Pharmacological stimulation of brain carnitine palmitoyl-transferase-1 decreases food intake and body weight

Am J Physiol Regul Integr Comp Physiol. 2008 Feb;294(2):R352-61. doi: 10.1152/ajpregu.00862.2006. Epub 2007 Dec 5.


Inhibition of brain carnitine palmitoyl-transferase-1 (CPT-1) is reported to decrease food intake and body weight in rats. Yet, the fatty acid synthase (FAS) inhibitor and CPT-1 stimulator C75 produces hypophagia and weight loss when given to rodents intracerebroventricularly (icv). Thus roles and relative contributions of altered brain CPT-1 activity and fatty acid oxidation in these phenomena remain unclarified. We administered compounds that target FAS or CPT-1 to mice by single icv bolus and examined acute and prolonged effects on feeding and body weight. C75 decreased food intake rapidly and potently at all doses (1-56 nmol) and dose dependently inhibited intake on day 1. Dose-dependent weight loss on day 1 persisted through 4 days of postinjection monitoring. The FAS inhibitor cerulenin produced dose-dependent (560 nmol) hypophagia for 1 day, weight loss for 2 days, and weight regain to vehicle control by day 3. The CPT-1 inhibitor etomoxir (32, 320 nmol) did not alter overall day 1 feeding. However, etomoxir attenuated the hypophagia produced by C75, indicating that CPT-1 stimulation is important for C75's effect. A novel compound, C89b, was characterized in vitro as a selective stimulator of CPT-1 that does not affect fatty acid synthesis. C89b (100, 320 nmol) decreased feeding in mice for 3 days and produced persistent weight loss for 6 days without producing conditioned taste aversion. Similarly, intraperitoneal administration decreased feeding and body weight without producing conditioned taste aversion. These results suggest a role for brain CPT-1 in the regulation of energy balance and implicate CPT-1 stimulation as a pharmacological approach to weight loss.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 4-Butyrolactone / analogs & derivatives
  • 4-Butyrolactone / pharmacology
  • Animals
  • Body Weight / drug effects
  • Body Weight / physiology*
  • Carnitine O-Palmitoyltransferase / metabolism*
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Eating / drug effects
  • Eating / physiology*
  • Energy Metabolism / drug effects
  • Energy Metabolism / physiology
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • Epoxy Compounds / pharmacology
  • Fatty Acid Synthesis Inhibitors / metabolism
  • Fatty Acids / metabolism
  • Female
  • Hypothalamus / cytology
  • Hypothalamus / drug effects
  • Hypothalamus / enzymology*
  • Injections, Intraventricular
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / enzymology
  • Pregnancy
  • Rats


  • 4-methylene-2-octyl-5-oxofuran-3-carboxylic acid
  • Enzyme Inhibitors
  • Epoxy Compounds
  • Fatty Acid Synthesis Inhibitors
  • Fatty Acids
  • Carnitine O-Palmitoyltransferase
  • etomoxir
  • 4-Butyrolactone