Hexosamines stimulate leptin production in transgenic mice

Hexosamine flux has been shown to mediate aspects of nutrient sensing in in sulin sensitive tissues and has been hypothesized to represent a satiety si gnal that results in shunting of fuel toward storage as fat. It has been re cently reported that in vitro treatment of fat and muscle cells with hexosa mines and acute glucosamine infusion in intact fats stimulate leptin secret ion. In order to investigate the effects of chronic, physiologic increases in hexosamine flux on leptin we have examined leptin mRNA and serum leptin in mice overexpressing the rate-limiting enzyme for hexosamine synthesis, G FA, in muscle and fat. Increased levels of UDP-N-acetylglucosamine, the pri ncipal end-product of the hexosamine pathway were seen in transgenic fat, c onsistent with the overexpression of GFA. After overnight fasting, the tran sgenic mice were hyperleptinemic compared to littermate controls (4.5 +/- 0 .5 ng/ml in transgenic, 2.8 +/- 0.2 in control, p = 0.005) despite equal bo dy weights. In the random-fed state, the leptin levels of control mice incr eased to 4.1 +/- 0.5 ng/ml (p = 0.01) whereas the leptin levels in the tran sgenics did not increase any further (3.7 +/- 0.4 ng/ml). Leptin mRNA level s were also increased in transgenic fat (2.7 +/- 0.6 in transgenic compared to 0.8 +/- 0.2 in control, arbitrary units normalized to actin, p < 0.007) . Despite increased leptin, the transgenic animals did not have lower body fat content. We conclude that hexosamine flux in fat regulates leptin synth esis and secretion.