Novel aspects of Gdf15 biology and function - Abstract Growth differentiation factor 15 (GDF15) is a stress-induced cytokine that is a biomarker of multiple disease states, including obesity and type 2 diabetes, but whether GDF15 contributes to disease progression or plays a role in mitigating disease is still debated. GDF15 is best-known for its role in suppressing feeding following activation of the GDF15 receptor GFRAL and its co-receptor RET in specific regions of the brain. More recent evidence suggests pharmacological doses of GDF15 can maintain energy expenditure during caloric restriction via GRAL-dependent, b-adrenergic receptor signaling in skeletal muscle. In several preclinical animal models of obesity and type 2 diabetes, GDF15 treatment reduces body weight and improves glucose homeostasis and insulin resistance. Because body weight loss is associated with improved insulin sensitivity, understanding whether GDF15 has direct effects on glucose homeostasis independent of changes in body weight has been difficult to discern. Recent reports in the literature and our own preliminary data suggest GDF15 can signal independent of GFRAL to improve insulin resistance, particularly in the liver where GDF15 is produced within hepatocytes in response to dietary stress. In this application, we seek to investigate and characterize a novel pathway by which hepatocyte-produced GDF15 improves obesity-associated insulin resistance independent of GFRAL-receptor signaling and body weight loss. We will also determine the stress signaling pathways within liver hepatocytes, in vivo, responsible for the upregulation of Gdf15 expression and increased levels of circulating GDF15 during obesity. Based on our preliminary data and recent reports in the literature, we hypothesize that hepatocyte-derived GDF15 improves insulin sensitivity directly, independent of changes in body weight and GFRAL-receptor signaling, via novel signaling within the liver resulting from an interaction with matrix metalloproteinase-14 (MMP14). In Aim 1, we will determine whether endogenous GDF15 produced by hepatocytes in response to obesity is sufficient and necessary for the modulation of hepatic insulin sensitivity in a body weight- and GFRAL-independent manner. In Aim 2, we will characterize the structural basis and functional consequences of GDF15-MMP14 binding, as well as the molecular signaling and physiological effects of several novel GDF15 mutants. We believe that our proposed work will directly support the NIDDK mission by enhancing our basic understanding of a signaling molecule currently under development as a therapeutic for obesity and type 2 diabetes, and may support the development of novel variants of GDF15 with tailored biological activity.
