昼夜节律生物钟调控糖脂代谢稳态在奶牛酮病中作用的研究进展

doi:10.16431/j.cnki.1671-7236.2025.07.043

摘要/Abstract

摘要： 酮病是围产期奶牛糖脂代谢失衡而导致的一种营养代谢性疾病，主要表现为体内酮体的积累和游离性脂肪酸的升高，同时伴随血糖、胰岛素浓度异常和胰高血糖素浓度的升高。该病严重危害奶牛的健康和生产性能，给奶牛养殖业造成巨大损失。酮病发生的核心环节是糖脂代谢紊乱，生物钟作为哺乳动物重要的内源性稳态调控系统，可通过调节糖脂代谢相关激素分泌、限速酶基因与核受体基因的表达来调控机体糖脂代谢的昼夜节律稳态。笔者对奶牛酮病与糖脂代谢紊乱的联系、生物钟在哺乳动物糖脂代谢昼夜节律稳态调控中的作用、生物钟调控奶牛代谢生理的昼夜节律和酮病对奶牛糖脂代谢昼夜节律的影响进行了综述，以期从时间生物学的角度更全面地认识奶牛酮病的发病机制，为探究精准、高效的酮病防控与治疗策略提供新的思路。

关键词: 酮病; 昼夜节律; 糖脂代谢; 调控机制

Abstract: Ketosis is a nutritional metabolic disease caused by the imbalance of glucose and lipid metabolism in perinatal dairy cows.It is mainly manifested by the accumulation of ketone bodies and the increase of free fatty acids,accompanied by abnormal concentration of blood sugar,insulin and glucagon.The disease seriously endangers the health and production performance of dairy cows and causes huge losses to the dairy farming industry.The core link of ketosis is the disorder of glucose and lipid metabolism.As an important endogenous homeostasis regulation system in mammals,the circadian clock can regulate the circadian rhythm of glucose and lipid metabolism by regulating the secretion of hormones related to glucose and lipid metabolism,the expression of rate-limiting enzyme genes and nuclear receptor genes.This paper reviewed the connection between ketosis and glycolipid metabolism disorders in dairy cows,the role of the circadian clock in the regulation of circadian rhythm homeostasis of lipid and carbohydrate metabolism in mammals,the circadian rhythm of metabolic physiology regulated by circadian clock in dairy cows,and the effects of ketosis on the circadian rhythm of glucose and lipid metabolism in dairy cows,in order to understand the pathogenesis of ketosis in dairy cows more comprehensively from the perspective of chronobiology,and provide new ideas for exploring accurate and efficient prevention and treatment strategy of ketosis.

Key words: ketosis; circadian rhythm; glycolipid metabolism; regulation mechanism

中图分类号:

S857.2⁺1

刘纪君, 王逢博, 韦峰, 靳亚平, 张海森, 陈华涛. 昼夜节律生物钟调控糖脂代谢稳态在奶牛酮病中作用的研究进展[J]. 中国畜牧兽医, 2025, 52(7): 3449-3458.

LIU Jijun, WANG Fengbo, WEI Feng, JIN Yaping, ZHANG Haisen, CHEN Huatao. Research Progress on the Role of Circadian Clock in Regulating Glucose and Lipid Metabolism Homeostasis of Ketosis in Dairy Cows[J]. China Animal Husbandry & Veterinary Medicine, 2025, 52(7): 3449-3458.

