Isoproterenol decreases leptin release from rat and human adipose tissue through posttranscriptional mechanisms

Abstract

. Isoproterenol decreases leptin release from rat and human adipose tissue through posttranscriptional mechanisms. Am J Physiol Endocrinol Metab 288: E798 -E804, 2005. First published December 7, 2004 doi:10.1152 doi:10. /ajpendo.00446.2004 and in vitro studies indicate that ␤-adrenergic receptor agonists decrease leptin release from fat cells in as little as 30 min. Our objective was to determine whether alterations in leptin biosynthesis or secretion were involved in the short-term adrenergic regulation of leptin in human and rat adipose tissue. Isoproterenol (Iso) decreased leptin release from incubated adipose tissue of both nonobese and obese subjects to similar extent (Ϫ28 vs. Ϫ21% after 3 h). Inhibition of protein synthesis with cycloheximide did not block the effect of Iso on leptin release from human adipose tissue, suggesting that the Iso effect is independent of leptin synthesis. Iso also tended to increase tissue leptin content at the end of the 3-h incubation, as expected from the observed inhibition of release. Consistent with a posttranslational mechanism, Iso treatment did not affect leptin mRNA levels or relative rate of leptin biosynthesis as directly assessed by [35 S]methionine incorporation into immunoprecipitable leptin. In contrast to these results in human adipose tissues, Iso did not decrease basal leptin release from rat adipose tissue. However, Iso did decrease insulin-stimulated leptin release by inhibiting the ability of insulin to increase leptin biosynthesis without detectably affecting leptin mRNA levels. Thus, in both human and rat, adrenergic regulation of posttranscriptional events (secretion in humans, translation in rats) may contribute to the rapid decline in circulating leptin that occurs when the sympathetic nervous system is activated, such as during fasting and cold exposure. Furthermore, the rat does not provide an ideal model to study mechanisms of cellular leptin regulation in humans.adipocytes; ␤-adrenergic receptor ALTHOUGH SERUM LEPTIN LEVELS in humans are strongly correlated with percent body fat, circulating leptin levels also undergo short-term changes independently of alterations in adiposity (7,15,28). Consistent with prior studies using rodent models (29), recent studies in humans suggest that activation of the sympathetic nervous system or stimulation of ␤-adrenergic receptors (␤-AR) decreases plasma leptin over a relatively short time frame (hours) (8,9,22,23). Cold exposure (23) or infusion of adrenergic agonists (8, 9, 21) decreases plasma leptin and subcutaneous adipose tissue interstitial leptin concentration in humans after ϳ3 h (20). With fasting, decreases in leptin levels are thought be due to an activation of ␤-AR in combination with the decrease in insulin levels (11).We (22) have previously shown that isoproterenol (Iso) decreases leptin release from human adipose tissue fragments in vitro within the same time frame and by the same magnitude as has been reported in vivo, i.e., in 30 -60 min. Thus the in vivo decreases in leptin may be due, at lea...

Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion

“…In studies of rat adipocytes or adipose tissue, stimulation of ␤-AR did not affect basal leptin secretion but antagonized the insulin stimulation of leptin secretion after as little as 30 min of treatment (24,65). In human adipose tissue, however, ␤-AR stimulation decreased basal leptin release without affecting leptin biosynthesis (65).…”

“…In human adipose tissue, however, ␤-AR stimulation decreased basal leptin release without affecting leptin biosynthesis (65). Thus there may be significant species differences in the adrenergic regulation of leptin.…”

“…Our studies in rat adipose tissue used biosynthetic labeling to directly demonstrate the translational control of leptin by feeding, starvation, insulin, and adrenergic agonists (40,65). Short-term starvation (14 h) decreases relative rates of leptin biosynthesis despite little or no effect on mRNA levels.…”

“…In vitro, insulin increases rates of leptin biosynthesis by approximately two-to threefold in adipose tissue of younger rats (6 -7 wk old) without affecting leptin mRNA levels and has a smaller effect (up to 1.5-fold) in older/more obese rats (12-14 wk old). The magnitude of the insulin effect on leptin mRNA translation is also greater in starved compared with fed rats (40,65), most likely attributable to the lower baseline. Consistent with the importance of the translational control in the nutritional regulation of leptin expression, more leptin mRNA is associated with polysome fractions in adipose tissue from fed compared with starved rats.…”

“…␤-AR agonists decrease leptin synthesis and secretion within hours without affecting leptin mRNA levels (17,65). Addition of isoproterenol, a ␤-AR agonist, to incubations of rat adipose tissue acutely blocks the insulin stimulation of relative rates of leptin biosynthesis without affecting leptin mRNA levels (65).…”