β3肾上腺素受体激动剂CL316243对高脂饮食诱导肥胖小鼠心功能的影响
|
摘要
目的通过检测超声相关指标,评价β3肾上腺素受体激动剂CL316243对高脂饮食诱导肥胖小鼠心功能的改善情况。方法将30只雌性小鼠随机分为对照组10只和肥胖组20只,肥胖组给予高脂饮食16周以构建肥胖模型,随后将肥胖组随机等分为普通肥胖组和肥胖用药组。给予肥胖用药组小鼠14 d皮下注射CL316243 (1 mg/(kg·d)),普通肥胖组和对照组小鼠皮下注射生理盐水。利用小动物超声检测3组小鼠心功能指标。称重后,Western blotting法检测小鼠内脏周围脂肪组织中的解耦连蛋白1 (UCP-1)、蛋白激酶B (AKT)和磷酸化AKT (P-AKT)蛋白表达。结果与对照组比较,肥胖组小鼠体重显著升高,普通肥胖组高于肥胖用药组,差异有统计学意义(P <0.05)。与对照组比较,普通肥胖组射血分数和短轴舒缩率显著降低,左室质量指数、左室每搏输出量、收缩期剩余容量、左室舒张内径、左室收缩内径、左室舒张期后壁厚度显著增加,差异有统计学意义(P <0.05);肥胖用药组仅左室每搏输出量和收缩期剩余容量高于对照组,同时显著低于普通肥胖组,差异有统计学意义(P <0.05)。与普通肥胖组比较,肥胖用药组小鼠UCP-1蛋白和P-AKT蛋白表达明显上升,P-AKT表达水平与AKT表达水平比值升高,差异有统计学意义(P <0.05)。结论β3肾上腺素受体激动剂CL316243能改善高脂饮食诱导肥胖小鼠受损的心功能,这可能是通过促进白色脂肪棕色化,缓解其胰岛素抵抗状态来实现的。
Objective To evaluate the effect of beta 3 adrenergic receptor agonist CL31624 on cardiac function in obese mice induced by high-fat diet by detecting related ultrasoric features. Methods Thirty female mice were randomly divided into control group(10 mice) and obesity group(20 mice). The obesity group which induced by high-fat diet for 16 weeks was divided into normal obesity group and obesity medication group equally. The obesity medication group were subcutaneously injected with CL316243(1 mg/( kg·d)), the normal obesity group and the control group were subcutaneously injected with saline. Small animal ultrasound was used to detect the cardiac function indexes of three groups. After weighing, the expressions of uncoupling protein-1(UCP-1), protein kinase B(AKT) and phosphorylated-protein kinase B(P-AKT) were detected by Western blotting. Results Compared with the control group, the weight of the obesity group increased significantly, and that of normal obesity group was higher than that of the obesity medication group(P <0.05). Compared with the control group, ejection fraction and short-axis systolic rate were significantly decreased in the normal obesity group, while left ventricular mass index, left ventricular output per stroke, systolic residual volume, left ventricular diastolic diameter, left ventricular systolic diameter and left ventricular posterior wall thickness were significantly increased in the normal obesity group(P < 0.05). Left ventricular output per stroke and systolic residual volume in obesity medication group were higher than those of the control group, and were significantly lower than those of the normal obesity group(P < 0.05). Compared with the normal obesity group, the expression of UCP-1 protein and P-AKT protein in the obesity medication group increased significantly, and the ratio of P-AKT to AKT increased significantly(P < 0.05). Conclusion Beta 3 adrenergic receptor agonist CL316243 can improve the impaired cardiac function in obese mice induced by high-fat diet, which may be achieved by promoting white fat browning and alleviating insulin resistance.
