In mice and humans, fasting results in a rise of serum growth hormone (GH). In mice, this coincides with increased Gh and growth hormone releasing hormone receptor (Ghrhr) mRNA. Fasting also results in increased serum ghrelin and decreased serum leptin. We have shown that pituitary somatotropes are dependent on circulating leptin to maintain sufficient stores of GH and GHRHR proteins. We hypothesized that the GH rise seen in fasted mice with reduced serum leptin was due to ghrelin‐stimulated pathways. However, a review of the literature revealed a study by Steyn et al. (2011) which demonstrated an acute decline in GH pulses in male mice after 12–18 h of fasting. This study suggests that somatotropes may have time‐dependent responses, with shorter fasting responses driven by the absence of leptin signals.Our fasting study was composed of three groups of male mice: 1) mice fasted for 6, 12, 24, or 48 hours, 2) mice fasted for 24 and 48 hours with 10% glucose in the drinking water, and 3) mice fed ad libitum. Body weight and serum glucose were significantly reduced with all fasting times. After 6 h of fasting, serum leptin levels were reduced from 9625.63 pg/ml (fed controls) to 1798.15 pg/mL with a further reduction to 774.17 pg/ml after 12 h, which was maintained following 24 and 48 h fasting. Ghrelin levels were unchanged with 6, 12 and 24 h fasting but significantly increased by 55.4% with 48 h fasting. Serum GH was unchanged with 6 and 12 h fasting, but was significantly reduced from 7765 pg/ml (fed) to 2253 pg/ml after the 24 h fast (p=0.03 ANOVA). In the 48 h fasted mice, serum GH was significantly increased over fed mice, from 1828 pg/ml (fed) to 10569 pg/ml (p=0.01 ANOVA). There were significant increases in pituitary Ghrhr mRNA after 24 and 48 h fasting and Gh mRNA was increased after 6 and 48 h of fasting. However, GH and GHRHR content were unchanged.This study has uncovered time‐dependent differential responses to fasting by somatotropes in male mice. The reduced serum GH after 24 h correlated well with the reduction in serum leptin. Similarly, the prolonged fasting (48 h) and elevated serum GH correlated well with the rise in ghrelin. The high Gh and Ghrhr mRNA levels corresponds with rising ghrelin levels. Reduced serum GH at 24 h indicates that somatotropes remain dependent on leptin signals for GH secretion. However, with normal GH or GHRHR content, this points to a defect in a signaling pathway needed for secretion that has yet to be determined.Support or Funding InformationNIH grants 5 R01 HD087057‐03 (GVC and AM), 5 R01 HD 093461‐01 (AM and GVC), and 5 R01 DK113776‐02 (GVC and AM). NIGMS grants P20 GM103425 and P30GM11070 (PI Dr. Edgar Garcia‐Rill). NSF funded Southern Regional Education Board Dissertation Award (TKM).