugahid, Douaa; Şengül, Tuğçe; You, Xintian; Wang, Yongbo; Steil, Leif; Bergmann, Nora; Radkë, Michaël; Ofenbauer, Andreas; Gesell-Salazar, Manuela; Balogh, András; Kempa, Stefan; Tursun, Baris; Robbins, Charles T.; Völker, Uwe; Chen, W.; Nelson, Lonnie A.; Gotthardt, Michael

doi:10.1038/s41598-019-56007-8

Cited by 29 publications

(27 citation statements)

References 63 publications

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“…PDK4 is a major negative regulator of PDH activity, that in turn regulates the whole body oxidative carbohydrate metabolism. In hibernating bear muscle, recent studies have shown that PDK4 is upregulated compared to summer active state [10,61] and expression of PDK4 during hibernation appear thus to be disconnected from direct regulation by CB1. CB1 receptor antagonism also leads to an increased uptake of glucose in muscle via PI3K signaling [60], and glycolysis appears preserved in bear skeletal muscle during hibernation, as suggested by an overall increase in the protein abundance of all glycolytic enzymes [10].…”

Section: Discussionmentioning

confidence: 99%

Specific shifts in the endocannabinoid system in hibernating brown bears

Boyer

Cussonneau

Brun

et al. 2020

Preprint

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In small hibernators, global downregulation of the endocannabinoid system (ECS), which is involved in modulating neuronal signaling, feeding behavior, energy metabolism, and circannual rhythms, has been reported to possibly drive physiological adaptation to the hibernating state. In hibernating brown bears ( Ursus arctos ), we hypothesized that beyond an overall suppression of the ECS, seasonal shift in endocannabinoids compounds could be linked to bear’s peculiar features that include hibernation without arousal episodes and capacity to react to external disturbance. We explored circulating lipids in serum and the ECS in plasma and metabolically active tissues in free-ranging subadult Scandinavian brown bears when both active and hibernating. In winter bear serum, in addition to a 2-fold increase in total fatty acid concentration, we found significant changes in relative proportions of circulating fatty acids, such as a 2-fold increase in docosahexaenoic acid C22:6 n-3 and a decrease in arachidonic acid C20:4 n-6. In adipose and muscle tissues of hibernating bears, we found significant lower concentrations of 2-arachidonoylglycerol (2-AG), a major ligand of cannabinoid receptors 1 (CB1) and 2 (CB2). Lower mRNA level for genes encoding CB1 and CB2 were also found in winter muscle and adipose tissue, respectively. The observed reduction in ECS tone may promote fatty acid mobilization from body fat stores, and favor carbohydrate metabolism in skeletal muscle of hibernating bears. Additionally, high circulating level of the endocannabinoid-like compound N-oleoylethanolamide (OEA) in winter could favor lipolysis and fatty acid oxidation in peripheral tissues. We also speculated on a role of OEA in the conservation of an anorexigenic signal and in the maintenance of torpor during hibernation, while sustaining the capacity of bears to sense stimuli from the environment.

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Section: Discussionmentioning

confidence: 99%

Specific shifts in the endocannabinoid system in hibernating brown bears

Boyer

Cussonneau

Brun

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…PDK4 is a major negative regulator of PDH activity, that in turn regulates the whole body oxidative carbohydrate metabolism. In hibernating bear muscle, recent studies have shown that PDK4 is upregulated compared to summer active state [ 10 , 58 ] and expression of PDK4 during hibernation appear thus to be disconnected from direct regulation by CB1. CB1 receptor antagonism also leads to an increased uptake of glucose in muscle via PI3K signaling [ 59 ], and glycolysis appears preserved in bear skeletal muscle during hibernation, as suggested by an overall increase in the protein abundance of all glycolytic enzymes [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

