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.北美灰熊（Ursus arctos horribilis）演化出了卓越的代谢适应性，具体体现为在活动季大量蓄积脂肪，随后在冬眠期间禁食。这类体重波动却不会引发人类肥胖相关的有害生理效应。为深入解析这类季节性生理转变，本研究对圈养北美灰熊开展了胰岛素耐受试验与葡萄糖耐受试验，系统表征了循环脂肪因子（adipokines）的年度动态谱，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；同时利用熊臀脂肪细胞体外（in vitro）培养模型，检测了胰岛素与β肾上腺素能受体的敏感性。研究结果显示：冬眠期灰熊表现为胰岛素抵抗，而在春季、秋季的活动期则胰岛素敏感；冬眠灰熊可维持血糖正常（euglycemic），这可能与高胰岛素血症（hyperinsulinemia）及高胰高血糖素血症（hyperglucagonemia）有关。活动季全程脂肪因子浓度相对较低，但在冬眠前的10月中旬，当机体脂肪含量达到峰值时，脂肪因子浓度也升至顶峰；冬眠期血清甘油水平最高，提示脂肪分解（lipolysis）仍在持续进行。中枢给药瘦素可在10月降低灰熊摄食量，但在8月无此效应，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：冬眠灰熊下丘脑内可见强阳性的磷酸化信号转导与转录激活因子3（phosphorylated signal transducer and activator of transcription 3, p-STAT3）标记，而活动期灰熊的该标记几乎消失。冬眠期采集的脂肪细胞在冬眠血清中培养时表现为胰岛素抵抗，但若换用活动季血清培养则恢复胰岛素敏感性；对活动季血清进行热处理可大幅削弱该转化效应。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。