Obesity: A Somatotrope Perspective

Abstract

With the obesity epidemic increasing steadily in the United States, learning how energy homeostasis is regulated is imperative (1, 2). Leptin has been a molecule of great interest for this reason. The road to leptin discovery began in 1950 at Jackson Laboratories when a spontaneous mutation arose resulting in hyperphagia and severe obesity (3). The mutation was named the obese mutation, and Ob/Ob mice were the focus of decades of research. The gene encoding leptin was finally cloned in 1994 (4). Its receptor was cloned the year after (5). Leptin acts as an indicator of energy stores and regulates appetite through regulation of orexogenic (NPY and AgRP) and anorexogenic ( MSH) signals in the hypothalamus (6). Although mutations in leptin and its receptor are associated with severe obesity in mice, rats, and humans (3–5, 7, 8), these mutations account for a very small fraction of human obesity cases (9–13). Even so, learning more about leptin and its role in energy homeostasis promises to provide researchers and health professionals with important information about obesity. Sensing energy stores is important for growth and metabolism, which need to be closely linked to nutrition. Somatotrope cells in the anterior pituitary gland secrete GH, which regulates growth and body mass through stimulation of long bone growth, muscle anabolism, and lipolysis (14, 15). Thus, GH decreases fat and increases muscle mass. Several nutrition-sensing hormones regulate somatotrope function, including ghrelin, insulin, and leptin (16–19). Although many studies aimed at understanding obesity have focused on the role of ghrelin, a potent secretagogue for GH, very few have ventured downstream to the somatotrope cells (20–23). Ghrelin is released by distinct endocrine cells of the stomach in response to fasting and is important for energy homeostasis (16). Leptin, which is produced by adipose tissue and by the pituitary, acts as a satiety factor in the hypothalamus and can stimulate GH production (14, 17). Over 80% of somatotrope cells express the receptor for leptin, Leprb (24). Ob/Ob and Db/Db mice, which lack leptin signaling, have reduced somatotrope numbers and reduced serum GH levels (15, 17). Whether the effect of leptin on somatotrope function is direct or indirect due to increased adipose tissue, metabolic disease, or hypogonadism has been difficult to ascertain. The paper by Syed et al in this issue of Endocrinology addresses the role of the leptin receptor in somatotrope function. The authors employed a Gh-Cre mouse (25) to delete the long form of the leptin receptor (Leprb) specifically in somatotrope cells (30). Somatotrope-specific Leprb deletion mutants exhibit a reduction in serum GH levels leading to reduced fat burning and changes in adipokines resulting in obesity by 5–6 months of age (26–28). Syed et al find that the number of somatotrope cells in leptin receptor deletion mutants is normal based on in situ hybridization for Gh mRNA but that most these somatotrope cells do not contain enough GH to be detected by immunohistochemistry, suggesting that somatotrope cells are not functioning normally. The authors demonstrate that the failure in somatotrope function is due to reduced sensitivity to GHRH. However, treatment with both GHRH and ghrelin restored GHRH sensitivity, increased the number of GH-immunoreactive cells to normal proportions, and increased serum GH to normal levels (30). These studies suggest that leptin receptor is necessary for maintaining somatotrope sensitivity to GHRH and that ghrelin is key for this process. This is valuable mechanistic information about how leptin signaling regulates somatotrope function to affect energy homeostasis. Syed et al answer several key questions about the interplay between metabolism and somatotrope function and uncover many more questions that need to be ad-