参考文献

[1] VANHOLDER T,PAPEN J,BEMERS R,et al.Risk factors for subclinical and clinical ketosis and association with production parameters in dairy cows in the Netherlands[J].Journal of Dairy Science,2015,98(2):880-888.
[2] CONTRERAS G A,SORDILLO L M.Lipid mobilization and inflammatory responses during the transition period of dairy cows[J]. Comparative Immunology,Microbiology and Infectious Diseases,2011,34(3):281-289.
[3] ZHANG F,LI D,WU Q,et al.Prepartum body conditions affect insulin signaling pathways in postpartum adipose tissues in transition dairy cows[J].Journal of Animal Science and Biotechnology,2019,10:38.
[4] 程林,马云,马燕芬,等.围产期奶牛酮病的发病机制和预警标志物研究进展[J].动物营养学报,2024,36(6):3462-3473.CHENG L,MA Y,MA Y F,et al.Research progress on pathogenesis and early warning markers of ketosis in dairy cows during perinatal period[J].Chinese Journal of Animal Nutrition,2024,36(6):3462-3473.(in Chinese)
[5] 毛景东.奶牛酮病的发病机制及防治措施[J].中国牛业科学,2016,42(4):6-8.MAO J D.The pathogenesis and control measures of cow ketone disease[J]China Cattle Science,2016,42(4):6-8.(in Chinese)
[6] HERDT T H.Ruminant adaptation to negative energy balance.Influences on the etiology of ketosis and fatty liver[J].The Veterinary Clinics of North America： Food Animal Practice,2000,16(2):215-230.
[7] 赵刚,毕德峰.奶牛酮病的病因分析与诊治[J].养殖技术顾问,2012,5:144-145.ZHAO G,BI D F.Etiological analysis and diagnosis of ketosis in dairy cows[J]. Modern Animal Husbandry Science & Technology,2012,5:144-145.(in Chinese)
[8] MCART J A A,NYDAM D V,OSPINA P A,et al.A field trial on the effect of propylene glycol on milk yield and resolution of ketosis in fresh cows diagnosed with subclinical ketosis[J].Journal of Dairy Science,2011,94(12):6011-6020.
[9] KENÉZ Á,RUDA L,DÄNICKE S,et al.Insulin signaling and insulin response in subcutaneous and retroperitoneal adipose tissue in Holstein cows during the periparturient period[J].Journal of Dairy Science,2019,102(12):11718-11729.
[10] JAAKSON H,KARIS P,LING K,et al.Adipose tissue insulin receptor and glucose transporter 4 expression,and blood glucose and insulin responses during glucose tolerance tests in transition Holstein cows with different body condition[J].Journal of Dairy Science,2018,101(1):752-766.
[11] LOOR J J,EVERTS R E,BIONAZ M,et al.Nutrition-induced ketosis alters metabolic and signaling gene networks in liver of periparturient dairy cows[J]. Physiological Genomics,2007,32(1):105-116.
[12] PIECHOTTA M,MYSEGADES W,LIGGES U,et al.Antepartal insulin-like growth factor 1 and insulin-like growth factor binding protein 2 concentrations are indicative of ketosis in dairy cows[J].Journal of Dairy Science,2015,98(5):3100-3109.
[13] ZHANG H,WU L,XU C,et al.Plasma metabolomic profiling of dairy cows affected with ketosis using gas chromatography/mass spectrometry[J]. BMC Veterinary Research,2013,9:186.
[14] WANG Y,GAO Y,XIA C,et al.Pathway analysis of plasma different metabolites for dairy cow ketosis[J].Italian Journal of Animal Science,2016,15(3):545-551.
[15] KARIS P,JAAKSON H,LING K,et al.Body condition and insulin resistance interactions with periparturient gene expression in adipose tissue and lipid metabolism in dairy cows[J].Journal of Dairy Science,2020,103(4):3708-3718.
