Although volume overload may contribute to the development of HFpEF, recent data suggest that the metabolic, endocrine, and natriuretic peptide clearance receptor (NPR-C) signal transduction may play a crucial role in the pathobiology of the obesity-HFpEF phenotype (Matsukawa et al., 1999; Nakatsuji et al., 2010; Bordicchia et al., 2016; Oh et al., 2019). This evidence concerns the gene NPR3 and obesity due to melanocortin 4 receptor deficiency.