C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight.
Central nervous system administration of C75 produces hypophagia and weight loss in rodents identifying C75 as a potential drug against obesity and type 2 diabetes. However, the mechanism underlying this effect is unknown. Here we show that C75-CoA is generated chemically, in vitro and in vivo from C75 and that it is a potent inhibitor of carnitine palmitoyltranferase 1 (CPT1), the rate-limiting step of fatty-acid oxidation. Three-D docking and kinetic analysis support the inhibitory effect of C75-CoA on CPT1. Central nervous system administration of C75 in rats led to C75-CoA production, inhibition of CPT1 and lower body weight and food intake. Our results suggest that inhibition of CPT1, and thus increased availability of fatty acids in the hypothalamus, contribute to the pharmacological mechanism of C75 to decrease food intake.
Mera
Paula
P
Department of Biochemistry and Molecular Biology and IBUB (Institute of Biomedicine University of Barcelona), Spain.
Bentebibel
Assia
A
López-Viñas
Eduardo
E
Cordente
Antonio G
AG
Gurunathan
Chandrashekaran
C
Sebastián
David
D
Vázquez
Irene
I
Herrero
Laura
L
Ariza
Xavier
X
Gómez-Puertas
Paulino
P
Asins
Guillermina
G
Serra
Dolors
D
García
Jordi
J
Hegardt
Fausto G
FG
D015107:4-Butyrolactone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D000214:Acyl Coenzyme A / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology*; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D017433:Protein Structure, Secondary / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015431:Weight Loss / Q000187:drug effects / Q000502:physiology
C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D000214:Acyl Coenzyme A; C510483:C75-coenzyme A; D002334:Carnitine O-Palmitoyltransferase; D015107:4-Butyrolactone