Exploring the Cardioprotective Role of Adropin-GPR19 Signaling in Diabetic Cardiomyopathy

Diabetic cardiomyopathy (DCM) represents a distinct and increasingly prevalent complication of diabetes mellitus, characterized by structural and functional cardiac abnormalities independent of traditional cardiovascular risk factors. Diabetic cardiomyopathy features striking changes in cardiomyocyte fuel metabolism, which promote the transition into an advanced pathological state. Alterations in fuel metabolism include an increased reliance on fatty acid oxidation for mechanical energy production, at the expense of other substrates such as glucose. The resultant loss of metabolic flexibility can lead to reduced cardiac work efficiency and contractile dysfunction. The cellular mechanisms that drive changes in fuel substrate utilization are not fully understood, and this deficiency represents a major impediment to the development of novel treatments. This thesis explores the intricate mechanisms underlying DCM, focusing on the role of adropin-GPR19 signaling. Adropin, a novel peptide hormone, has emerged as a potential regulator of metabolic and cardiovascular health, while GPR19, its putative receptor, is implicated in mediating various physiological responses. We hypothesized that adropin-GPR19 signaling mediates the regulation of cardiac substrate use to reverse energy metabolism deficits and improve functional output in the diabetic heart. This research leverages a combination/series of in vivo and ex vivo metabolic approaches, utilizing knockout mutagenesis and pre-clinical animal models of DCM, to investigate the effects of adropin-GPR19 signaling on cardiac function, structure, and metabolic pathways. Results from this thesis demonstrate the potential therapeutic relevance of adropin in DCM, revealing its capacity to modulate cardiac metabolic flexibility, structural remodeling, and contractile function. Moreover, sex-dependent differences in adropin-GPR19 signaling were observed, providing novel insights into the complex interplay between metabolic derangements and cardiac dysfunction in male and female mice. The findings of this thesis shed light on the multifaceted nature of DCM, highlighting the significance of adropin-GPR19 signaling in cardiac pathophysiology. As such, these insights have promising implications for the development of novel therapeutic strategies targeting metabolic and cardiovascular dysfunction in diabetic patients. Collectively, the data presented in this thesis advances our understanding of DCM, and contributes to the ongoing efforts to mitigate its detrimental effects by highlighting the cardioprotective role of adropin-GPR19 signaling, and thus its therapeutic potential for clinical applications.