将OB-Rb基因导入对瘦素抵抗的胰岛可逆转致糖尿病表型。
OB-Rb gene transfer to leptin-resistant islets reverses diabetogenic phenotype.
作者信息
Wang M Y, Koyama K, Shimabukuro M, Newgard C B, Unger R H
机构信息
Gifford Laboratories for Diabetes Research, University of Texas Southwestern Medical Center, Dallas 75235, USA.
出版信息
Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):714-8. doi: 10.1073/pnas.95.2.714.
Abstract
In obese Zucker diabetic fatty (ZDF) rats with mutant leptin receptors, pancreatic islets have an approximately 50-fold increase in fat (TG), overproduce nitric oxide (NO), and lack a normal proinsulin mRNA response to fatty acids. We overexpressed the wild-type full-length "b" isoform of the leptin receptor (OB-Rb) in ZDF islets by perfusing ZDF pancreata with recombinant adenovirus containing the cDNA encoding OB-Rb. In cultured islets isolated from these animals, leptin lowered islet TG by 87% and completely blocked TG formation from free fatty acids. Overproduction of NO was reduced, and the preproinsulin mRNA response to free fatty acids was restored. This establishes defective leptin action as the proximate cause of lipotoxic diabetes in ZDF rats.
摘要
在具有突变瘦素受体的肥胖Zucker糖尿病脂肪（ZDF）大鼠中，胰岛中的脂肪（甘油三酯）增加了约50倍，一氧化氮（NO）产生过多，并且缺乏对脂肪酸的正常胰岛素原mRNA反应。我们通过用含有编码OB-Rb的cDNA的重组腺病毒灌注ZDF胰腺，在ZDF胰岛中过表达瘦素受体的野生型全长“b”亚型（OB-Rb）。在从这些动物分离的培养胰岛中，瘦素使胰岛甘油三酯降低了87%，并完全阻断了游离脂肪酸形成甘油三酯的过程。NO的过量产生减少，并且对游离脂肪酸的胰岛素原前体mRNA反应得以恢复。这确定了瘦素作用缺陷是ZDF大鼠脂毒性糖尿病的直接原因。
相似文献
1
OB-Rb gene transfer to leptin-resistant islets reverses diabetogenic phenotype.将OB-Rb基因导入对瘦素抵抗的胰岛可逆转致糖尿病表型。
Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):714-8. doi: 10.1073/pnas.95.2.714.
2
Overexpression of leptin receptors in pancreatic islets of Zucker diabetic fatty rats restores GLUT-2, glucokinase, and glucose-stimulated insulin secretion.在Zucker糖尿病脂肪大鼠的胰岛中，瘦素受体的过表达可恢复葡萄糖转运蛋白2、葡萄糖激酶以及葡萄糖刺激的胰岛素分泌。
Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11921-6. doi: 10.1073/pnas.95.20.11921.
3
Leptin normalizes the impaired response of proinsulin mRNA to long chain fatty acids in heterozygous Zucker diabetic fatty rats.瘦素可使杂合子Zucker糖尿病肥胖大鼠中胰岛素原mRNA对长链脂肪酸的受损反应恢复正常。
J Biol Chem. 1997 Oct 10;272(41):25648-51. doi: 10.1074/jbc.272.41.25648.
4
Enhanced de novo lipogenesis in the leptin-unresponsive pancreatic islets of prediabetic Zucker diabetic fatty rats: role in the pathogenesis of lipotoxic diabetes.糖尿病前期Zucker糖尿病脂肪大鼠瘦素无反应性胰岛中从头脂肪生成增强：在脂毒性糖尿病发病机制中的作用
Diabetes. 1998 Dec;47(12):1904-8. doi: 10.2337/diabetes.47.12.1904.
5
Direct antidiabetic effect of leptin through triglyceride depletion of tissues.瘦素通过组织甘油三酯消耗产生的直接抗糖尿病作用。
Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4637-41. doi: 10.1073/pnas.94.9.4637.
