Acute intravenous leptin infusion increases glucose turnover but not skeletal muscle glucose uptake in ob/ob mice

The mouse ob, gene encodes leptin, an adipocyte hormone that regulates body weight and energy expenditure. Leptin has potent metabolic effects on fat and glucose metabolism. A mutation of the ob gene results in mice with seve re hereditary obesity and diabetes that can be corrected by treatment with the hormone. In lean mice, leptin acutely increases glucose metabolism in a n insulin-independent manner, which could account, at least in part, for so me of the antidiabetic effect of the hormone. To investigate further the ac ute effect of leptin on glucose metabolism in insulin-resistant obese diabe tic mice, leptin (40 ng . g(-1) . h(-1)) was administered intravenously for 6 h in C57B1/6J ob/ob mice. Leptin increased glucose turnover and stimulat ed glucose uptake in brown adipose tissue (BAT), brain, and heart with no i ncrease in heart rate. A slight increase in all splanchnic tissues was also noticed. Conversely, no increase in skeletal muscle or white adipose tissu e (WAT) glucose uptake was observed. Plasma insulin concentration increased moderately but neither glucose, glucagon, thyroid hormones, growth hormone , nor IGF-1 levels were different from phosphate-buffered saline-infused C5 7B1/6J ob/ob mice. In addition, leptin stimulated hepatic glucose productio n, which was associated with increased glucose-6-phosphatase activity. Conv ersely, PEPCK activity was rather diminished. Interestingly, hepatic insuli n receptor substrate (IRS)I-associated phosphatidylinositol 3-kinase activi ty was slightly elevated, but neither the content of glucose transporter GL UT2 nor the phosphorylation state of the insulin receptor and IRS-1 were ch anged by acute leptin treatment. Hepatic lipid metabolism was not stimulate d during the acute leptin infusion, since the content of triglycerides, gly cerol, and citrate was unchanged. These findings suggest that in ob/ob mice , the antidiabetic antiobesity effect of leptin could be the result of a pr ofound alteration of glucose metabolism in Liver, BAT, heart, and consequen tly, glucose turnover Insulin resistance of skeletal muscle and WAT, while not affected by acute leptin treatment, could also be corrected in the long term and account for some of leptin's antidiabetic effects.