Specific shifts in the endocannabinoid system in hibernating brown bears

et al. 2020

View full text Add to dashboard Cite

In small hibernators, global downregulation of the endocannabinoid system (ECS), which is involved in modulating neuronal signaling, feeding behavior, energy metabolism, and circannual rhythms, has been reported to possibly drive physiological adaptation to the hibernating state. In hibernating brown bears (Ursus arctos), we hypothesized that beyond an overall suppression of the ECS, seasonal shift in endocannabinoids compounds could be linked to bear’s peculiar features that include hibernation without arousal episodes and capacity to react to external disturbance. We explored circulating lipids in serum and the ECS in plasma and metabolically active tissues in free-ranging subadult Scandinavian brown bears when both active and hibernating. In winter bear serum, in addition to a 2-fold increase in total fatty acid concentration, we found significant changes in relative proportions of circulating fatty acids, such as a 2-fold increase in docosahexaenoic acid C22:6 n-3 and a decrease in arachidonic acid C20:4 n-6. In adipose and muscle tissues of hibernating bears, we found significant lower concentrations of 2-arachidonoylglycerol (2-AG), a major ligand of cannabinoid receptors 1 (CB1) and 2 (CB2). Lower mRNA level for genes encoding CB1 and CB2 were also found in winter muscle and adipose tissue, respectively. The observed reduction in ECS tone may promote fatty acid mobilization from body fat stores, and favor carbohydrate metabolism in skeletal muscle of hibernating bears. Additionally, high circulating level of the endocannabinoid-like compound N-oleoylethanolamide (OEA) in winter could favor lipolysis and fatty acid oxidation in peripheral tissues. We also speculated on a role of OEA in the conservation of an anorexigenic signal and in the maintenance of torpor during hibernation, while sustaining the capacity of bears to sense stimuli from the environment.

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“…In nonhibernating mammals, CNR1 activation leads to higher expression of the AMPKα1 subunit and a decrease of PDK4 expression that in turn enhances PDH activity [23,45,48,49]. Interestingly, recent studies have shown that PDK4 is upregulated in hibernating bear skeletal muscle [10,50], whereas A1 and B subunits of PDH are downregulated [10], and AMPK activity is reduced [51]. In hibernating bear muscle, AMPK and PDK4 expressions appear thus to be disconnected from direct regulation by CNR1.…”

Section: Discussionmentioning

confidence: 99%

Specific shifts in the endocannabinoid system in hibernating brown bears

Boyer

Cussonneau

Brun

et al. 2020

Preprint

View full text Add to dashboard Cite

In small hibernators, global downregulation of the endocannabinoid system (ECS), which is involved in modulating neuronal signaling, feeding behavior, energy metabolism, and circannual rhythms, has been reported to possibly drive physiological adaptation to the hibernating state. We hypothesized that specific changes should occur in hibernating brown bears ( Ursus arctos ) due to specific features, including hibernation during half the year at only mild hypothermia while remaining physically inactive without drinking or eating, and the absence of arousal episodes although bears remain sensitive to external disturbances. We explored circulating lipids and the ECS in plasma and metabolically active tissues (muscle and adipose tissue), in free-ranging subadult Scandinavian brown bears when both active and hibernating. In winter bear serum, in addition to a 2-fold increase in total fatty acid concentration, we found significant changes in relative proportions of circulating fatty acids, such as a 2-fold increase in docosahexaenoic acid and a decrease in arachidonic acid. In adipose and muscle tissues of hibernating bears, we found lower concentrations of both two major ligands for endocannabinoid receptors, 2-arachidonoylglycerol (2-AG) and anandamide (AEA). Gene expression was reduced for enzymes that synthesize endocannabinoid compounds, whereas an increase was observed for catabolic enzymes. Reduction in ECS tone may promote mobilization of fat stores and favor carbohydrate metabolism in skeletal muscle of hibernating bears. Additionally, high circulating of the endocannabinoid-like compound N-oleoylethanolamide (OEA) in winter could favor lipolysis and fatty acid oxidation in peripheral tissues. We also speculated on a role of OEA in the maintenance of torpor (reduction in locomotion), while promoting the capacity of bears to sense stimuli from the environment.

show abstract

Proteomic and Transcriptomic Changes in Hibernating Grizzly Bears Reveal Metabolic and Signaling Pathways that Protect against Muscle Atrophy

Cited by 29 publications

References 63 publications

Specific shifts in the endocannabinoid system in hibernating brown bears

Specific shifts in the endocannabinoid system in hibernating brown bears

Specific shifts in the endocannabinoid system in hibernating brown bears

Specific shifts in the endocannabinoid system in hibernating brown bears

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