A functional melanocortin system may be required for chronic CNS-mediated antidiabetic and cardiovascular actions of leptin.
OBJECTIVE
We recently showed that leptin has powerful central nervous system (CNS)-mediated antidiabetic and cardiovascular actions. This study tested whether the CNS melanocortin system mediates these actions of leptin in diabetic rats.


METHODS
A cannula was placed in the lateral ventricle of Sprague-Dawley rats for intracerebroventricular infusions, and arterial and venous catheters were implanted to measure mean arterial pressure (MAP) and heart rate 24 h/day and for intravenous infusions. After recovery from surgery for 8 days, rats were injected with streptozotocin (STZ), and 5 days later, either saline or the melanocortin 3 and 4 receptor (MC3/4R) antagonist SHU-9119 (1 nmol/h) was infused intracerebroventricularly for 17 days. Seven days after starting the antagonist, leptin (0.62 microg/h) was added to the intracerebroventricular infusion for 10 days. Another group of diabetic rats was infused with the MC3/4R agonist MTII (10 ng/h i.c.v.) for 12 days, followed by 7 days at 50 ng/h.


RESULTS
Induction of diabetes caused hyperphagia, hyperglycemia, and decreases in heart rate (-76 bpm) and MAP (-7 mmHg). Leptin restored appetite, blood glucose, heart rate, and MAP back to pre-diabetic values in vehicle-treated rats, whereas it had no effect in SHU-9119-treated rats. MTII infusions transiently reduced blood glucose and raised heart rate and MAP, which returned to diabetic values 5-7 days after starting the infusion.


CONCLUSIONS
Although a functional melanocortin system is necessary for the CNS-mediated antidiabetic and cardiovascular actions of leptin, chronic MC3/4R activation is apparently not sufficient to mimic these actions of leptin that may involve interactions of multiple pathways.
da Silva
Alexandre A
AA
Department of Physiology and Biophysics and Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi, USA. asilva@physiology.umsmed.edu
do Carmo
Jussara M
JM
Freeman
J Nathan
JN
Tallam
Lakshmi S
LS
Hall
John E
JE
D000818:Animals; D001066:Appetite / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000503:physiopathology*; D005247:Feeding Behavior / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D020738:Leptin / Q000627:therapeutic use*; D053486:Melanocortins / Q000502:physiology*; D009074:Melanocyte-Stimulating Hormones / Q000627:therapeutic use*; D051381:Rats; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D018043:Receptors, Corticotropin / Q000037:antagonists & inhibitors*
D007004:Hypoglycemic Agents; D020738:Leptin; D053486:Melanocortins; D018043:Receptors, Corticotropin; C103272:SHU 9119; D009074:Melanocyte-Stimulating Hormones