[16] MANN S,URH C,SAUERWEIN H,et al.Short communication:The association of adiponectin and leptin concentrations with prepartum dietary energy supply,parity,body condition,and postpartum hyperketonemia in transition dairy cows[J].Journal of Dairy Science,2018,101(1):806-811.
[17] CHEN Y,DONG Z,LI R,et al.Changes in selected biochemical parameters during subclinical and clinical ketosis in dairy cows[J]. Medycyna Weterynaryjna,2018,74(11):727-730.
[18] FRIEDRICHS P.mRNA expression of chemerin and its receptor in a subcutaneous and a visceral fat depot of dairy cows fed with high or low portions of concentrate during the transition period[J].Logic & Logical Philosophy,2014,57(3):193-215.
[19] DENG Q,MA D,SHI Z,et al.Effects of β-hydroxybutyric acid on the synthesis and assembly of very low-density lipoprotein in bovine hepatocytes in vitro[J].Journal of Animal Physiology and Animal Nutrition,2016,100(2):331-336.
[20] 杨阳,储明星,刘秋月.生物钟作用机制及其对动物年节律产生的影响[J].遗传,2023,45(5):409-424.YANG Y,CHU M X,LIU Q Y.The mechanism of circadian clock and its influence on animal circannual rhythm[J]. Hereditas,2023,45(5):409-424.(in Chinese)
[21] DE ASSIS L V M,OSTER H.The circadian clock and metabolic homeostasis:Entangled networks[J].Cellular and Molecular Life Science,2021,78(10):4563-4587.
[22] CHALLET E,PÉVET P.Interactions between photic and nonphotic stimuli to synchronize the master circadian clock in mammals[J].Frontiers in Bioscience:A Journal and Virtual Library,2003,8:s246-s257.
[23] 郭金虎,马晓红,甘锡惠.时差的生理影响及治疗[J].自然杂志,2021,43(4):297-307.GUO J H,MA X H,GAN X H.Physiological effects of jet lag,social jet lag and the treatments[J].Chinese Journal of Nature,2021,43(4):297-307.(in Chinese)
[24] KONDRATOV R V,SHAMANNA R K,KONDRATOVA A A,et al.Dual role of the CLOCK/BMAL1 circadian complex in transcriptional regulation[J].Federation of American Societies for Experimental Biology,2006,20(3):530-532.
[25] CRUMBLEY C,BURRIS T P.Direct regulation of CLOCK expression by REV-ERB[J].Public Library of Science,2011,6(3):e17290.
[26] YAMAJUKU D,SHIBATA Y,KITAZAWA M,et al.Cellular DBP and E4BP4 proteins are critical for determining the period length of the circadian oscillator[J].Federation of European Biochemical Societies,2011,585(14):2217-2222.
[27] PATKE A,YOUNG M W,AXELROD S.Molecular mechanisms and physiological importance of circadian rhythms[J]. Nature Reviews Molecular Cell Biology,2020,21(2):67-84.
[28] 杨捷,刘子龙,高玉雯,等.似昼夜节律与糖脂代谢的研究进展[J].空军军医大学学报,2024,45(2):206-210.YANG J,LIU Z L,GAO Y W,et al.Research progress of circadian rhythm and glycolipid metabolism[J].Journal of Air Force Medical University,2024,45(2):206-210.(in Chinese)
[29] MARCHEVA B,RAMSEY K M,BUHR E D,et al.Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes[J].Nature,2010,466(7306):627-631.
[30] VASEY C,MCBRIDE J,PENTA K.Circadian rhythm dysregulation and restoration:The role of melatonin[J].Nutrients,2021,13(10):3480.
[31] IITAKA C,MIYAZAKI K,AKAIKE T,et al.A role for glycogen synthase kinase-3beta in the mammalian circadian clock[J].The Journal of Biological Chemistry,2005,280(33):29397-29402.
[32] RAKSHIT K，MATVEVENKO A V.Induction of core circadian clock transcription factor bmal1 enhances β-cell function and protects against obesity-induced glucose intolerance[J].Diabetes,2021,70(1):143-154.
