Rigano K S, Gehring J L, Evans Hutzenbiler B D, Chen A V, Nelson O L, Vella C A, Robbins C T, Jansen H T
School of Biological Sciences, Washington State University, Pullman, WA, 99164, USA.
Department of Integrative Physiology and Neuroscience, Washington State University, VBRB Room 205, MS7620, Pullman, WA, 99164, USA.
J Comp Physiol B. 2017 May;187(4):649-676. doi: 10.1007/s00360-016-1050-9. Epub 2016 Dec 16.
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（棕熊指名亚种）已经进化出了显著的代谢适应性，包括在活跃季节大量积累脂肪，随后在冬眠期间禁食。然而，这些体重的波动并不会像人类肥胖那样产生相同的有害影响。为了更好地理解这些季节性转变，我们对圈养的灰熊进行了胰岛素和葡萄糖耐量测试，描绘了循环脂肪因子的年度变化情况，并测试了一年中不同时间中枢给予瘦素的厌食作用。我们还使用熊的臀脂肪细胞培养物在体外测试胰岛素和β-肾上腺素能敏感性。熊在冬眠期间对胰岛素抵抗，但在春季和秋季活跃期敏感。冬眠的熊保持血糖正常，这可能是由于高胰岛素血症和高胰高血糖素血症。在整个活跃季节，脂肪因子浓度相对较低，但在10月中旬冬眠前脂肪含量最高时达到峰值。血清甘油在冬眠期间最高，表明脂肪持续分解。中枢给予瘦素在10月可减少食物摄入，但在8月则不然，这揭示了大脑对其厌食作用的敏感性存在季节性变化。这一点得到了冬眠熊下丘脑内强烈的磷酸化信号转导和转录激活因子3标记的支持；在活跃熊中这种标记几乎消失。冬眠期间收集的脂肪细胞与冬眠血清一起培养时对胰岛素抵抗，但与活跃季节血清一起培养时则变得敏感。对活跃血清进行热处理可阻断大部分这种作用。阐明负责冬眠熊生理机能的细胞机制可能为代谢紊乱的新治疗方法提供思路。
