[1]周鑫,王澜,张晨亮,等.长期间歇性冷暴露干预脂肪组织代谢调控机体葡萄糖稳态 [J].第三军医大学学报,2019,41(11):1044-1051.
 ZHOU Xin,WANG Lan,ZHANG Chenliang,et al.Long-term intermittent cold exposure regulates glucose homeostasis via intervening metabolism of adipose tissue in mice [J].J Third Mil Med Univ,2019,41(11):1044-1051.
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长期间歇性冷暴露干预脂肪组织代谢调控机体葡萄糖稳态
 
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《第三军医大学学报》[ISSN:1000-5404/CN:51-1095/R]

卷:
41卷
期数:
2019年第11期
页码:
1044-1051
栏目:
基础医学
出版日期:
2019-06-15

文章信息/Info

Title:
Long-term intermittent cold exposure regulates glucose homeostasis via intervening metabolism of adipose tissue in mice
 
作者:
周鑫王澜张晨亮林树宋治远
陆军军医大学(第三军医大学)第一附属医院心血管内科,重庆市介入心脏病学研究所
Author(s):
ZHOU Xin WANG Lan ZHANG Chenliang LIN Shu SONG Zhiyuan

Department of Cardiology, Chongqing Institute of Interventional Cardiology, First Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China

关键词:
糖代谢冷暴露棕色脂肪白色脂肪棕色化转录组测序
Keywords:
glucose metabolism cold exposure brown adipose tissue browning of white fat adipose transcriptome profiling analysis
分类号:
Q591.4; Q591.5; R339.55
文献标志码:
A
摘要:

目的 通过对小鼠进行长期间歇性冷暴露,探讨冷暴露对机体葡萄糖稳态的改善作用以及对高脂饮食诱导葡萄糖稳态损害的预防作用,并分析脂肪组织在该过程中所起的调控作用。方法 取24只8周龄雄性C57BL/6J小鼠均分成4组,分别为对照组(正常普通饲料+常温)、冷暴露组(正常普通饲料+4 ℃,2 h/d)、高脂对照组(高脂饲料+常温)、高脂+冷暴露组(高脂饲料+4 ℃,2 h/d)。在分组后1、8、16、22周时分别进行葡萄糖耐量和胰岛素耐量实验,22周后取小鼠肩胛处棕色脂肪和腹股沟皮下脂肪进行转录组测序。结果22周间歇性冷暴露在不影响小鼠体质量的前提下,可以显著降低体内皮下脂肪的质量[对照组(0.338±0.024)g vs 冷暴露组(0.221±0.016)g,P<0.05],显著提升棕色脂肪的质量[对照组(0.079±0.003)g vs 冷暴露组(0.095±0.005)g, P<0.05],并使糖耐量水平提高25.9%(P<0.01),胰岛素敏感性提升50.4%(P<0.01),葡萄糖稳态改善的程度和冷暴露的时间呈正相关。在高脂饮食条件下,22周间歇性冷暴露显著抑制了其引发的体质量增加[高脂对照组(43.3±1.8)g vs 高脂+冷暴露组(32.9±0.7)g, P<0.01]和皮下脂肪质量增加[高脂对照组(1.186±0.215)g vs高脂+冷暴露组(0.434±0.059)g,P<0.05],并使糖耐量不足改善了25.5%(P<0.01),胰岛素抵抗改善了33.9%(P<0.01)。转录组测序分析表明长期间歇性冷暴露显著激活棕色脂肪和白色脂肪的葡萄糖代谢、PI3K-Akt和胰岛素信号通路(P<0.05),但在高脂饮食条件下冷暴露对白色脂肪组织葡萄糖代谢相关通路的激活作用不明显。结论 长期间歇性冷暴露可以显著改善小鼠葡萄糖稳态,并可以预防高脂饮食对葡萄糖稳态的损害,其可能是通过激活脂肪组织葡萄糖代谢、PI3K-Akt和胰岛素信号通路来发挥作用。

Abstract:

