Central leptin administration increases insulin sensitivity, independent of food intake, and sympathetic activity in diabetic rats

Leptin, an adipocyte-derived hormone, has been associated with both obesity and diabetes. Previous studies have suggested that leptin may play an important role in overall energy metabolism, especially with regard to glucose metabolism. To further address this issue, we examined the effects of central leptin on insulin sensitivity in diabetic rats. Animals were implanted with an intracebroventricular (ICV) cannula directed to the lateral ventricle. Streptozotocin (50 mg/kg I.V.) was administered to induce diabetes. Chronic daily injections of ICV leptin (10 μg/day) or vehicle were given beginning 2 days after the establishment of hyperglycemia in diabetic animals. To determine the effect of leptin independent of changes in food intake, pair-feeding was performed by assigning each pair-fed rat to a partner in the leptin treatment group. The amount of food provided to each pair-fed animal on each treatment day was equal to the measured amount consumed by its leptin-treated partner during the previous 24-hour period. At the completion of the study, rats were fasted for six hours, and insulin sensitivity was evaluated by the steady-state plasma glucose (SSPG) method. A jugular cannula was used to continuously infuse insulin (2.5 mU/kg/min), glucose (8 mg/kg/min), and somatostatin (0.5 μg/min) for 170 min. SSPG was determined during the last 20 minutes of infusion. By the third day of central leptin injection, blood glucose concentrations dramatically decreased in diabetic animals and were normalized by the fourth day. This level was maintained throughout the remainder of the study. While diabetic rats were insulin resistant, insulin sensitivity was dramatically increased in leptin-treated animals. Body weight of leptin-treated rats was not decreased. Food restriction did not normalize blood glucose concentrations in diabetic rats. Therefore, the effect of leptin was independent of food intake and body weight. Plasma catecholamine concentrations were significantly increased, suggesting sympathetic activation after central leptin administration. Circulating leptin levels were not increased in animals injected with central leptin. Thus, it appears that central leptin leads to an increase in the sensitivity to circulating insulin, which helps to normalize blood glucose concentrations in diabetic animals. Conversely, these data are consistent with the idea that low central leptin status, whether caused by low circulating leptin levels or leptin resistance, may lead to insulin resistance.