Hexosamines and nutrient excess induce leptin production and leptin receptor activation in pancreatic islets and clonal beta-cells.

Activation of the hexosamine biosynthesis pathway leads to insulin resistance in muscle and adipose tissue. In these tissues leptin gene expression is increased by glucosamine. In the present study we found that glucosamine rapidly activates the production of leptin and OB-Rb, which encodes the functional leptin receptor, in both primary pancreatic islets and clonal beta-cells. Secretion of leptin from clonal beta-cells into the medium was detected readily. In addition, the level of the transcripts encoding signal transducer and activator of transcription-3 and -5, both implicated in leptin signal transduction in islet beta-cells, was increased by glucosamine, although to a lesser degree than mRNA levels of leptin and OB-Rb. High glucose (16.7 mM) induced leptin biosynthesis in primary pancreatic islet cells, and the addition of 1 mM palmitate caused an additional incremental effect. The hexosamine-mediated induction of the leptin system in clonal beta-cells was associated with increased responsiveness to leptin, as demonstrated by a 2.6 +/- 0.3-fold (P < 0.01) increase in tyrosine phosphorylation of signal transducer and activator of transcription-3. These findings are the first evidence of inducible leptin production in pancreatic islets and suggest that islet cells, like skeletal muscle, demonstrate a linkage between increased nutrient availability and both leptin expression and leptin responsiveness.

Quercetin and resveratrol potently reduce estrogen sulfotransferase activity in normal human mammary epithelial cells.

Estrogen sulfotransferase (EST) is the sole sulfotransferase expressed in normal human breast epithelial cells and has an important function in determining free estrogen hormone levels in these cells. In the present study we examined the inhibitory effect of the dietary polyphenols quercetin and resveratrol on EST activity, i.e. 17beta-estradiol (E2) sulfation. Both the compounds potently inhibited recombinant human EST in a competitive fashion with K(i) values of about 1 microM. In fact, both polyphenols could serve as substrates for EST. In order to extend the studies to more physiologically relevant conditions, we examined whether inhibition of EST also occurred in the intact cultured human mammary epithelial (HME) cells. The mean baseline EST activity (E2 sulfate formation) in the HME cells was 4.4 pmol/h per mg protein. The IC(50) for resveratrol was very similar to that for recombinant EST, i.e. about 1 microM. Surprisingly, quercetin was 10 times more potent in the HME cells with an IC(50) of about 0.1 microM, a concentration that should be possible to achieve from the normal dietary content of this flavonoid.