SIRT1 and obesity due to melanocortin 4 receptor deficiency: However, in some metabolic disorders, Parp2-knockout mice showed enhanced SIRT1 activity and improved metabolic functions, and were protected against high-fat diet-induced obesity, which were not due to augmented NAD+ levels, but to an increase in SIRT1 expression, as PARP2 acts as a direct negative regulator of the SIRT1 promoter [59].