Elahu S. Gosney

Endocrine Parameters and Phenotypes of the Growth Hormone Receptor Gene Disrupted (GHR−/−) Mouse

Disruption of the GH receptor (GHR) gene eliminates GH-induced intracellular signaling and, thus, its biological actions. Therefore, the GHR gene disrupted mouse (GHR-/-) has been and is a valuable tool for helping to define various parameters of GH physiology. Since its creation in 1995, this mouse strain has been used by our laboratory and others for numerous studies ranging from growth to aging. Some of the most notable discoveries are their extreme insulin sensitivity in the presence of obesity. Also, the animals have an extended lifespan, which has generated a large number of investigations into the roles of GH and IGF-I in the aging process. This review summarizes the many results derived from the GHR-/- mice. We have attempted to present the findings in the context of current knowledge regarding GH action and, where applicable, to discuss how these mice compare to GH insensitivity syndrome in humans.

The Role of GH in Adipose Tissue: Lessons from Adipose-Specific GH Receptor Gene-Disrupted Mice

GH receptor (GHR) gene-disrupted mice (GHR-/-) have provided countless discoveries as to the numerous actions of GH. Many of these discoveries highlight the importance of GH in adipose tissue. For example GHR-/- mice are insulin sensitive yet obese with preferential enlargement of the sc adipose depot. GHR-/- mice also have elevated levels of leptin, resistin, and adiponectin, compared with controls leading some to suggest that GH may negatively regulate certain adipokines. To help clarify the role that GH exerts specifically on adipose tissue in vivo, we selectively disrupted GHR in adipose tissue to produce Fat GHR Knockout (FaGHRKO) mice. Surprisingly, FaGHRKOs shared only a few characteristics with global GHR-/- mice. Like the GHR-/- mice, FaGHRKO mice are obese with increased total body fat and increased adipocyte size. However, FaGHRKO mice have increases in all adipose depots with no improvements in measures of glucose homeostasis. Furthermore, resistin and adiponectin levels in FaGHRKO mice are similar to controls (or slightly decreased) unlike the increased levels found in GHR-/- mice, suggesting that GH does not regulate these adipokines directly in adipose tissue in vivo. Other features of FaGHRKO mice include decreased levels of adipsin, a near-normal GH/IGF-1 axis, and minimal changes to a large assortment of circulating factors that were measured such as IGF-binding proteins. In conclusion, specific removal of GHR in adipose tissue is sufficient to increase adipose tissue and decrease circulating adipsin. However, removal of GHR in adipose tissue alone is not sufficient to increase levels of resistin or adiponectin and does not alter glucose metabolism.

Evaluation of growth hormone (GH) action in mice: discovery of GH receptor antagonists and clinical indications.

The discovery of a growth hormone receptor antagonist (GHA) was initially established via expression of mutated GH genes in transgenic mice. Following this discovery, development of the compound resulted in a drug termed pegvisomant, which has been approved for use in patients with acromegaly. Pegvisomant treatment in a dose dependent manner results in normalization of IGF-1 levels in most patients. Thus, it is a very efficacious and safe drug. Since the GH/IGF-1 axis has been implicated in the progression of several types of cancers, many have suggested the use of pegvisomant as an anti-cancer therapeutic. In this manuscript, we will review the use of mouse strains that possess elevated or depressed levels of GH action for unraveling many of GH actions. Additionally, we will describe experiments in which the GHA was discovered, review results of pegvisomants preclinical and clinical trials, and provide data suggesting pegvisomants therapeutic value in selected types of cancer.

The use of proteomics to study infectious diseases.

Technology surrounding genomics, or the study of an organisms genome and its gene use, has advanced rapidly resulting in an abundance of readily available genomic data. Although genomics is extremely valuable, proteins are ultimately responsible for controlling most aspects of cellular function. The field of proteomics, or the study of the full array of proteins produced by an organism, has become the premier arena for the identification and characterization of proteins. Yet the task of characterizing a proteomic profile is more complex, in part because many unique proteins can be produced by the same gene product and because proteins have more diverse chemical structures making sequencing and identification more difficult. Proteomic profiles of a particular organism, tissue or cell are influenced by a variety of environmental stimuli, including those brought on by infectious disease. The intent of this review is to highlight applications of proteomics used in the study of pathogenesis, etiology and pathology of infectious disorders. While many infectious agents have been the target of proteomic studies, this review will focus on those infectious diseases which rank among the highest in worldwide mortalities, such as HIV/AIDS, tuberculosis, malaria, measles, and hepatitis.

GH in the Central Nervous System: Lessons from the Growth Hormone Receptor Knockout Mouse

Various central nervous system (CNS) tissues express both growth hormone (GH) and its receptor (GHR), including those involved in memory and cognition. Studies show the presence of GHR in the pituitary, choroid plexus, hypothalamus, hippocampus, pituitary and the spinal cord during development and, to a lesser extent, in adults. This expression implies a role of GH signaling in growth, development and functionality of the CNS. While data on the function of GH in the CNS is sparse, several studies have been conducted using the GHR knockout (-/-) mouse in order to better understand this role. Abnormal growth hormone signaling in humans is the cause of various diseases that include Laron syndrome, GH deficiency and acromegaly. This article will review the research conducted using the GHR-/- mouse on the role of GH signaling in the CNS. Where possible, we will attempt to contextualize the animal data with respect to human disease.

Growth Hormone Antagonists: A Pharmacological Tool in Present and Future Therapies

Publisher Summary This chapter discusses the experimental methodologies that resulted in the discovery of growth hormone antagonists (GHAs). It also examines the in vitro and in vivo data that led to the approval of clinical use of GHA (pegvisomant). The structure-function analysis of growth hormone (GH) resulted in the discovery of a growth hormone antagonist. The antagonistic activity of the GH analogs provides the basis for development of the GHA as a new type of drug. The GHA competes with native GH and inhibits its proper or functional binding to and activation of GH receptors. Subsequent development of a Pegvisomant resulted in a novel drug for the treatment of acromegalic individuals. The ability of Pegvisomant to normalize elevated circulating IGF-I levels in patients with acromegaly serves as a new therapeutic approach toward this disorder. Furthermore, the chapter illustrates the potential role of GHAs in the treatment of certain types of cancer, as an insulin sensitizer, and in treatment of diabetes end organ damage.

GHR Knockout and the CNS

The GHR −/− mouse has proven to be a useful and unique model to study the role of GH on growth, development, and function of the CNS. GHR−/− mice show a relative increase in the size of the brain and pituitary with concomitant changes in the morphology of these tissues. The disruption of GH signaling alters the feedback mechanisms that control GH expression. This results in changes in expression of several hypothalamic proteins that influence GH expression and also results in structural changes in the pituitary. Several measures of motorneuron development were unaltered in the GHR−/− mouse, indicating this is a GH-independent process. An examination of the brain of GHR−/− animals shows increased neuron cell density and hypoplasia of glial cells compared to controls. The single investigation of cognition in these animals has shown protection from age-related decline in memory in the GHR−/− mice. There is a great opportunity to use these mice to facilitate further research into the role GH plays in neural development and function.