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

Human obesity and high fat feeding in rats are associated with the developm ent of insulin resistance and perturbed carbohydrate and lipid metabolism. It has been proposed that these metabolic abnormalities may be reversible b y interventions that increase plasma leptin. Up to now, studies in nongenet ic animal models of obesity and in human obesity have concentrated on multi ple injection therapy with mixed results. Our study sought to determine whe ther a sustained, moderate increase in plasma leptin, achieved by administr ation of a recombinant adenovirus containing the leptin cDNA (AdCMV-leptin) would be effective in reversing the metabolic abnormalities of the obese p henotype. 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 tall P < 0.01). KF rats also had imp aired glucose tolerance and were markedly insulin resistant, as demonstrate d 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-stimulat ed skeletal muscle glucose uptake was normalized in hyperleptinemic rats, a n effect that correlated closely with a 60% (P < 0.001) decrease in mTG. Im portantly, HF rats that received a control adenovirus containing the beta-g alactosidase cDNA and were calorically matched to AdCMV-leptin-treated anim als remained hyperglycemic, hyperinsulinemic, insulin resistant, and mainta ined elevated mTG. We conclude that a gene-therapeutic intervention that el evates plasma leptin moderately for a sustained period reverses diet-induce d hyperglycemia, hyperinsulinemia, and skeletal muscle insulin resistance, and that these improvements are tightly linked to leptin-induced reductions in mTG.