6
Lipoapoptosis in beta-cells of obese prediabetic fa/fa rats. Role of serine palmitoyltransferase overexpression.肥胖糖尿病前期fa/fa大鼠β细胞中的脂肪凋亡。丝氨酸棕榈酰转移酶过表达的作用。
J Biol Chem. 1998 Dec 4;273(49):32487-90. doi: 10.1074/jbc.273.49.32487.
7
Protection against lipoapoptosis of beta cells through leptin-dependent maintenance of Bcl-2 expression.通过瘦素依赖性维持Bcl-2表达来保护β细胞免受脂肪凋亡。
Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9558-61. doi: 10.1073/pnas.95.16.9558.
8
Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion.功能性瘦素受体mRNA在胰岛中的表达及瘦素对胰岛素分泌的直接抑制作用。
Diabetes. 1997 Feb;46(2):313-6. doi: 10.2337/diab.46.2.313.
9
Leptin- or troglitazone-induced lipopenia protects islets from interleukin 1beta cytotoxicity.瘦素或曲格列酮诱导的脂肪减少可保护胰岛免受白细胞介素1β的细胞毒性作用。
J Clin Invest. 1997 Oct 1;100(7):1750-4. doi: 10.1172/JCI119700.
10
Antecedent hyperglycemia, not hyperlipidemia, is associated with increased islet triacylglycerol content and decreased insulin gene mRNA level in Zucker diabetic fatty rats.在Zucker糖尿病脂肪大鼠中，前驱高血糖而非高脂血症与胰岛甘油三酯含量增加及胰岛素基因mRNA水平降低有关。
Diabetes. 2001 Nov;50(11):2481-6. doi: 10.2337/diabetes.50.11.2481.
引用本文的文献
1
Contribution of animal models to diabetes research: Its history, significance, and translation to humans.动物模型对糖尿病研究的贡献：其历史、意义及其向人类的转化。
J Diabetes Investig. 2023 Sep;14(9):1015-1037. doi: 10.1111/jdi.14034. Epub 2023 Jul 3.
2
The Role of Fatty Acids in Ceramide Pathways and Their Influence on Hypothalamic Regulation of Energy Balance: A Systematic Review.脂肪酸在神经酰胺途径中的作用及其对下丘脑能量平衡调节的影响：一项系统综述。
Int J Mol Sci. 2021 May 19;22(10):5357. doi: 10.3390/ijms22105357.
3
Role of Leptin in the Digestive System.瘦素在消化系统中的作用。
Front Pharmacol. 2021 Apr 12;12:660040. doi: 10.3389/fphar.2021.660040. eCollection 2021.
4
Acid sphingomyelinase downregulation alleviates vascular endothelial leptin resistance in rats.酸性鞘磷脂酶下调可减轻大鼠血管内皮瘦素抵抗。
Acta Pharmacol Sin. 2020 May;41(5):650-660. doi: 10.1038/s41401-019-0328-3. Epub 2019 Dec 17.
5
Functional Relationship between Leptin and Nitric Oxide in Metabolism.瘦素与一氧化氮在代谢中的功能关系。
Nutrients. 2019 Sep 6;11(9):2129. doi: 10.3390/nu11092129.
6
Inhibition of central de novo ceramide synthesis restores insulin signaling in hypothalamus and enhances β-cell function of obese Zucker rats.抑制中枢从头合成神经酰胺可恢复肥胖 Zucker 大鼠下丘脑中的胰岛素信号转导并增强β细胞功能。
Mol Metab. 2018 Feb;8:23-36. doi: 10.1016/j.molmet.2017.10.013. Epub 2017 Nov 7.
7
Effects of leptin replacement therapy on pancreatic β-cell function in patients with lipodystrophy.瘦素替代疗法对脂肪营养不良患者胰腺β细胞功能的影响。
Diabetes Care. 2014 Apr;37(4):1101-7. doi: 10.2337/dc13-2040. Epub 2014 Feb 4.
