This “leptin-aldosterone-neprilysin axis activation”, when observed in part as natriuretic peptide deficiency syndrome, as observed in obesity-related HFpEF pathophysiology, may exacerbate the interaction of leptin and aldosterone to promote sodium retention, plasma volume expansion, and regional (such as myocardial) and systemic inflammation and fibrosis (Figure 3) [23,33,43,51]. This evidence concerns the gene MME and obesity due to melanocortin 4 receptor deficiency.