Several single hit models used to study HFpEF are: (1) hypertension model induced by Angiotensin-II (Ang-II) infusion or genetic sensitivity to salt (39–46), (2) aging model, induced by natural aging or genetically accelerated (senescence accelerated mouse, SAM) (47–51), (3) obesity or diabetes, induced by high fat or western type diet, leptin receptor (db/db) or leptin (ob/ob) deficiency (52–61). The gene discussed is AGT; the disease is obesity due to melanocortin 4 receptor deficiency.