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

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.灰熊（Ursus arctos horribilis）演化出了卓越的代谢适应策略：在活动季大量蓄积脂肪，随后在冬眠期间禁食。然而这类体重波动并不会引发人类肥胖相关的诸多有害生理影响。为深入解析这类季节性生理转变，本研究团队对圈养灰熊开展了胰岛素耐量试验（insulin tolerance test）与葡萄糖耐量试验（glucose tolerance test），对循环脂肪因子（adipokines）的年度动态谱进行了系统表征，并在一年中的不同时段测试了中枢给药瘦素（leptin）的厌食效应。本研究还通过熊臀部脂肪细胞体外（in vitro）培养体系，检测了其胰岛素与β肾上腺素能（beta-adrenergic）敏感性。灰熊在冬眠状态下表现为胰岛素抵抗（insulin resistance），但在春季与秋季的活动期则对胰岛素敏感。冬眠中的灰熊可维持正常血糖（euglycemia），这一现象可能与高胰岛素血症（hyperinsulinemia）及高胰高血糖素血症（hyperglucagonemia）有关。活动季中，循环脂肪因子浓度整体处于较低水平，但在冬眠前的10月中旬——此时灰熊体脂含量达到峰值——脂肪因子浓度达到峰值。冬眠期间血清甘油水平最高，这提示脂肪分解（lipolysis）过程仍在持续进行。10月时中枢给药瘦素可降低灰熊的摄食量，但8月时无此效应，这表明大脑对瘦素厌食效应的敏感性存在季节性差异。这一结论得到了实验证据的支持：冬眠灰熊的下丘脑（hypothalamus）内可检测到强阳性的磷酸化信号转导与转录激活因子3（signal transducer and activator of transcription 3, STAT3）标记信号，而在活动期灰熊体内此类标记信号几乎完全消失。从冬眠灰熊体内采集的脂肪细胞，在使用冬眠期血清培养时表现为胰岛素抵抗，但若更换为活动季血清培养则会恢复胰岛素敏感性。对活动季血清进行热处理可大幅削弱这一效应。阐明调控冬眠灰熊生理状态的细胞机制，可为代谢紊乱的新型治疗方案提供理论依据。