The primary aim of this thesis was to investigate ways to safely leverage the adrenergic signalling pathway to utilize thermogenic fat and skeletal muscle for treating metabolic disease. To this end, our research first provided key evidence that adrenergically stimulated glucose uptake in brown adipocytes operates independently of the canonical insulin/AKT pathway, highlighting that this pathway provides a mechanism to bypass the core signalling defects present in insulin resistant states (Paper I). We subsequently identified Myo1c as a novel, specific regulator of this process in a BAT specific manner, providing a new molecular target within this pathway (Paper II).

To enable the direct identification of novel modulators of thermogenesis, we established isothermal microcalorimetry as a high-throughput platform capable of quantifying both UCP1 dependent and independent heat production in murine and human adipocytes (Paper III). Additionally, we complimented this work through a detailed pharmacological characterization of the β₃ AR agonist Mirabegron, clarifying that its beneficial effects in our rodent models were indeed β₃ AR and UCP1 dependent (Paper IV). Concurrently, to address the critical issue of translatability, we developed a physiologically humanized mouse model, which demonstrated that rodent classical BAT recapitulates the molecular and morphological signatures of human thermogenic tissue (Paper V).

This mechanistic work provided the framework for the design of next generation therapeutics that could activate adrenergic signalling in a functionally selective manner to avoid cardiovascular side effects and desensitization associated with conventional agonism. We first developed ATR-127, a dual β_2/3 AR agonist that served as an essential proof of concept to show that the separation of metabolic efficacy from cardiovascular effects was indeed possible (Paper VI). This led to the further development of the refined, clinically validated candidate, ATR-258, a GRK2 biased β₂ agonist that demonstrated broad preclinical efficacy, inducing healthy weight loss characterized by a significant reduction of fat mass with the preservation of lean mass. This potent muscle sparing effect was also observed in models of late-stage diabetes and sarcopenia. Furthermore, ATR-258 showed significant utility in combination regimens, providing complementary benefits such as preventing the lean mass loss associated with incretin analogues and producing additive glycemic effects with SGLT2 inhibitors. This robust preclinical profile was ultimately confirmed for its safety and tolerability in a first-in-human clinical trial (Paper VII)