Defective Wnt Signaling: A Potential Contributor to Cardiometabolic Disease?

Hypertension is a major public health problem associated with the increased risk for heart disease and stroke, leading causes of death worldwide. Despite recent treatment advances, hypertension remains present in approximately one-third of adults in the U.S. (1). The majority of hypertensive subjects are now obese and many suffer from insulin resistance, which exacerbates the risk for cardiovascular disease. While there is a well-established clinical association, the mechanisms linking hypertension and insulin resistance are not fully understood. A better understanding of hypertension mechanisms and related metabolic comorbidities will improve targeted treatment approaches and healthrelated outcomes in this disease. Aberrant Wnt pathway signaling may be one such mechanism linking hypertension, obesity, and type 2 diabetes. The Wnt family of secreted glycoprotein ligands is highly implicated in embryonic development and regulates numerous physiological processes including body axis patterning and cellular adhesion, migration, and differentiation. As shown in Fig. 1, in the canonical pathway (2), Wnt proteins bind the Frizzled G-protein–coupled receptor and coreceptors, such as LDL receptor–related protein (LRP) 5 and 6. Activation of these receptors signals the intracellular phosphoprotein Dishevelled to traffic the destruction complex (including glycogen synthase kinase 3b [GSK-3b]) to the plasma membrane. This allows for stabilization and translocation of b-catenin to the nucleus to coactivate T-cell factor (TCF) and lymphoid enhancing factor transcription factors. Noncanonical Wnt pathways, which are independent of b-catenin, have also been identified and play a role in the regulation of cell polarity and intracellular calcium levels. Defective Wnt signaling has been implicated in numerous conditions including cancer, aging, osteoporosis, Alzheimer disease, and cardiometabolic disease. Polymorphisms of LRP5 are associated with obesity (3), and LRP6 mutations result in coronary artery disease and features of metabolic syndrome, including hypertension in clinical studies (4,5). Carriers of LRP6 mutations also exhibit hyperinsulinemia and reduced insulin sensitivity, associated with diminished insulin signaling in skeletal muscle (6). Mutations in the transcription factor 7-like 2 gene also increase the risk for type 2 diabetes (7). In animal models, the Wnt/b-catenin signaling pathway has been shown to contribute to the modulation of insulin secretion, b-cell function, energy expenditure, and cholesterol metabolism in various tissues (8–11). While these findings suggest that the Wnt pathway is important in metabolic regulation, studies examining its importance to whole-body metabolism are limited. Furthermore, there is no information on the effects of Wnt signaling on blood pressure regulation and related mechanisms. In this issue of Diabetes, Cheng et al. (12) determine the effects of central Wnt administration on blood pressure in well-established animal models of hypertension. Interactions between Wnt and insulin signaling pathways within the nucleus tractus solitarii (NTS), an autonomic brainstem region integral to cardiovascular control, were also examined. This study included normotensive Wistar Kyoto (WKY), spontaneously hypertensive (SHR), and fructose-fed rats. Animals received chronic 14-day intracerebroventricular infusion of vehicle, Wnt3a (a highly transforming Wnt protein), the LRP antagonist Dickkopf-1 (DKK1), or the GSK-3b inhibitor TWS119. Systolic blood pressure and heart rate were measured at baseline and during treatment by the tail-cuff method. Levels of insulin, nitric oxide, and insulin and Wnt signaling pathway components were determined in NTS tissue sections. The findings from this study suggest that 1) hypertension is associated with downregulation of canonical Wnt signaling pathways within the NTS, 2) central infusion of Wnt3a lowers blood pressure and increases nitric oxide within the NTS of hypertensive rats through LRP coreceptor activation, 3) Wnt3a infusion enhances