Pharmacological stimulation of brain carnitine palmitoyl-transferase-1 decreases food intake and body weight.
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.
Aja
Susan
S
Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA. saja1@jhmi.edu
Landree
Leslie E
LE
Kleman
Amy M
AM
Medghalchi
Susan M
SM
Vadlamudi
Aravinda
A
McFadden
Jill M
JM
Aplasca
Andrea
A
Hyun
Jayson
J
Plummer
Erica
E
Daniels
Khadija
K
Kemm
Matthew
M
Townsend
Craig A
CA
Thupari
Jagan N
JN
Kuhajda
Francis P
FP
Moran
Timothy H
TH
Ronnett
Gabriele V
GV
D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology*; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D054872:Fatty Acid Synthesis Inhibitors / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D011247:Pregnancy; D051381:Rats
C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D054872:Fatty Acid Synthesis Inhibitors; D005227:Fatty Acids; D002334:Carnitine O-Palmitoyltransferase; C054207:etomoxir; D015107:4-Butyrolactone