Eliminating leptin signals to somatotropes reduces GH and fertility and causes obesity in adults

Abstract

Leptin restores growth hormone (GH) in leptin‐deficient animals, suggesting a role in somatotrope maintenance. To determine leptin's importance to somatotropes, we ablated the leptin receptor (LEPR) selectively using targeted Cre‐recombinase in somatotropes of mice bearing two floxed alleles of LEPR exon 17, thereby removing the JAK binding site of LEPR‐b. We detected no early or extrapituitary expression of Cre‐Recombinase and 3 generations showed >95% viability. In adult males or females, the mutation reduced serum GH by 50‐84% and reduced % of pituitary cells bearing LEPR‐b or GH. For example, pituitary cells with LEPR‐b in males declined from 37 ± 1% (controls) to 20 ± 2% (heterozygotes) and 11 ± 1% (homozygotes) and GH cells in males were reduced from 26 ± 2% (controls) to 12 ± 1% or 7 ± 1% in F2 or F3 generation homozygotes, respectively. In spite of reduced GH, mutant mice grew normally. However, a 70% reduction in corpora lutea in F2 homozygotes correlated with a significant reduction in litter size. By 3‐4.5 months of age, homozygote males showed significant weight gains (30% over controls) and a 1.8‐fold increase in percent body fat by DEXA analysis. Females showed these changes by 6 months. Direct leptin signaling to somatotropes is thus important especially in functions related to maintaining GH, fertility and body composition. Supported by DK26687 (SC), and core facilities funded by P20 RR020146 and P30 NS047546.