A novel NAMPT activator ameliorates obesity by repressing ACSL1-dependent lipid synthesis.

Excessive incorporation of long-chain fatty acids (LCFAs) into triglycerides in adipose tissue is a key contributor to obesity and related metabolic disorders, and pharmacologically modulating this process remains challenging. Here, we synthesized a library of β-indoquinazolinone derivatives via palladium-catalyzed oxidative addition complex chemistry and identified compound b2b as a potent and selective anti-obesity candidate. b2b inhibited triglyceride accumulation in adipocytes in vitro and significantly reduced adiposity, body weight, and lipid metabolic disturbances in diet-induced obese mice without observable toxicity. Mechanistic studies revealed that b2b directly activates nicotinamide phosphoribosyltransferase (NAMPT) and elevates intracellular NAD+ levels to enhance the NAD+-dependent regulatory protein SIRT1 activity. This activation leads to transcriptional repression of acyl-CoA synthetase long-chain family member 1 (ACSL1), thereby inhibiting LCFAs incorporation into triglycerides. These findings demonstrate that pharmacological activation of the NAMPT-NAD+-SIRT1 axis by b2b offers a novel strategy for obesity treatment.