INS and Glucose intolerance: As expected, intake of HFD induced hyperglycemia and glucose intolerance (Supplementary Figure 3A and 3E) in both SIRT1+/- and SIRT1-/- mice as demonstrated by the significantly increased area under the curve of IPGTT compared with that in WT mice (Supplementary Figure 3C); however, there were no differences in IPITT among the HFD groups (Supplementary Figure 3B and 3D), indicating that a higher dose of insulin of 1 IU/kg [30] or 1.2 IU/kg body weight [33] might be needed.