Objective To evaluate the effect of beta 3 adrenergic receptor agonist CL31624 on cardiac function in obese mice induced by high-fat diet by detecting related ultrasoric features. Methods Thirty female mice were randomly divided into control group(10 mice) and obesity group(20 mice). The obesity group which induced by high-fat diet for 16 weeks was divided into normal obesity group and obesity medication group equally. The obesity medication group were subcutaneously injected with CL316243(1 mg/( kg·d)), the normal obesity group and the control group were subcutaneously injected with saline. Small animal ultrasound was used to detect the cardiac function indexes of three groups. After weighing, the expressions of uncoupling protein-1(UCP-1), protein kinase B(AKT) and phosphorylated-protein kinase B(P-AKT) were detected by Western blotting. Results Compared with the control group, the weight of the obesity group increased significantly, and that of normal obesity group was higher than that of the obesity medication group(P <0.05). Compared with the control group, ejection fraction and short-axis systolic rate were significantly decreased in the normal obesity group, while left ventricular mass index, left ventricular output per stroke, systolic residual volume, left ventricular diastolic diameter, left ventricular systolic diameter and left ventricular posterior wall thickness were significantly increased in the normal obesity group(P < 0.05). Left ventricular output per stroke and systolic residual volume in obesity medication group were higher than those of the control group, and were significantly lower than those of the normal obesity group(P < 0.05). Compared with the normal obesity group, the expression of UCP-1 protein and P-AKT protein in the obesity medication group increased significantly, and the ratio of P-AKT to AKT increased significantly(P < 0.05). Conclusion Beta 3 adrenergic receptor agonist CL316243 can improve the impaired cardiac function in obese mice induced by high-fat diet, which may be achieved by promoting white fat browning and alleviating insulin resistance.
引文
[1]Denis GV,Obin MS.Metabolically healthy obesity:origins and implications[J].Molecular Aspects of Medicine,2013,34(1):59-70
[2]Townsend K,Tseng YH.Brown adipose tissue:recent insights into development,metabolic function and therapeutic potential[J].Adipocyte,2012,1(1):13-24
[3]Shin W,Okamatsu OY,Machida K,et al.Impaired adrenergic agonist-dependent beige adipocyte induction in aged mice[J].Obesity,2017,25(2):417-423
[4]Xiao C,Goldgof M,Gavrilova O,et al.Anti-obesity and metabolic efficacy of theβ3-adrenergic agonist,CL-316243,in mice at thermoneutrality compared to 22°C[J].Obesity,2015,23(7):1450-1459
[5]Mele J,Muralimanoharan S,Maloyan A,et al.Impaired mitochondrial function in human placenta with increased maternal adiposity[J].American Journal of PhysiologyEndocrinology and Metabolism,2014,307(5):E419-E425
[6]Zhao Ying,Yang Ning,Li Han-ying,et al.Systemic evaluation of vascular dysfunction by high-resolution sonography in an Nω-Nitro-l-Arginine Methyl ester hydrochlorideinduced mouse model of preeclampsia-like symptoms[J].Journal of Ultrasound in Medicine,2017,37(3):657-666
[7]曲芊诺,张田,樊跃平.脂肪“变色”与减重[J].肿瘤代谢与营养电子杂志,2018,5(1):102-106
[8]黄海艳,汤其群.产热脂肪对代谢性疾病的治疗潜能[J].复旦学报:医学版,2017,44(6):757-764
[9]Murano I,Barbatelli G,Giordano A,et al.Noradrenergic parenchymal nerve fiber branching after cold acclimatisation correlates with brown adipocyte density in mouse adipose organ[J].Journal of Anatomy,2009,214(1):171-178
[10]van Marken LWD,Vanhommerig JW,Smulders NM,et al.Cold-activated brown adipose tissue in healthy men[J].New England Journal of Medicine,2009,360(15):1500-1508
[11]Himms HJ,Melnyk A,Zingaretti MC,et al.Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes[J].American Journal of Physiology-Cell Physiology,2000,279(3):C670-C681
