We have recently demonstrated that specific targeting of lipolysis in adipose tissue through genetic deletion or pharmacological inhibition of the rate-limiting enzyme in triacylglycerol hydrolysis, adipose tissue triglyceride lipase (ATGL), is sufficient to protect from and even treat obesity-related HFpEF induced by the combination of a high-fat diet and the nitric oxide synthase inhibitor, L-NAME (ie, two-hit HFpEF model) [12]. Here, PNPLA2 is linked to obesity due to melanocortin 4 receptor deficiency.