Effects of FK866 on skeletal muscle and liver nicotinamide phosphoribosyl transferase (Nampt) concentrations and Lysine acetylation status

Nampt regulates intracellular NAD + levels. We investigated the effects of Nampt inhibition via the selective inhibitor FK866 on tissue Nampt concentrations in mice. NAD + levels regulate sirtuin activity (histone deacetylase), so we also assessed global changes in protein acetylation in Lysine (Lys) residues. Female ICR mice (≈8 wk old) received i.p. injections of FK866 (100mg/kg body weight). Samples were collected 1 hr after injection (acute), or after 3 d of daily injections (chronic). For the chronic treatment, tissues were removed 4 h after the last injection. Liver and gastrocnemius (gas) muscle samples were removed and prepared for immunoblots to determine Nampt expression and Lys acetylation. To evaluate acute changes in energy metabolism, we also measured blood glucose (BG). Nampt concentrations were significantly elevated in chronically treated liver tissue (control, 1.00 ± 0.03, FK866, 1.45 ± 0.04 arbitrary units, p<0.0001), but remained unchanged in gas muscle. No changes in global Lys acetylation were detected. FK866 injection significantly and acutely increased BG concentrations, (total area under curve, control: 271 ± 5.9 mg/dL/120min (mean ± S.E.M.); FK866, 342 ± 27.5 mg/dL/120 min; p<0.05). BG concentrations returned to baseline levels within 2 h of injection. In conclusion, three days of FK866 increases Nampt concentrations in liver but not gastrocnemius muscle. We did not detect altered acetylation patterns as a result of FK866 treatment. Acute FK866 treatment temporarily increases BG.