C75, a known inhibitor of
fatty acid synthase is postulated to cause significant
weight loss through decreased hypothalamic
neuropeptide Y (NPY) production. Peripherally, C75, an
alpha-methylene-gamma-butyrolactone, reduces adipose tissue and
fatty liver, despite high levels of
malonyl-CoA. To investigate this paradox, we studied the effect of C75 on
fatty acid oxidation and energy production in diet-induced obese (DIO) mice and cellular models. Whole-animal calorimetry showed that C75-treated DIO mice had a 50% greater
weight loss, and a 32.9% increased production of energy because of
fatty acid oxidation, compared with paired-fed controls.
Etomoxir, an inhibitor of
carnitine O-palmitoyltransferase-1 (CPT-1), reversed the increased energy expenditure in DIO mice by inhibiting
fatty acid oxidation. C75 treatment of rodent adipocytes and hepatocytes and human
breast cancer cells increased
fatty acid oxidation and
ATP levels by increasing CPT-1 activity, even in the presence of elevated concentrations of
malonyl-CoA. Studies in human
cancer cells showed that C75 competed with
malonyl-CoA, as measured by CPT-1 activity assays. Thus, C75 acts both centrally to reduce food intake and peripherally to increase
fatty acid oxidation, leading to rapid and profound
weight loss, loss of adipose mass, and resolution of
fatty liver. The pharmacological stimulation of CPT-1 activity is a novel finding. The dual action of the C75 class of compounds as
fatty acid synthase inhibitors and CPT-1 agonists has therapeutic implications in the treatment of
obesity and type II diabetes.