8
Thyroid hormone drives fetal cardiomyocyte maturation.甲状腺激素促进胎儿心肌细胞成熟。
FASEB J. 2012 Jan;26(1):397-408. doi: 10.1096/fj.10-179895. Epub 2011 Oct 5.
9
Gender dimorphism in skeletal muscle leptin receptors, serum leptin and insulin sensitivity.骨骼肌瘦素受体、血清瘦素及胰岛素敏感性的性别二态性。
PLoS One. 2008;3(10):e3466. doi: 10.1371/journal.pone.0003466. Epub 2008 Oct 21.
10
Effects of conjugated linoleic acid and troglitazone on lipid accumulation and composition in lean and Zucker diabetic fatty (fa/fa) rats.共轭亚油酸和曲格列酮对正常及Zucker糖尿病肥胖（fa/fa）大鼠脂质蓄积及组成的影响
Lipids. 2006 Mar;41(3):241-7. doi: 10.1007/s11745-006-5093-7.
本文引用的文献
1
WKY Fatty Rat as a Model of Obesity and Non-insulin-dependent Diabetes Mellitus.WKY肥胖大鼠作为肥胖和非胰岛素依赖型糖尿病的模型。
Ilar News. 1990 Jan;32(3):13-15. doi: 10.1093/ilar.32.3.13.
2
How obesity causes diabetes in Zucker diabetic fatty rats.肥胖如何导致 Zucker 糖尿病肥胖大鼠发生糖尿病。
Trends Endocrinol Metab. 1997 Sep;8(7):276-82. doi: 10.1016/s1043-2760(97)00094-5.
3
Leptin normalizes the impaired response of proinsulin mRNA to long chain fatty acids in heterozygous Zucker diabetic fatty rats.瘦素可使杂合子Zucker糖尿病肥胖大鼠中胰岛素原mRNA对长链脂肪酸的受损反应恢复正常。
J Biol Chem. 1997 Oct 10;272(41):25648-51. doi: 10.1074/jbc.272.41.25648.
4
Leptin- or troglitazone-induced lipopenia protects islets from interleukin 1beta cytotoxicity.瘦素或曲格列酮诱导的脂肪减少可保护胰岛免受白细胞介素1β的细胞毒性作用。
J Clin Invest. 1997 Oct 1;100(7):1750-4. doi: 10.1172/JCI119700.
5
beta-cell function in normal rats made chronically hyperleptinemic by adenovirus-leptin gene therapy.通过腺病毒-瘦素基因疗法使正常大鼠长期处于高瘦素血症状态下的β细胞功能。
Diabetes. 1997 Aug;46(8):1276-80. doi: 10.2337/diab.46.8.1276.
6
Role of nitric oxide in obesity-induced beta cell disease.一氧化氮在肥胖诱导的β细胞疾病中的作用。
J Clin Invest. 1997 Jul 15;100(2):290-5. doi: 10.1172/JCI119534.
7
Induction by leptin of uncoupling protein-2 and enzymes of fatty acid oxidation.瘦素诱导解偶联蛋白-2及脂肪酸氧化酶的生成。
Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6386-90. doi: 10.1073/pnas.94.12.6386.
8
Direct antidiabetic effect of leptin through triglyceride depletion of tissues.瘦素通过组织甘油三酯消耗产生的直接抗糖尿病作用。
Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4637-41. doi: 10.1073/pnas.94.9.4637.
9
Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion.功能性瘦素受体mRNA在胰岛中的表达及瘦素对胰岛素分泌的直接抑制作用。
Diabetes. 1997 Feb;46(2):313-6. doi: 10.2337/diab.46.2.313.
10
A novel leptin receptor isoform in rat.大鼠中的一种新型瘦素受体亚型。
FEBS Lett. 1996 Aug 26;392(2):87-90. doi: 10.1016/0014-5793(96)00790-9.
Zotero 插件