Regulation of leptin expression in human adipose tissue

Leptin is a small peptide hormone produced by adipose tissue. Serum leptin levels correlate with adiposity and are thought to signal central systems to decrease food intake and increase energy expenditure. We hypothesized that insulin and glucocorticoid, important hormones in the fed and obese states, mediate upregulation of leptin expression. We investigated the in vitro regulation of leptin expression in adipose tissue from subcutaneous and omental (visceral) fat depots of severely obese women and men. Leptin mRNA and secretion were 2–3 fold higher in subcutaneous vs. omental adipose tissue. Culture with dexamethasone (a synthetic glucocorticoid) transiently increased leptin mRNA ∼2 fold in both depots after 1d culture. Insulin did not increase leptin mRNA in either depot, but increased leptin secretion 1.5–3 fold in subcutaneous tissue throughout 7d of culture. The combination of insulin and dexamethasone increased leptin mRNA and secretion ∼2–3 fold in both depots at day 1 and maintained leptin expression throughout 7d of culture. We conclude that insulin and glucocorticoid have depot-specific effects and function synergistically as long-term regulators of leptin expression in adipose tissue from obese subjects. Because leptin mRNA and leptin secretion did not always change in parallel in response to hormonal treatments, we asked whether leptin is stored within adipose tissue prior to secretion, and whether these stores are regulated hormonally. We developed an assay for tissue leptin content and determined that detergent increased detectable tissue leptin by ∼2-fold, suggesting that leptin is stored in a membrane-bound location. Subcutaneous tissue leptin was ∼1.6-fold higher than omental, paralleling the differences in leptin secretion and expression. Inhibition of protein synthesis decreased tissue leptin content, but did not decrease leptin secretion until after 3h of incubation. Culture of adipose tissue for 2d with the combination of insulin and dexamethasone, but neither hormone alone, increased tissue leptin content ∼2-fold in both depots. Although insulin did not affect tissue leptin content, it potentiated leptin secretion (as a % of tissue stores). This data suggests that adipose tissue leptin storage and secretion per se are regulated. Taken together, these studies provide insight into how leptin levels are upregulated in the obese.