SUN-041 - Balancing GH Excess and Antagonism: A Translational Mouse Model of Treated Acromegaly

Acromegaly is a rare endocrine disorder, often caused by a pituitary adenoma, and characterized by chronically elevated levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Understanding the physiological consequences of acromegaly therapies are essential for more informed and effective patient care. First-line treatment is surgery to remove the tumor, but when surgery is not possible or ineffective, pharmacological treatments are utilized - such as the GH antagonist (GHA) pegvisomant – to normalize IGF-1 levels as a proxy of GH action. Bovine growth hormone (bGH) transgenic mice are used to model acromegaly, and GHA transgenic mice are used to model GH antagonism in healthy mice. The combination of the two mouse lines, referred to as bGH x GHA or “Combo” mice, provides a translational model of acromegaly treated with a GH antagonist and allows investigation of the physiological effects of antagonizing GH action in the setting of GH excess. Thus, the purpose of this study is to characterize select physical, endocrine, and metabolic parameters in these novel Combo mice. A cohort of male and female of all four genotypes (WT, bGH, GHA, and bGH x GHA Combo) was studied and subsequently sacrificed at 8 months of age. Before dissection, body composition, oGTT, and ITT were assessed. At dissection, organs were collected, weighed and processed for histology or flash frozen, and serum was collected for ELISAs and Luminex assays. Despite expression of both transgenes, the opposing hormonal actions of GH and GHA appeared to counterbalance in Combo mice. That is, Combo mice had body length and composition similar to WT mice, while bGH were larger and leaner and GHA were smaller with greater adiposity, as expected. IGF-1 levels in Combo mice were also similar to WT levels. Gross morphology of organs in the Combo mice most closely resembled the WT phenotype, with a few notable exceptions. The differences included select adipose depots being smaller in the Combo mice, which varied based on sex, and the spleen and liver of the Combo mice were significantly larger that WT. Additional data to be presented include oGTT, ITT, liver triglyceride content, circulating GH and adipokine levels, and histological assessments of fibrosis and adipocyte cell size, providing further insight into tissue-specific metabolic outcomes. Further investigation into the molecular mechanisms of the phenotype observed are underway. Overall, these findings suggest that we have successfully generated a translational mouse model of acromegaly controlled with GH antagonism.
Acknowledgments: This work is supported in part by the NIH grant AG059779, and the State of Ohio’s Eminent Scholar Program includes a gift from Milton and Lawrence Goll.

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