[33] TOLEDO M,BATISTA-GONZALEZ A,MERHEB E,et al.Autophagy regulates the liver clock and glucose metabolism by degrading CRY1[J].Cell Metabolism,2018,28(2):268-281.
[34] KOHSAKA A,LAPOSKY A D,RAMSEY K M,et al.High-fat diet disrupts behavioral and molecular circadian rhythms in mice[J].Cell Metabolism,2007,6(5):414-421.
[35] BERG R V,KOOIHMAN S,NOORDAM R,et al.A diurnal rhythm in brown adipose tissue causes rapid clearance and combustion of plasma lipids at wakening[J].Cell Reports,2018,22(13):3521-3533.
[36] DUEZ H,STAELS B.The nuclear receptors REV-ERBs and RORs integrate circadian rhythms and metabolism[J].Diabetes & Vascular Disease Research,2008,5(2):82-88.
[37] MASRI S,RIGOR P,CERVANTES M,et al.Partitioning circadian transcription by SIRT6 leads to segregated control of cellular metabolism[J].Cell,2014,158(3):659-672.
[38] LEBLANC S J,OSAWA T,DUBUC J.Reproductive tract defense and disease in postpartum dairy cows[J].Theriogenology,2011,76(9):1610-1618.
[39] LEMBERGER T,SALADIN R,VÁZQUEZ M,et al.Expression of the peroxisome proliferator-activated receptor α gene is stimulated by stress and follows a diurnal rhythm[J].Journal of Biological Chemistry,1996,271(3):1764-1769.
[40] CANAPLE L,RAMBAUD J,DKHISSI-BENYAHYA O,et al.Reciprocal regulation of brain and muscle arnt-like protein 1 and peroxisome proliferator-activated receptor α defines a novel positive feedback loop in the rodent liver circadian clock[J].Molecular Endocrinology,2006,20(8):1715-1727.
[41] BARNEA M,MADAR Z,FROY O.High-fat diet delays and fasting advances the circadian expression of adiponectin signaling components in mouse liver[J].Endocrinology,2009,150(1):161-168.
[42] SALFER I J,MORELLI M C,YING Y,et al.The effects of source and concentration of dietary fiber,starch,and fatty acids on the daily patterns of feed intake,rumination,and rumen pH in dairy cows[J].Journal of Dairy Science,2018,101(12):10911-10921.
[43] DEVRIES T J,VON KEYSERLINGK M A G,BEAUCHEMIN K A.Short communication:Diurnal feeding pattern of lactating dairy cows[J].Journal of Dairy Science,2003,86(12):4079-4082.
[44] HEDLUND L,LISCHKO M M,ROLLAG M D,et al.Melatonin:Daily cycle in plasma and cerebrospinal fluid of calves[J]. Science,1977,195(4279):686-687.
[45] LEFCOURT A M,BITMAN J,WOOD D L,et al.Circadian and ultradian rhythms of peripheral growth hormone concentrations in lactating dairy cows[J]. Domestic Animal Endocrinology,1995,12(3):247-256.
[46] BITMAN J,KAHL S,WOOD D L,et al.Circadian and ultradian rhythms of plasma thyroid hormone concentrations in lactating dairy cows[J]. The American Journal of Physiology,1994,266(6 Pt 2):R1797-R1803.
[47] BITMAN J,WOOD D L,LEFCOURT A M.Rhythms in cholesterol,cholesteryl esters,free fatty acids,and triglycerides in blood of lactating dairy cows[J].Journal of Dairy Science,1990,73(4):948-955.
[48] LEFCOURT A M,HUNTINGTON J B,AKERS R M,et al.Circadian and ultradian rhythms of body temperature and peripheral concentrations of insulin and nitrogen in lactating dairy cows[J]. Domestic Animal Endocrinology,1999,16(1):41-55.
[49] 曹锦承.长光周期对锦江牛秋冬季节生产性能、行为和代谢日节律的影响[D].南京：南京农业大学,2022.CAO J C.Effects of long photoperiod on performance,behavior and metabolic day rhythm of Jinjiang cattle in autumn and winter[D].Nanjing：Nanjing Agricultural University,2022.(in Chinese)
