Life in the fat lane: seasonal regulation of insulin sensitivity, food intake, and adipose biology in brown bears

Abstract

Grizzly bears (Ursus arctos horribilis) have evolved remarkable metabolic adaptations including enormous fat accumulation during the active season followed by fasting during hibernation. However, these fluctuations in body mass do not cause the same harmful effects associated with obesity in humans. To better understand these seasonal transitions, we performed insulin and glucose tolerance tests in captive grizzly bears, characterized the annual profiles of circulating adipokines, and tested the anorectic effects of centrally administered leptin at different times of the year. We also used bear gluteal adipocyte cultures to test insulin and beta-adrenergic sensitivity in vitro. Bears were insulin resistant during hibernation but were sensitive during the spring and fall active periods. Hibernating bears remained euglycemic, possibly due to hyperinsulinemia and hyperglucagonemia. Adipokine concentrations were relatively low throughout the active season but peaked in mid-October prior to hibernation when fat content was greatest. Serum glycerol was highest during hibernation, indicating ongoing lipolysis. Centrally administered leptin reduced food intake in October, but not in August, revealing seasonal variation in the brain's sensitivity to its anorectic effects. This was supported by strong phosphorylated signal transducer and activator of transcription 3 labeling within the hypothalamus of hibernating bears; labeling virtually disappeared in active bears. Adipocytes collected during hibernation were insulin resistant when cultured with hibernation serum but became sensitive when cultured with active season serum. Heat treatment of active serum blocked much of this action. Clarifying the cellular mechanisms responsible for the physiology of hibernating bears may inform new treatments for metabolic disorders.

Novel treatment strategies for chronic kidney disease: insights from the animal kingdom

“…wild bears and bears in captivity (P.S., unpublished work), suggesting that nutrients and feeding patterns might contribute to the metabolic changes required for hibernation. A transition in energy metabolism from carbohydrates during summer to lipids during winter is facilitated by a switch from insulin sensitivity in the summer to insulin resistance during hibernation (193). The observation that central administration of leptin to captive grizzly bears leads to reduced food intake in October, but not in August, implies that seasonal variations exist in the sensitivity of the bear brain to the anorexic effects of leptin (193).…”

“…A transition in energy metabolism from carbohydrates during summer to lipids during winter is facilitated by a switch from insulin sensitivity in the summer to insulin resistance during hibernation (193). The observation that central administration of leptin to captive grizzly bears leads to reduced food intake in October, but not in August, implies that seasonal variations exist in the sensitivity of the bear brain to the anorexic effects of leptin (193). In addition, seasonal variations in gut microbiota might also contribute to changes in energy metabolism in hibernating bears, as transplantation of summer gut microbiota from wild bears promoted adiposity without affecting glucose tolerance in germ-free mice (194).…”

Functional macronutritional generalism in a large omnivore, the brown bear

“…Brown bears in the wild, however, may be precluded from foraging to meet such nutritional preferences, because foods high in lipid or carbohydrate necessary to maintain a balanced intake are generally most available during late summer and autumn (Coogan et al., ). That foods available to achieve the optimal macronutrient ratio for primarily fat mass gain co‐occur with the prehibernation hyperphagic period, is suggestive of the functional significance and selective pressures shaping their behavioral dietary preferences; the nutritional and energetic demands necessary for hibernation require the acquisition of sufficient food resources (Rigano et al., ), with higher demands for females birthing cubs (López‐Alfaro, Robbins, Zedrosser, & Nielsen, ). It is unclear, however, the extent to which bears regulate their diets in the wild.…”

Specific shifts in the endocannabinoid system in hibernating brown bears

“…Genetic or pharmacological inactivation of CB2 receptor contribute to reduce adipose tissue in ammation, increase insulin sensitivity and skeletal muscle glucose uptake [37,38]. Strikingly, insulin resistance has been described in hibernating bears adipocytes [66]. As bears don't experience health consequences of circannual high body fat storage [67], a reduced CB2 signaling in adipose tissue could dampen adipose tissue in ammation.…”