Since these subjects have a middle or subclinical PA, with no clear evidence of inflammation, renal/vascular damage (Figure 3), or concomitant cardiometabolic disease, we hypothesize the LCN2 fails to increase in these PA subjects since they require a concomitant hit as inflammation (78, 79), obesity (high adipose tissue) (74), or high salt intake (72) to increase the circulating LCN2 levels. The gene discussed is LCN2; the disease is obesity due to melanocortin 4 receptor deficiency.