Objective By stimulating intermittent cold exposure to mice for a long term, to investigate the effect of cold exposure on amelioration of glucose homeostasis and prevention of glucose homeostasis disorder induced by high-fat diet (HFD), and analyze the regulative effect of adipose tissue in the process. MethodsA total of 24 male C57 BL/6J male mice (8 weeks old) were equally divided into 4 groups, that is, control group (normal diet+room temperature), cold exposure group (normal diet+4 ℃, 2 h/d), HFD group (HFD feeding+room temperature), and HFD and cold exposure group. Intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (IPITT) were carried out in 1, 8, 16 and 22 weeks after intervention. In 22 weeks after intervention, scapular brown adipose tissue (BAT) and inguinal white adipose tissue (WATi) were collected for transcriptome profiling analysis. ResultsWhen having no effect on the bodyweight, intermittent cold exposure for 22 weeks significantly reduced the weight of WATi (0.221±0.016 vs 0.338±0.024 g, P<0.05), but increased the weight of BAT (0.095±0.005 vs 0.079±0.003 g, P<0.05) when compared with the control group, and elevated glucose tolerance by 25.9% (P<0.01) and enhanced insulin sensitivity by 50.4% (P<0.01). The amelioration of glucose homeostasis was positively correlated with the length of cold exposure. However, in the mice with HFD feeding, the cold exposure inhibited the increase of bodyweight (43.3±1.8 vs 32.9±0.7 g, P<0.01) and WATi (1.186±0.215 vs 0.434±0.059 g, P<0.05), and improved insufficient glucose tolerance by 25.5% (P<0.01) and insulin resistance by 33.9% (P<0.01) when compared to the mice of HFD and cold exposure group. Transcriptome profiling analysis showed that long-term intermittent cold exposure obviously activated the glycolysis in the brown fat and white fat tissues, and the PI3K-Akt and insulin signaling pathways (P<0.01), but HFD reversed the activation of glycolysis-related pathways in white fat tissues. Conclusion Long-term intermittent cold exposure may promote glucose homeostasis and prevent glucose homeostasis disorder induced by HFD via activating glycolysis, PI3K-Akt and insulin signaling pathways in adipose tissue.
 

参考文献/References:

