Title of project

Long-Acting Growth Hormone in Metabolic Regulation: mechanistic characterization and therapeutic opportunities to improve weight loss quality

Abstract

Growth hormone (GH) plays a critical endocrine role in regulating whole-body energy homeostasis. Yet, for over 30 years, nearly all preclinical studies have used recombinant human GH that is shorter acting due to half-life. In this PhD project, I will characterize the impact of the first long-acting GH, which was recently developed by Novo Nordisk for once-weekly administration in humans. I will dissect the tissue-specific contributions of this long-acting GH using inducible, tissue-specific GH receptor knockout mice combined with cutting-edge physiological and molecular metabolic phenotyping. This advent of long-acting GH also opens the possibility of therapeutic application to metabolic diseases. In particular, the abilities of GH to preserve muscle and selectively reduce fat mass are especially appealing considering the lean mass loss that is observed with current GLP-1-based obesity therapies. However, GH by itself is also associated with adverse effects, including decreased insulin sensitivity and increased IGF-1 levels, which diminish feasibility as a cardiometabolic monotherapy. Thus, we hypothesize that combining GH and GLP-1 could potentially enhance the efficacy, quality, and tolerability of weight loss and mitigate the negative features linked to each individual pathway. Our preliminary data show that GH signalling can reverse GLP-1-induced lean mass loss, accelerate fat reduction, and yield additional benefits to liver health, all without elevating systemic IGF-1 or causing insulin resistance. We will also strive to design GH-GLP-1 unimolecular polyagonists as a means of treating metabolic diseases more effectively. By integrating advanced genetic, molecular, and pharmacological approaches, this project aims to deepen our fundamental understanding of GH endocrine action and pioneer strategies that improve the quality and safety of weight loss for patients living with obesity.