A NUTRIENT-SENSING PATHWAY REGULATES LEPTIN GENE-EXPRESSION IN MUSCLEAND FAT

Leptin, the protein encoded by the obese (ob) gene, is synthesized and released in response to increased energy storage in adipose tissue(1- 4). However, it is still not known how incoming energy is sensed and t ransduced into increased expression of the ob gene. The hexosamine bio synthetic pathway is a cellular 'sensor' of energy availability(5-8) a nd mediates the effects of glucose on the expression of several gene p roducts(9-12). Here we provide evidence for rapid activation of ob gen e expression in skeletal muscle by glucosamine. Increased tissue conce ntrations of the end product of the hexosamine biosynthetic pathway, U DP-N-acetylglucosamine (UDP-GlcNAc), result in rapid and marked increa ses in leptin messenger RNA and protein levels (although these levels were much lower than those in fat). Plasma leptin levels and leptin mR NA and protein levels in adipose tissue also increase. Most important, stimulation of leptin synthesis is reproduced by either hyperglycaemi a or hyperlipidaemia, which also increase tissue levels of UDP-N-acety lglucosamine in conscious rodents(7). Finally, incubation of 3T3-L1 pr e-adipocytes and L6 myocytes with glucosamine rapidly induces ob gene expression. Our findings are the first evidence of inducible leptin ex pression in skeletal muscle and unveil an important biochemical Link b etween increased availability of nutrients and leptin expression.