[50] SUAREZ-TRUJILLO A,WERNERT G,SUN H,et al.Exposure to chronic light-dark phase shifts during the prepartum nonlactating period attenuates circadian rhythms,decreases blood glucose,and increases milk yield in the subsequent lactation[J].Journal of Dairy Science,2020,103(3):2784-2799.
[51] MCCABE C J,SUAREZ-TRUJILLO A,TEEPLE K A,et al.Chronic prepartum light-dark phase shifts in cattle disrupt circadian clocks,decrease insulin sensitivity and mammary development,and are associated with lower milk yield through 60 days postpartum[J].Journal of Dairy Science,2021,104(2):2422-2437.
[52] SUAREZ-TRUJILLO A,HOANG N,ROBINSON L,et al.Effect of circadian system disruption on the concentration and daily oscillations of cortisol,progesterone,melatonin,serotonin,growth hormone,and core body temperature in periparturient dairy cattle[J].Journal of Dairy Science,2022,105(3):2651-2668.
[53] NIU M,YING Y,BARTELL P A,et al.The effects of feeding time on milk production,total-tract digestibility,and daily rhythms of feeding behavior and plasma metabolites and hormones in dairy cows[J]. Journal of Dairy Science,2014,97(12):7764-7776.
[54] 宝华,宋利文,张航,等.围产后期亚临床酮病对奶牛氧化应激、免疫功能和生产性能的影响[J].饲料工业,2019,40(15):49-56.BAO H,SONG L W,ZHANG H,et al.Effects of subclinical ketosis on oxidative stress,immune function and production performance of dairy cows in postpartum[J].Feed Industry,2019,40(15):49-56.(in Chinese)
[55] 李胜利,郝阳毅,王蔚,等.围产期奶牛糖脂代谢与健康养殖研究进展[J].动物营养学报,2020,32(10):4708-4715.LI S L,HAO Y Y,WANG W,et al.Research progress on glucose-lipid metabolism and healthy feeding in transition dairy cows[J].Chinese Journal of Animal Nutrition,2020,32(10):4708-4715.(in Chinese)
[56] BODEN G.Obesity,insulin resistance and free fatty acids[J].Current Opinion in Endocrinology,Diabetes,and Obesity,2011,18(2):139-143.
[57] DUFFIELD T.Subclinical ketosis in lactating dairy cattle[J].The Veterinary Clinics of North America，Food Animal Practice,2000,16(2):231-253.
[58] SU Y,FOPPEN E,MANSUR MACHADO F S,et al.The role of the daily feeding rhythm in the regulation of the day/night rhythm in triglyceride secretion in rats[J].Chronobiology International,2018,35(7):885-895.
[59] SEELY C R,BACH K D,BARBANO D M,et al.Effect of hyperketonemia on the diurnal patterns of energy-related blood metabolites in early-lactation dairy cows[J].Journal of Dairy Science,2021,104(1):818-825.
[60] 李雅婷.产后健康和酮病奶牛血液氧化应激水平及免疫相关因子含量的昼夜变化规律研究[D].杨凌：西北农林科技大学,2023.LI Y T.Study on diurnal variations of blood oxidative stress levels and concentrations of immune related factors in postpartum health and ketotic dairy cows[D].Yangling：Northwest A&F University,2023.(in Chinese)
[61] RAKSHIT K,HSU T W,MATVEYENKO A V.Bmal1 is required for beta cell compensatory expansion,survival and metabolic adaptation to diet-induced obesity in mice[J].Diabetologia,2016,59(4):734-743.
[62] 王逢博.产后奶牛酮病发病规律调查与酮病相关诊断指标昼夜差异探究[D].杨凌：西北农林科技大学,2024.WANG F B.Investigation on the pathogenesis regularity of ketosis in postpartum dairy cows and exploration on circadian differences in ketosis-related diagnostic indicators[D].Yangling：Northwest A&F University,2024.(in Chinese)