[1]CHONDRONIKOLA M, VOLPI E, BRSHEIM E, et al. Brown adipose tissue is linked to a distinct thermoregulatory response to mild cold in people[J]. Front Physiol, 2016, 7: 129. DOI:10.3389/fphys.2016.00129.
[2]CYPESS A M, LEHMAN S, WILLIAMS G, et al. Identification and importance of brown adipose tissue in adult humans[J]. N Engl J Med, 2009, 360(15): 1509-1517. DOI:10.1056/NEJMoa0810780.
[3]NEDERGAARD J, BENGTSSON T, CANNON B. Unexpected evidence for active brown adipose tissue in adult humans[J]. Am J Physiol Endocrinol Metab, 2007, 293(2): E444-E452. DOI:10.1152/ajpendo.00691.2006.
[4]EMANUELLI B, VIENBERG S G, SMYTH G, et al. Interplay between FGF21 and insulin action in the liver regulates metabolism[J]. J Clin Invest, 2015, 125(1): 458. DOI:10.1172/JCI80223.
[5]KOHLIE R, PERWITZ N, RESCH J, et al. Dopamine directly increases mitochondrial mass and thermogenesis in brown adipocytes[J]. J Mol Endocrinol, 2017, 58(2): 57-66. DOI:10.1530/JME-16-0159.
[6]ROSENWALD M, PERDIKARI A, RLICKE T, et al. Bi-directional interconversion of brite and white adipocytes[J]. Nat Cell Biol, 2013, 15(6): 659-667. DOI:10.1038/ncb2740.
[7]LOWELL B B, SPIEGELMAN B M. Towards a molecular understanding of adaptive thermogenesis[J]. Nature, 2000, 404(6778): 652-660. DOI:10.1038/35007527.
[8]BARTELT A, MERKEL M, HEEREN J. A new, powerful player in lipoprotein metabolism: brown adipose tissue[J]. J Mol Med, 2012, 90(8): 887-893. DOI:10.1007/s00109-012-0858-3.
[9]SHIN H, MA Y, CHANTURIYA T, et al. Lipolysis in brown adipocytes is not essential for cold-induced thermogenesis in mice[J]. Cell Metab, 2017, 26(5): 764-777.e5. DOI:10.1016/j.cmet.2017.09.002.
[10]SCHLEIN C, TALUKDAR S, HEINE M, et al. FGF21 lowers plasma triglycerides by accelerating lipoprotein catabolism in white and brown adipose tissues[J]. Cell Metab, 2016, 23(3): 441-453. DOI:10.1016/j.cmet.2016.01.006.
[11]YANG L K, TAO Y X. Physiology and pathophysiology of the β3-adrenergic receptor[J]. Prog Mol Biol Transl Sci, 2019, 161: 91-112. DOI:10.1016/bs.pmbts.2018.09.003.
[12]STANFORD K I,MIDDELBEEK R J,TOWNSEND K L,et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity[J]. J Clin Invest, 2013, 123(1): 215-223. DOI:10.1172/JCI62308.
[13]SHANKAR K, KUMAR D, GUPTA S, et al. Role of brown adipose tissue in modulating adipose tissue inflammation and insulin resistance in high-fat diet fed mice[J]. Eur J Pharmacol, 2019. DOI:10.1016/j.ejphar.2019.02.044.
[14]HORIE T, NISHINO T, BABA O, et al. MicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice[J]. Nat Commun, 2013, 4: 2883. DOI:10.1038/ncomms3883.
[15]HANSSEN M J, HOEKS J, BRANS B, et al. Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus[J]. Nat Med, 2015, 21(8): 863-865. DOI:10.1038/nm.3891.
[16]KOPECKY J, CLARKE G, ENERBCK S, et al. Expression of the mitochondrial uncoupling protein gene from the AP2 gene promoter prevents genetic obesity[J]. J Clin Invest, 1995, 96(6): 2914-2923. DOI:10.1172/JCI118363.
[17]BAI Y, SUN Q. Macrophage recruitment in obese adipose tissue[J]. Obes Rev, 2015, 16(2): 127-136. DOI:10.1111/obr.12242.
[18]CHUNG N, PARK J, LIM K. The effects of exercise and cold exposure on mitochondrial biogenesis in skeletal muscle and white adipose tissue[J]. J Exerc Nutrition Biochem, 2017, 21(2): 39-47. DOI:10.20463/jenb.2017.0020.
[19]FLACHS P, ADAMCOVA K, ZOUHAR P, et al. Induction of lipogenesis in white fat during cold exposure in mice: link to lean phenotype[J]. Int J Obes (Lond), 2017, 41(6): 997. DOI:10.1038/ijo.2017.61.
[20]SYAMSUNARNO M R, ISO T, YAMAGUCHI A, et al. Fatty acid binding protein 4 and 5 play a crucial role in thermogenesis under the conditions of fasting and cold stress[J]. PLoS ONE, 2014, 9(6): e90825. DOI:10.1371/journal.pone.0090825.
[21]CLOOKEY S L, WELLY R J, SHAY D, et al. Beta 3 adrenergic receptor activation rescues metabolic dysfunction in female estrogen receptor alpha-null mice[J]. Front Physiol, 2019, 10: 9. DOI:10.3389/fphys.2019.00009.
[22]PUIGSERVER P, WU Z, PARK C W, et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis[J]. Cell, 1998, 92(6): 829-839.
[23]KLEINER S, MEPANI R J, LAZNIK D, et al. Development of insulin resistance in mice lacking PGC-1α in adipose tissues[J]. Proc Natl Acad Sci U S A, 2012, 109(24): 9635-9640. DOI:10.1073/pnas.1207287109.
[24]YANG Q Y, LIANG X W, SUN X F, et al. AMPK/α-ketoglutarate axis dynamically mediates DNA demethylation in the prdm16 promoter and brown adipogenesis[J]. Cell Metab, 2016, 24(4): 542-554. DOI:10.1016/j.cmet.2016.08.010.
[25]FISHER F M, KLEINER S, DOURIS N, et al. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis[J]. Genes Dev, 2012, 26(3): 271-281. DOI:10.1101/gad.177857.111.
[26]CUEVAS-RAMOS D, MEHTA R, AGUILAR-SALINAS C A. Fibroblast growth factor 21 and browning of white adipose tissue[J]. Front Physiol, 2019, 10: 37. DOI:10.3389/fphys.2019.00037.
[27]LAEGER T, BAUMEIER C, WILHELMI I, et al. FGF21 improves glucose homeostasis in an obese diabetes-prone mouse model independent of body fat changes[J]. Diabetologia, 2017, 60(11): 2274-2284. DOI:10.1007/s00125-017-4389-x.
[28]HANKIR M K, KLINGENSPOR M. Brown adipocyte glucose metabolism: A heated subject[J]. EMBO Rep, 2018, 19(9): e46404. DOI:10.15252/embr.201846404.
[29]CANNON B, NEDERGAARD J. Brown adipose tissue: function and physiological significance[J]. Physiol Rev, 2004, 84(1): 277-359. DOI:10.1152/physrev.00015.2003.
[30]HIMMS-HAGEN J. Lipid metabolism in warm-acclimated and cold-acclimated rats exposed to cold[J]. Can J Physiol Pharmacol, 1965, 43: 379-403.
 

更新日期/Last Update: 2019-06-06