Correction of diet-induced hyperglycemia, hyperinsulinemia, and skeletal muscle insulin resistance by moderate hyperleptinemia

American Journal of Physiology - Endocrinology and Metabolism - Tập 278 Số 3 - Trang E563-E569 - 2000
Roland Buettner1,2, Christopher B. Newgard3,1,2, Christopher J. Rhodes1,2,4, Robert M. O’Doherty1,2
1Gifford Laboratories for Diabetes Research, and Departments of
2Internal Medicine
3Biochemistry and
4Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75235

Tóm tắt

Human obesity and high fat feeding in rats are associated with the development of insulin resistance and perturbed carbohydrate and lipid metabolism. It has been proposed that these metabolic abnormalities may be reversible by interventions that increase plasma leptin. Up to now, studies in nongenetic animal models of obesity and in human obesity have concentrated on multiple injection therapy with mixed results. Our study sought to determine whether a sustained, moderate increase in plasma leptin, achieved by administration of a recombinant adenovirus containing the leptin cDNA (AdCMV-leptin) would be effective in reversing the metabolic abnormalities of the obese phenotype. Wistar rats fed a high-fat diet (HF) were heavier ( P< 0.05), had increased fat mass and intramuscular triglycerides (mTG), and had elevated plasma glucose, insulin, triglyceride, and free fatty acids compared with standard chow-fed (SC) control animals (all P < 0.01). HF rats also had impaired glucose tolerance and were markedly insulin resistant, as demonstrated by a 40% reduction in insulin-stimulated muscle glucose uptake ( P < 0.001). Increasing plasma leptin levels to 29.0 ± 1.5 ng/ml (from 7.0 ± 1.4 ng/ml, P < 0.001) for a period of 6 days decreased adipose mass by 40% and normalized plasma glucose and insulin levels. In addition, insulin-stimulated skeletal muscle glucose uptake was normalized in hyperleptinemic rats, an effect that correlated closely with a 60% ( P < 0.001) decrease in mTG. Importantly, HF rats that received a control adenovirus containing the β-galactosidase cDNA and were calorically matched to AdCMV-leptin-treated animals remained hyperglycemic, hyperinsulinemic, insulin resistant, and maintained elevated mTG. We conclude that a gene-therapeutic intervention that elevates plasma leptin moderately for a sustained period reverses diet-induced hyperglycemia, hyperinsulinemia, and skeletal muscle insulin resistance, and that these improvements are tightly linked to leptin-induced reductions in mTG.

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Tài liệu tham khảo

10.1172/JCI119865

10.1126/science.7624778

10.1073/pnas.93.25.14795

10.1038/nm1295-1311

10.1038/27376

10.1073/pnas.94.16.8878

10.1152/jappl.1988.64.4.1428

10.1073/pnas.90.7.2812

10.1172/JCI116337

10.1152/ajpendo.1997.273.4.E708

10.1073/pnas.91.23.10878

10.2337/diab.46.3.348

10.1002/jcb.240550005

10.1038/sj.gt.3300565

10.1073/pnas.94.25.13921

10.2337/diab.46.11.1768

10.1152/ajpendo.1999.277.3.E544

Pan D. A., 1997, J. Clin. Invest., 46, 983

10.1126/science.7624776

10.1016/S0026-0495(96)90260-7

10.2337/diab.45.4.531

10.1016/0952-3278(95)90016-0

10.1210/endo.138.8.5327

10.2337/diab.42.3.457

10.1074/jbc.273.47.31615

10.1042/bj3130215

10.1172/JCI119171

10.1055/s-2007-979872

Wititsuwannakul D., 1977, J. Biol. Chem., 252, 7812, 10.1016/S0021-9258(17)41039-8

10.2337/diab.46.2.215