MON-482 Sex-Dependent Biphasic Response by Somatotropes to Fasting and Loss of Leptin Signaling

Fasting results in a well-established rise in serum growth hormone (GH) in mice and humans. In mice, this coincides with increases in Gh and growth hormone releasing hormone receptor (Ghrhr) mRNA, as well as serum ghrelin. However, fasting also results in a dramatic decline in serum leptin and we have shown that pituitary somatotropes are dependent on circulating leptin to maintain sufficient stores of GH and GHRHR proteins. This study was designed to determine the mechanisms by which GH increases in the presence of reduced serum leptin in fasted mice. We hypothesized that the rise in GH was due to ghrelin-stimulated pathways and therefore developed a fasting model to test this. However, a review of the literature revealed a study by Steyn et al. (2011) that demonstrated an acute decline in GH pulses in male mice after 12-18 hours of fasting, which suggest that somatotropes may display a biphasic response to fasting, with the early or acute phase driven by the absence of leptin signals. We tested this hypothesis in 3 groups of male and female mice: group 1 was fasted for 24 hours; group 2 was also fasted for 24 hours and received 10% glucose water, which is known to normalize serum leptin; and group 3 mice were fed ad libitum. Following a 24 h fast, leptin levels declined significantly from 5.5±2 ng/ml to 0.37±0.1 ng/ml (Student’s t; p=0.01) along with significant decreases in body weight, serum glucose and insulin. Fasted mice receiving glucose water showed a significant recovery in leptin to 6.9±2.7 ng/ml (Student’s t; p=0.03 n=8) along with a recovery in serum glucose and insulin. In agreement with Steyn et al. (2011), serum GH in male mice showed a significant decline from 10.7±3 ng/ml (fed) to 3±0.6 ng/ml after the 24 h fast (p=0.04 ANOVA). Glucose water and the recovery in serum glucose, leptin and insulin were unable to normalize GH levels in fasted male. In contrast, fasted female mice had a 2.2 fold (p= 0.0427) increase in serum GH and no change with glucose water. There was a significant increase in pituitary Ghrhr and Gh mRNA in fasted male mice but not in fasted female mice. Assays of serum or mRNA levels of most pituitary hormones showed no significant changes following a 24 h fast. These studies have thus uncovered an acute response to fasting by GH cells in male mice, which correlates to reduced serum GH resulting from a loss of leptin signals. The data extends findings reported previously showing that male somatotropes are more dependent on leptin signals than female somatotropes. Whereas the high Gh and Ghrhr mRNA support somatotrope stimulation, the somatotropes are unable to secrete normal levels of GH in the male, suggesting defects at the level of GH or GHRHR protein expression.