Seasonal Changes in Endocannabinoid Concentrations between Active and Hibernating Marmots (Marmota flaviventris)

Abstract

Hibernation is a naturally occurring model for studying diseases such as obesity and osteoporosis. Hibernators, marmots (Marmota flaviventris) among them, are able to nearly double their body mass by increasing fat stores prior to hibernation without the negative consequences of obesity. They are also physically inactive for extended periods of time without experiencing negative effects on the skeleton. The endocannabinoid system is involved in modulating neural signaling, circannual rhythms, behavior, appetite, thermogenesis, and bone and energy metabolism. These systems are also altered to maintain homeostasis during hibernation. This study aims to better understand the involvement of the endocannabinoid system in the regulation of physiological processes during hibernation by quantifying the seasonal variation of endocannabinoids and endocannabinoid-like ligands in both active and hibernating marmots. We hypothesized that there would be significant changes in endocannabinoid concentrations at the tissue level in marmots between active and hibernating states. Concentrations were measured in brain, serum, brown adipose tissue, white adipose tissue, bone marrow, cortical bone, and trabecular bone using microflow chromatography coupled with tandem quadrupole mass spectrometry. Significant changes were found, such as a 30-fold decrease in 2-arachidonoyl glycerol (2-AG) in cortical bone during hibernation. Many endocannabinoid and endocannabinoid-like ligands decreased in brown adipose tissue, white adipose tissue, and cortical bone, while several ligands increased in bone marrow. This result supports our hypothesis and suggests the possibility of a peripherally controlled shift in energy metabolism, reduction in bone metabolism, and suppression of the immune system during hibernation.

Specific shifts in the endocannabinoid system in hibernating brown bears

“…We hypothesized that: drastic reduction in metabolic activity, lack of intake of dietary PUFAs, significant increase in the serum DHA/AA ratio, and perhaps reduction in tissue AA-phospholipids concentration, could lead to a global reduction in ECS tone during the hibernation period. The reduction in ECS tone has already been documented in hibernating marmots [21,29], but was not confirmed in large-bodied hibernators. In addition to the decrease in tissue concentration of 2-AG and AEA that we reported, we observed an unexpected 3-fold increase in OEA circulating levels in hibernating bears, whereas no seasonal differences in OEA content in muscle or adipose tissues were observed.…”

“…Considering the pleiotropic roles of ECS in neuronal signaling, regulation of behavior, appetite, energy metabolism, and circannual rhythms, it is not surprising to see important changes during hibernation. A decrease in ECS tone has notably been observed in hibernating marmots (Marmota monax and flaviventris) and ground squirrels (Spermophilus richardsonii) [21,28,29]. We hypothesized that a similar decrease could occur in hibernating bears, although specific changes due to their unique features during hibernation (mild hypothermia, no food intake, no periodic arousal, and maintenance of alertness) could also be expected.…”

Characterization of Seasonal Pharmacokinetic Variability in Woodchucks

“…Reduction in renal clearance and decrease in plasma atrial natriuretic factor were reported in hibernating marmots (Marmota flaviventris), a closely related species (Zatzman and South, 1972;Zatzman and Thornhill, 1989), and the hibernating thirteen-lined ground squirrel (Citellus tridecemlineatus) (Hong, 1957). In addition, seasonal changes in endocannabinoid concentrations between active and hibernating marmots were observed (Mulawa et al, 2018).…”

Specific shifts in the endocannabinoid system in hibernating brown bears

“…We hypothesized that drastic reduction in metabolic activity, lack of intake of dietary PUFAs, signi cant increase in the serum DHA/AA ratio, and perhaps reduction in tissue AA-phospholipids concentration, could lead to a global reduction in ECS tone during the hibernation period. The reduction in ECS tone has already been documented in hibernating marmots [31,42], but not con rmed in large-bodied hibernators.…”

“…Several ECS circulating compounds have been quanti ed in hibernating black bears, during and around the torpor phase [41] ,with no major changes observed except a slight increase in 2-AG in the period of metabolic drop before torpor. Although a decrease in ECS tone has been observed in hibernating marmots (Marmota monax and aviventris) and ground squirrels (Spermophilus richardsonii) [31,42,43], we hypothesize that a similar decrease should occur in hibernating bears, not excluding speci c changes due to their unique features during hibernation (mild hypothermia, no periodic arousal, and maintenance of alertness). Therefore, we explored here seasonal variations in fatty acid composition and ECS tone, in both circulating compartment and in muscle and adipose tissues, in winter-hibernating and summer-active brown bears.…”