A cholecystokinin-1 receptor agonist (CCK-8) mediates increased permeability of brain barriers to leptin.
OBJECTIVE
Leptin regulates energy expenditure and body weight by acting both on the hypothalamus and on peripheral targets. Central actions of leptin are enhanced by cholecystokinin (CCK). The interaction between leptin and CCK makes physiological sense, as rats lacking CCK1 receptors are resistant to peripheral leptin but not to leptin directly infused into the brain. We have recently reported that CCK enhances leptin effects by increasing the entry of leptin into the CNS. The aim of this work was to further characterize the effect of CCK (10 microg kg(-1)) on leptin kinetics as well as the CCK receptor subtype involved in the interaction between CCK and leptin.


METHODS
Experiments were carried out both in free-feeding and in fasted rats receiving a single dose of leptin (100 microg kg(-1); i.p.). Parameters analysed over the next 6 h were plasma and cerebrospinal fluid concentrations of leptin.


RESULTS
We observed that CCK-8 depressed the increase in plasma leptin that followed the i.p. injection and simultaneously increased leptin concentration in the cerebrospinal fluid from 92+/-25 to 230+/-24 pg mL(-1) (P<0.05). The effect of CCK-8 was totally prevented by the CCK1 receptor antagonist, SR-27,897 (0.3 mg kg(-1), s.c.), but not by the CCK2 receptor antagonist, L-365,260 (1 mg kg(-1)).


CONCLUSIONS
These results show that CCK plays a role in regulating the access of leptin to the brain and suggest that CCK analogues, acting on CCK1 receptors, might be useful drugs in improving leptin actions within the brain.
Cano
V
V
Departamento de Farmacología, Tecnología y Desarrollo Farmacéutico, Universidad CEU-San Pablo, Madrid, Spain.
Merino
B
B
Ezquerra
L
L
Somoza
B
B
Ruiz-Gayo
M
M
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D004435:Eating; D007210:Indoleacetic Acids / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000097:blood; D007700:Kinetics; D020738:Leptin / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D008297:Male; D010671:Phenylurea Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000819:agonists / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012844:Sincalide / Q000008:administration & dosage / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology
D001570:Benzodiazepinones; D001786:Blood Glucose; D007210:Indoleacetic Acids; D007328:Insulin; D020738:Leptin; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; D011994:Recombinant Proteins; D013844:Thiazoles; C080460:SR 27897; C058121:L 365260; D012844:Sincalide