[12]郑宗基.β3肾上腺素受体激动剂对C57BL/6J小鼠脂肪组织棕色化相关基因和microRNAs的影响[D].广州:南方医科大学第一临床医学院,2013
[13]CantóC,Houtkooper RH,Pirinen E,et al.The NAD(+)precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity[J].Cell Metabolism,2012,15(6):838-847
[14]张艳梅,韩丽娜,余叶蓉,等.室壁分层分析技术评价超重及肥胖患者左室纵向应变的研究[J].临床超声医学杂志,2018,20(1):15-18
[15]Wilson CM,Angela BS,Nunes LA,et al.Central obesity is the key component in the association of metabolic syndrome with left ventricular global longitudinal strain impairment[J].Revista Espa?ola de Cardiología,2018,71(7):524-530
[16]Lee CH,Kim HJ,Lee YS,et al.Hypothalamic macrophage inducible nitric oxide synthase mediates obesityassociated hypothalamic inflammation[J].Cell Reports,2018,25(4):934-946
[17]Odegaard JI,Chawla A.Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis[J].Science,2013,339(6116):172-177
[18]王浩.胰岛素抵抗与心功能损害[J].转化医学杂志,2007,20(3):164-167
[19]张丽华,刘永斌,白锋.不同疗法对急性冠状动脉综合征合并2型糖尿病患者PCI术后抗血小板疗效比较[J].兰州大学学报:医学版,2017,43(4):39-45
[20]Saben JL,Boudoures AL,Asghar Z,et al.Maternal metabolic syndrome programs mitochondrial dysfunction via germline changes across three generations[J].Cell Reports,2016,16(1):1-8
[2]Townsend K,Tseng YH.Brown adipose tissue:recent insights into development,metabolic function and therapeutic potential[J].Adipocyte,2012,1(1):13-24
[3]Shin W,Okamatsu OY,Machida K,et al.Impaired adrenergic agonist-dependent beige adipocyte induction in aged mice[J].Obesity,2017,25(2):417-423
[4]Xiao C,Goldgof M,Gavrilova O,et al.Anti-obesity and metabolic efficacy of theβ3-adrenergic agonist,CL-316243,in mice at thermoneutrality compared to 22°C[J].Obesity,2015,23(7):1450-1459
[5]Mele J,Muralimanoharan S,Maloyan A,et al.Impaired mitochondrial function in human placenta with increased maternal adiposity[J].American Journal of PhysiologyEndocrinology and Metabolism,2014,307(5):E419-E425
[6]Zhao Ying,Yang Ning,Li Han-ying,et al.Systemic evaluation of vascular dysfunction by high-resolution sonography in an Nω-Nitro-l-Arginine Methyl ester hydrochlorideinduced mouse model of preeclampsia-like symptoms[J].Journal of Ultrasound in Medicine,2017,37(3):657-666
[7]曲芊诺,张田,樊跃平.脂肪“变色”与减重[J].肿瘤代谢与营养电子杂志,2018,5(1):102-106
[8]黄海艳,汤其群.产热脂肪对代谢性疾病的治疗潜能[J].复旦学报:医学版,2017,44(6):757-764
[9]Murano I,Barbatelli G,Giordano A,et al.Noradrenergic parenchymal nerve fiber branching after cold acclimatisation correlates with brown adipocyte density in mouse adipose organ[J].Journal of Anatomy,2009,214(1):171-178
[10]van Marken LWD,Vanhommerig JW,Smulders NM,et al.Cold-activated brown adipose tissue in healthy men[J].New England Journal of Medicine,2009,360(15):1500-1508
[11]Himms HJ,Melnyk A,Zingaretti MC,et al.Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes[J].American Journal of Physiology-Cell Physiology,2000,279(3):C670-C681
[12]郑宗基.β3肾上腺素受体激动剂对C57BL/6J小鼠脂肪组织棕色化相关基因和microRNAs的影响[D].广州:南方医科大学第一临床医学院,2013
[13]CantóC,Houtkooper RH,Pirinen E,et al.The NAD(+)precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity[J].Cell Metabolism,2012,15(6):838-847
[14]张艳梅,韩丽娜,余叶蓉,等.室壁分层分析技术评价超重及肥胖患者左室纵向应变的研究[J].临床超声医学杂志,2018,20(1):15-18
[15]Wilson CM,Angela BS,Nunes LA,et al.Central obesity is the key component in the association of metabolic syndrome with left ventricular global longitudinal strain impairment[J].Revista Espa?ola de Cardiología,2018,71(7):524-530
[16]Lee CH,Kim HJ,Lee YS,et al.Hypothalamic macrophage inducible nitric oxide synthase mediates obesityassociated hypothalamic inflammation[J].Cell Reports,2018,25(4):934-946
[17]Odegaard JI,Chawla A.Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis[J].Science,2013,339(6116):172-177
[18]王浩.胰岛素抵抗与心功能损害[J].转化医学杂志,2007,20(3):164-167
[19]张丽华,刘永斌,白锋.不同疗法对急性冠状动脉综合征合并2型糖尿病患者PCI术后抗血小板疗效比较[J].兰州大学学报:医学版,2017,43(4):39-45
[20]Saben JL,Boudoures AL,Asghar Z,et al.Maternal metabolic syndrome programs mitochondrial dysfunction via germline changes across three generations[J].Cell Reports,2016,16(1):1-8